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Kappers CUA. Huber GC. and Elizabeth C. Crosby EC. The comparative anatomy of the nervous system of vertebrates including man Volume I. (1936) The Macmillan Company, New York.

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This historic 1936 textbook describes comparative neurology by Huber and others. Volume 2 Kappers CUA. Huber GC. and Elizabeth C. Crosby EC. The comparative anatomy of the nervous system of vertebrates including man Volume II. (1936) The Macmillan Company, New York.

See also two earlier volumes by Cornelius Ubbo Ariëns Kappers (1877-1946) in Dutch Vergleichende Anatomie des Nervensystems Volume I and Volume II

Chapter I The Evolution And Morphology Of Nervous Elements

In the Protozoa no types of nervous organization are known, other than the fibrillar structures occurring in an excitomotor apparatus such as that present during the flagellate phase of the life history of the soil amoeba (Naegleria gruberi), described by Wilsori (’16), or those found in certain infusorians in connection with the ciliary apparatus. Examples of such fibrillar structures are the elaborate neuromotor mechanisms of Diplodinium ecaudatum {Sharp, ’14), Euplotes {Yocum, ’18 ; Taylor, ’20), and Trichonympha {Kofoid and Swezy, ’19; Hinshaw, ’26). Thus far such protoplasmic fibrillar differentiations do not appear to have been observed in sponges.^ However, Parker (’19) showed that in these latter animals, long muscle cells interconnected by protoplasmic bridges allow stimulations to spread over fairly great distances, and that different stimuli entering at the same time from different sources act as correlated or associated stimulations.

The first clearly demonstrable, structurally independent nerve cells are found in coelenterates, although the present knowledge of the nervous mechanisms in these forms is still incomplete. Over a decade ago Child (’21) substantiated a statement and its interpretation, made by Kleinenberg (’72), who described in the fresh water hydra certain cells which he regarded as neuromotor cells. These are cells in the epithelial layer and are often provided with hairs on the free surface which serve as aids in receiving impulses. The impulses, in turn, are elaborated by the muscular feet. Whether such cells may be regarded as nerve cells is still open to question. All epithelio-muscular cells receive and elaborate impulses. It is certain that neurons have not been observed to differentiate from such cells.

In addition to the cells described in the preceding paragraph, undoubted nerve cells make their appearance in coelenterates. These are of two types : (1) the neurosensory cells (sensory cells of Herrick, ’24a), and (2) more deeply situated, ganghon cells which form a subepithelial nerve plexus. The neurosensory cells may terminate directly on a muscle cell (as in the sea anemone) or the impulse may pass from the neurosensory to a primitive ganglion cell and be conveyed through the subepithelial net to the effector apparatus (as in the jellyfish). The Hertwigs (79 and ’80), Wolff (’04), 0. Hertwig (’18), Parker (’19), Droogleever Fortuyn (’20), Bozler (’27), Hanstrom (’29), and others have pointed out that almost always in these primitive nervous systems the entering impulses are received and sent on by neurosensory cells. These cells have a receptive as well as a conductive function. They are polarized cells always conducting from the surface to the effector apparatus or to the plexus in which they end. They precede the primitive ganglion cells in the sequence of activity of the nervous system and are probably more primitive than these latter cells. Furthermore, neurosensory cells are very numerous in

Coiiairaii certain of the lower vertebrates and, presumably, are to be regarded not only as phylogenetically older, but also, in part at least, as a possible source of the ganglion cells.

Sponges, then, represent that stage in evolution in which a primitive type of muscle tissue

has made its appearance unaccompanied with nervous elements” {Parker, ’19). However, C. J. Herrick (’24) appears to have regarded the structures in the sponge, termed muscles by Parker, as neuromotor mechanisms, although he considered that the receptors and the effectors are not so highly developed in these forms as in certain of the Protozoa.

Further evidence of the greater age, phylogenetically speaking, of the neurosensory cells is to be found in the more primitive and less differentiated character of these cells as compared with the primitive ganglion cells. Thus the cell bodies of the neurosensory cells do not have characteristic dendritic offshoots and do not contain tigroid substance. Their neuraxes, like those of certain ganglion cells, are unmedullated. These cells are much more numerous in the invertebrates than in the vertebrates. The visual cells of Amphioxus, the neurosensory cells of the parietal and lateral eyes, and the infundibular cells found in fishes are examples of neurosensory cells in the lower vertebrates. The peripheral olfactory neurons represent the most typical examples of such cells in the mammals.

The cell bodies of neurosensory cells usually lie in the surface epithelium and frequently their free borders carry one or more hairs. These sense hairs may be pointed or they may have knobs at the end, as in the infundibular organ of the fishes (fig. 2B). According to van der Siricht (’09), the centrosome lies at the peripheral protrusion of the olfactory cells. In cases where the main portion of the cell body lies below the covering epithelium, a prolongation of that cell body may reach the surface, as in che olfactory cells in figure 1 and figure 2C. In certain places, such as in the saccus vasculosus or the infundibular organ of fishes, the neurosensory cells lie in the surface epithelium of an internal organ. In the saccus vasculosus, the sense hairs extend into the ventricle, in which is the cerebrospinal fluid (fig. 2B). Sometimes neither the neurosensory cells nor their offshoots reach a surface, but are embedded in other tissue. Examples of such a condition are to be found in the visual cells of the compound eyes of insects and of worms. The spinal light-perceiving cells of Amphioxus are neurosensory cells found within the central nervous system (refer to fig. 61). Cells thus embedded are not provided with sense hairs but sometimes present a striated border.

Fig. 1. Neurosensory cells in the olfactory epithelium of a mammal and their connections with other neurons. V. Gehuchten.

Neurosensory cells have distinct fibrils in their protoplasm (figs. 2B and 62). These fibrils, which continue into the efferent process or neuraxis, sometimes show a special arrangement, as is the case in the light-perceiving cells of Amphioxus.

The efferent offshoot or the neuraxis often divides dichotomously (particularly in the lower vertebrates) and nearly always has synaptic relations with some other nerve cell (a neuron or, in lower animals, a subepithelial plexus of ganglion cells). As was stated previously, the neuraxes of neurosensory cells do not possess a myelin sheath as do the neuraxes of many neurons.

Their rate of conduction is slow.

Thus it is only 6-20 cm. per second in the fila olfactoria of the pike{Nicolai, ’01), whereas it may be as high as 120 m. per second in the nervus ischiadicus of mammals.

This indicates that the rate in the latter is at least 600 times that in the former.

The primitive character of the neurosensory cells is evident in those relatively rare cases in which such a cell carries on all the functions of a nervous path, including the reception and conduction of the stimuli and the direct innervation of the muscle fibers. Examples of this occur occasionally in coelenterates, such as the sea anemone and certain polyps, and in the tentacles of mollusks (Samassa, ’93).

Typical neurosensory cells of the invertebrates have long neuraxes and distinct neurofibrils. The rods and cones of the vertebrate retina, although in reality neurosensory cells, have very short neuraxes (see fig. 30) and the neurofibrils are inevident in their cell bodies. Schneider (’02) and Bernard and Cantab (’03) considered that these cells possess fibrillae, while Kolmer (’04) questioned their presence.^ However, in the neuraxes of these cells neurofibrils are evident {Ariens Kappers). In the neurosensory cells of the retina, the diplosomes lie in that part of the cell body which receives the stimulus (figs. 3A and 3B). In adults such diplosomes are found at the border of the inner and outer limb and are connected by a strong “outer thread” which is turned toward the top {Kolmer, ’04; Held, ’05 ; Retzius, ’05) and, less constantly, by a much finer “inner thread.” In the region of the rods and cones such special structures as the ellipsoid bodies and the visual purple may develop. For the relation of these to color vision, reference should be made to the special treatises on this subject. Rods and cones show a phototropic reaction toward light {Engelmann, ’85; van Genderen Start, ’87). Rods show a positive and cones a negative phototropism, but the reaction of the latter is slight, especially in higher animals {Garten, ’07).

According to Amhronn and Held (’90), the fila olfactoria of the pike have a lecithin-like substance within the fibers, as the neurites of young neurons may have before the formation of the

myelin sheaths. This probably offers a resistance to conduction.

Fig. 2. Different forms of neurosensory cells : A, of a coelenterate (Metridium dianthus, Havet ) ; B, of the saccus vasculosus of a fish (Trulta iridea, Dammerman) ;

C, of the olfactory epithelium of a rabbit (i». Gehuchten) ;

D, of a moliusk (Limax, Veratti).

These facts show clearly that nervous elements are able to show tropic reactions of two sorts ; those of a stimulo-petal as well as those of a stimulo-fugal type.

The differences between neurosensory cells and sense cells or neuroepithelial cells must be borne in mind. The latter are of more recent development — occurring first in arthropods — and are more nearly related to the sheath cells (lemnoblasts) than to the nerve cells. They have no neuraxes and do not present neurofibrils, although fibrils of sensory nerves may terminate on them or, according to certain observers {Heringa, ’17b, and others), may terminate both on and in them. Typical examples of sense cells are the hair cells situated between the Deiters’ cells in the organ of Corti, the hair cells found in the ampullary portions of the semicircular canals, and the sense cells present in the lateral line organs and in the taste buds (fig. 139). The sense cells often originate from ordinary epithelial cells. If they retain their position in an epithelial layer, they may be provided with hairs (for example, the sense cells in the taste buds and the auditory cells of the organ of Corti). However, they do not invariably reach the surface of the epithehum, but may be covered over by other epithelial cells as in the case of Merkel’s tactile disks (fig. 26A). Sometimes they are embedded in connective tissue, in which case they do not possess sense hairs. It is probable that, in certain cases, sense cells lower the threshold of perception. Their functional activities are in accord with the lack of formation of true neurofibrils within the cells. They may improve perception but are not conductors, having no neuraxes. Those fibrillae which are found on or, according to some writers, in them are to be regarded as the telodendria of peripheral neurons (London, ’05 ; Kohner, ’05 ; Boeke, ’08 and elsewhere). In the auditory cells (Held, ’04) and the taste cells of Botezat (’08), the centrosome lies at that side of the cell which is turned toward the stimulus. Sometimes it is connected with the sense hair in a manner similar to the relations of the diplosomes of the hairs of the neurosensory cells.

The fibrillar ellipsoidal portion of the rods is not to be considered as a neurofibrillar

formation.

Fig. 3. Neurosensory cells (rods and cones) of the retina.

A. In a salmon embryo after Furst. The position of the diplosomes is noted in the future peripheral part of the cells.

B. Adult rods (left) and cones (right) from the eye of a bony fish (Blennius), according to Kolmer. The position of the diplosomes and their connections with the outer (A./.) and inner threads (/./.) are to be noted.

The primitive ganglion

cells (see page 1) are found

as far down in the animal

scale as coelenterates. In

these animals they occur

in the subepithelial plexus.

In the medusae, a more

concentrated portion of S^aicytial arrangement of primitive

^ intestine of Pontobdella. Apathy,

this nerve net or plexus

forms a nerve ring around the margin of the umbrella. The primitive ganglion cells show a higher degree of differentiation than do the neurosensory cells, for not only are they provided with neurofibrils, but they also contain tigroid or Nissl substance (McClure, ’96; Wolff, ’04; Smallwood and Rogers, ’09). Such tigroid substance has never been found in the neurosensory cells. However, in comparison with the neurons of the higher invertebrates and the vertebrates, these ganglion cells are still very primitive. Their processes show no differentiation into neuraxes and dendrites. The same process may conduct in either direction, that is, cellulofugally or cellulopetally. Thus the nervous impulse in the umbrella of a medusa may run both clockwise and counterclockwise over the same nerve ring. The plexus thus formed by these primitive ganglion cells is spoken of as an asynaptic or nonsynaptic network. Recently Bozler (’27) has expressed doubt with regard to the syncytial character of the primitive ganghon cells in coelenterates, although most observers are inclined to regard this network as syncytial in character, the result of incomplete cell division, believing that the connecting bands of protoplasm are relatively broad.

Primitive ganglion cells do not have processes surrounded by myelin sheaths. Conduction is still very slow in such a plexus. Parker ('18) found that the impulse in Metridium traveled at a rate of 12-14 cm. per second at 21° C. Harvey (’22) found the rate to be 46 cm. per second in jellyfish. The average of these figures (that is, 24 cm. per second) indicates that the rapidity of conduction is little more in these primitive ganglion cells of coelenterates than in the

neurosensory cells (see the previous account). It is even less in the cells of Metridium than in the previously described neurosensory elements.

The types of cells mentioned above — (1) the neurosensory cells and (2) the primitive ganglion cells — are the only constituents of the primitive nervous system of the coelenterates. In the progress of higher evolution, nerve cells of these types become less numerous and are replaced by the synaptic polarized nerve cells or neurons typical of higher forms. In man, neurosensory cells occur only in the olfactory organ and in the retina. In all probability, primitive ganglion cells are represented in the amacrine cells of the retina

Fia. 5. Abdominal nerve cord of earthworm. Reizius, Above, two unipolar neurons ; medially placed, a primitive multipolar neuron.

{Ramon y Cajal, '93 and elsewhere). Somewhat similar cells are said to be found in the tectum of lower fishes {Tretjakoff, ’09) and in the bulbar formation of certain urodeles {Herrick, ’24).

The term neuron {Waldeyer, ’91) implies a polarized nerve cell with its cell body, its processes, and their terminations. Primitive neurons, which in the course of evolution are added to the neurosensory cells and to the primitive ganglion cells, have made their appearance in the flatworms. They are characterized by the presence of two types of processes, dendrites and neuraxes or axons. The dendrites are those processes which carry impulses toward the cell body (cellulopetally) ; the neuraxis or axon is that process which carries impulses away from the cell body (cellulofugally). In their simplest form these neurons resemble the neurosensory cells, differing only through the presence of one or two cytoplasmic prolongations which extend to the surface covering of the body. Such peripheral processes are dendrites. This specialization in the direction of conduction is not dependent upon a monoconductive character of the process itself, since it has been shown experimentally that either the neuraxis or the dendrite may carry stimuli in either direction. The action current demonstrates that when a fiber is stimulated in its course, the nervous current passes in both directions along the fiber from the point of stimulation. Not the process itself, then, but its topographic relations with other neurons and its position with regard to receptor or effector determine the direction in which impulses will pass along it. Since such relations are relatively constant, it is possible to predict with reasonable certainty that the direction of conduction over particular fibers will remain the same."* Similar polarization is found in the neurosensory cells, since the location of such a cell permits it to receive stimulation only at its cell body or sense hair, while its neuraxis must always carry impulses cellulofugally. Polarization, then, does not occur first in the neurons, although it finds there a morphologic expression in the differentiated structure of the receptive dendrites and the effective neuraxes. The cytological differentiation is primarily the result of the polarized transmission and not its cause. Once established, however, the specialized cytological structiue undoubtedly contributes to the smoothness of polarized transmission.

A dendrite is to be regarded solely as a prolongation of the cell body, which was the original receptor and is still the only one in a neurosensory cell. In every respect, dendrites retain the characteristics of the protoplasm of saji the cell body. They share in its trophic functions, as is nerve of an embryo of indicated by the presence of tigroid substances and cobaya. v. Gehuch oxydases within them (see below). The neuraxis differs transition stage from from the dendrite in structure, in having no tigroid sub- bipolar ganglion cell (a) to stance and no oxydases; probably it has more readily “o“opo>®ganglioncell(c). ionizable potassium salts. Consequently, the principles of structure remain very much the same in the neuron as in the neurosensory cell, the receptive portion being generally cell protoplasm and only the cellulofugal offshoot showing specialization. It is interesting in this connection, that the developing neuron or neuroblast shows resemblance to a neurosensory cell in that it has only a neuraxis at first. The dendrites arise later.

The differentiation of dendrites and neuraxes is not the only indication of the polarized character of the nemons. Although inherently both types of processes appear to be capable of conducting in either way, the impulse may be transmitted from one neuron to another only in one direction. The region where the stimulation passes from one neuron to the next is spoken of as a synapse, and synaptic conduction is strictly polarized. It is evident from the above facts that this is not due to a monoconductive character of the nerve processes involved, and the precise causes underlying this polarization at the S 3 mapse are still matters of considerable dispute. A further discussion of the synapse is to be found on page 23.

Only with the axon reflexes in the autonomic cells is conduction cellulopetal in the neuraxis.

Genetically, the sensory or afferent neuron is very closely allied to the neurosensory cells. Two indications of this have already been given and are as follows : (1) the neurosensory cells, because of their special position, have a polarization suggestive of the polarized condition which corresponds to that found in developing neurons, the neuroblasts ; (2) the fully differentiated neurosensory cells have only sensory functions. Further evidence in favor of the relation between neurosensory cells and sensory neurons is furnished by the fact that in certain invertebrates sensory roots consist partly of the processes of neurosensory cells and partly of those of true neurons. Thus it is sometimes difficult to state exactly where the division lies between those neurosensory cells with one or two peripheral offshoots and the typical sensory neurons. This relation between the two is so intimate that neurosensory cells are frequently designated merely as sensory neurons.

Fig. 7. A. Position of the centrosome in the dendritic process of an embryonic bipolar ganglion cell, van der Slricht.

B Position of the centrosome in a monopolar spinal ganglion cell of an adult rat. Hatai.

Motor neurons, also, are probably related genetically to neurosensory cells, for these latter cells, as the previous account has shown (see references to Samassa, ’93 ; Parker, ’19 ; Droogleever Fortuyn, ’20), are not only receptive but may also be directly connected with body musculature. When, in the more highly differentiated animals, a division of labor takes place, the neurosensory cell becomes the receptor or sensory side of the arc and an efferent mechanism (represented at first by the primitive ganglion cells) appears. This efferent mechanism is primarily without permanent polarization, but with temporary polarization impressed upon it at the instant of the passage of an impulse from the polarized neurosensory or primitive sensory cell.

Neurons of higher forms differ from neurosensory cells in having tigroid substance and dendrites, which, unlike the short and usually single receptive processes occasionally seen on neurosensory cells (Veratti, ’00a), are usually numerous and of considerable length. These dendrites permit the reception of stimulations by the neuron from different directions and from different sources, so that the impulse discharging over the neuraxis may be the resultant of a number of different stimulations.® A further difference between typical sensory neurons and neurosensory cells is to be foimd in the presence, at least frequently, of a myehn sheath around the neuraxis and, in certain cases, around the dendrites (particularly in the peripheral sensory nerves). A myelin sheath has been recognized as far down in phylogeny as the arthropods, although its relations are somewhat different there than in higher vertebrates (Retzius, ’90, and Nageotte ’16). The development of the myelin sheath increases the rapidity of conduction so that it may rise to 125 meters per second. It influences conduction through the elimination of fatty substances, which are poor conductors, from the neuraxis, and through the increase of the current due to the sheath itself {Gdthlin, ’13 and ’17), and serves as an insulator by preventing such lateral radiation from the neuraxis as does occur where these processes are entirely naked (see the account of the parallel fibers of the cerebellum, p. 700).

Fig. 8. A spinal ganglion cell with fenestrated border from Orthagoriscus mola. G. Levi.

Although neurons are found in the flatworms, they become much more abundant in higher invertebrates and are practically the only nerve cells present in the central nervous system of vertebrates. They vary in form, size, position, and specialized function, as well as in the number of their processes, and these differences have been made the basis of special classifications.

One of the most usual classifications is that into unipolar, bipolar, and multipolar types. The most primitive nemons are bipolar in form, having a single dendritic process and a neuraxis. They resemble most closely the neurosensory cells. They occur in the animal scale at least as low down as the flatworms. A variation of this type is the unipolar or monopolar neuron in which the dendrite and neuraxis arise from a single stem. According to Hanstrom (’29), this is a secondary condition due to a (trophic) migration of the cell body toward the periphery of the fiber tracts. Such monopolar types are found very frequently in annelids and arthropods and in the spinal and most of the cranial ganglia of vertebrates.

In the nematode, Distomum, Havet (’00) described rather deeply situated cells which he

termed nerve cells. Such cells have one or two processes running to the periphery, comparable in appearance to those of the neurosensory cells but showing side branches. These cells appear intermediate in type between the neurosensory cells and the typical sensory neurons. Similar cells having two or more receptive processes were described by Veralti (’00a) in mollusks, where they are particularly evident in the tentacles.

But while the cells of the ganglia are unipolar or bipolar in type, cells of the central nervous system are, with a few exceptions (such as certain neurons of the mesencephalic nucleus of the trigeminal), bipolar or multipolar in type. Many of the Purkinje cells of the cerebellum (fig. 48) afford typical examples of bipolar cells, with the neuraxis arising at one pole and a large dendrite, which soon divides, at the other pole. Peculiar bipolar cells occur rarely, in which two dendrites are given off from the cell body and the neuraxis arises as a branch from one of these dendrites. The horizontal cells of Ramon y Cajal (’91 and ’ll) and Retzius (’93a and ’94), present in the cortex of very young mammalian and human foetuses, are the only pluriaxonal neurons known. These cells produce two (and occasionally even three) neuraxes. Such neuraxes (fig. 9) do not leave the cell from neighboring areas on the cell body but arise from dendrites and in positions relatively far apart. They may give off collaterals.

Fig. 9. Horizontal cell from the molecular zone of the cerebral cortex of a rabbit eight days old. Ramdn y Cajal.

./I, neuraxis; D, dendrites; C, collaterals.

The majority of neurons in the vertebrate central nervous system are multipolar cells with several dendrites and one neuraxis for each cell. Typical examples of such types are found in the pyramidal cells of the cerebral cortex (fig. 10), the motor cells of the ventral horn of the cord (fig. 96), and the mitral cells of the olfactory bulb (fig. 1). But regardless of various classifications, all neurons have certain characteristics in common, which now will be summarized briefly.

The Structure of Neurons and Their Processes

As a liv’ing cell, the neuron has a protoplasmic structure comparable to that of other cells of the body. Usually this structure is regarded as colloidal in character and as having a great resemblance to an emulsion type {Greeley, ’04 ; Ralph Lillie, ’24). The cell body contains a large, spheroidal nucleus with a nuclear membrane inclosing a relatively small but variable amount of chromatin. One or more nucleoli are present ; rather large, spheroidal masses, from which, in certain cells, a so-called fiber of Roncoroni {Mend, '06; Schafer, ’12) extends into the cytoplasm. Certain observ’ers {Hatai, '01 ; Page May and Walker, ’07, and othens) believe that the nucleolus may migrate through the nuclear membrane ; other investigators regard the substance thus described as chrornidial ia character. In Lophius, Holmgren (’99, ’00) showed a depression of the nuclear membrane in the region of the nucleolus and a radiation of nuclear substance to form the tigroid substance of the cytoplasm.

A consideration of the cytoplasm (perikaryon) of the neuron shows it to be highly differentiated. A centrosome is sometimes evident. According to Ariens Kappers, the earliest account of a centrosome in a neuron was given for the frog ; this led to its recognition in the neurons of many animal types (for example, von Lenhossek, ’95, and Dehler, ’95, in the frog ; Lewis, ’96, in certain annelids ; Ramdn y Cajal, ’09, in batrachians, reptiles, and mammals) and to the demonstration of its presence in the large pyramidal cells of the postcentral gyrus of a thirty-year-old man. The position of the centrosome is somewhat variable. Often, but not always, it lies near the nucleus (Hatai, ’01 ; see also fig. lOD), and in the multipolar neurons is near the point of entrance of the principal dendrite (van der Slricht, ’09; see figs. 7 and lOD). According to Del Rio Hortega (’16c), the centrosome often acquires a bacillar form, particularly in older individuals. Then frequently alterations of a filamentous character appear, and part of the filament may extend out into the dendrite. It is possible that the process may be analogous to the formation of the outer thread in the rods and cones of the retina. Since it is questionable whether cell division in neurons ever occurs after the differentiation of the specific cytoplasmic constituents, such mitosis is certainly exceedingly rare, if ever present, in older individuals. Consequently the function of the centrosome in such neurons is unknown. It may be associated with the reception of impulses (Ariens Kappers, ’20).

In this connection, one is reminded that the granules (basal corpuscles) at the base of the hairs in the neurosensory cells and the diplosomes of the rods and cones — both derivatives of the centrosomes — are located in the cells near the point of entrance of the impulse. It likewise agrees with the fact discovered by Held (’09a), that the position of the centrosome coincides with that of the fibrillogenous zone. This zone is evidently the first center of stimulation (or its embryologic equivalent). Since the stimulofugal process, the neuraxis, is formed first (fig. 47), the centrosome lies first near its point of exit, but later shifts its position with the appearance of the principal dendrite. Such facts are of great interest in the study of the underlying principles of tissue differentiation and as applied to the conceptions advocated by Rabl (’89)j Driesch (’94), and Ariens Kappers (’20).

The neurofibrillar constituents of the neuron (figs. lOB, HA, and IIB) are present in the cell body, dendrites, and neuraxis. The presence of fibrils within the neuraxis had been commented upon earlier (Barker, ’99), but they were described first in cell bodies and dendrites by SchuUze (’71) and apparently are invariably present in properly fixed material. Precisely what the nature of these fibrils may be is still in controversy. According to SchuUze (’71), Ranvier (’74), Flemming (’82, ’95), Dogiel (’95), Lugaro (’97), Bethe (’03, see also ’08), Wolff (’05), Marui (’18), and others, they are fibrils extending as discrete structures throughout dendrites, cell body, and neuraxis to their ultimate destination. Apathy (’97, ’98, ’07, ’08) found a network of neurofibrils which constituted intercellular bridges in the leech. According to his theory, they took origin from so-called nerve cells and passed through a series of ganglion cells to their termination. In invertebrates and certain vertebrates, he found neurofibrils entering by the dendrites, ramifying and anastomosing within the cell body, and reuniting to enter the neuraxis. Other observers {Frommann, ’64 ; Ramon y Cajal, ’09 ; Bielschowsky , ’28, and many others) have regarded them as anastomosing, the major fibrils forming the heavier threads of a network ; still others have considered that they show indication of being tubular in character {Schafer, ’12, p. 234, fig. 368). Mann (’98) stated that the neurofibrils are the only portions of the nerve fiber continued across the nodes of Ranvier, but this statement is difficult of proof and lacks confirmation. Repeatedly the question as to the possibility of their being fixation artifacts has been raised. In some of the tissue culture work on developing motor and sympathetic nerves, the most careful examination of a living, developing fiber failed to reveal any indication of neurofibrils, although after fixation typical fibrils were present (Matsumato, ’20 ; Lewis and Lewis, ’24). However, Schultze (’71) had claimed that he was able to differentiate such fibrils in fresh cells which had been prepared without the use of fixatives or stains. By the use of polarized light, neurofibrils were seen by Grant Smith (’06) in both living and fixed material and Howard (’08) demonstrated neurofibrils both in the retinal cells of various vertebrates and in the nerve fibers as well. Bozler (’27) was able to find neurofibrils in the living nerve cells of Rhizostoma and Tiegs (’27 ; see also ’31) found them in teased fragments of living fetal rabbit cord. Recently de Renyi (’29) demonstrated the presence of neurofibrils in the giant nerve fibers of the lobster, although he had not demonstrated them in the frog (’29a). Moreover, intravitam stains demonstrate a neurofibrillar structure in the neiwe cells, but the objection that such stains are toxic has been raised by certain experimenters. Schafer (’12) thought that the ease with which neurofibrils show varicosities suggests that they are se mifl uid in character and referred to Carlson’s {Carlson, ’04, ’05 ; Jenkins and Carlson, ’03, ’04) experiments on the necessity for a fluid-conducting substance in the nerve as supporting evidence for this view {Schafer, ’12, p. 235). Jenkins and Carlson (see also Leydig, ’97) ascribed the most important role in nervous conduction to this more fluid perifibrillar substance, as did Parker (’29) and Ariens Kappers (’32), according to whom the neurofibrils are coagulation products, caused by frequent impulse currents.

Three points of view, then, regarding conductivity along the neuron have been presented ; (1) that it occurs along the neurofibrils — that these are the specific conducting elements ; (2) that it occurs in the more fluid neuroplasma between the more stable neurofibrils ; (3) that it is due to an interaction between the neurofibrils and the neuroplasm. Apathy (’97 and elsewhere) considered that in the primitive ganglion cells of invertebrates the neurofibrils pass from one cell body to the other, through the syncytial network. Schultze (’71), Bethe (’03, ’04, ’06, ’07, ’08, etc.), Wolff (’03), Bielschowsky (’05), Oudendal (’12), Marui (’18), and others believed that at times they are continuous across the synapse in the vertebrate nervous system, although this is not in accord with the views of radical supporters of the neuron theory {Retzius, ’08 ; Ramon y Cajal, ’06, ’09, etc., and many others). The fact that the nervous impulse may irradiate sidewise from the neuron shows that these fibrils are not a conditio sine qua non for conduction.

Fig. 10. A. Neuroblasts from the cortex of an embryo of Cavia cobaya, 23 cm. in length. Held. Note the plasmodeses between the first stage neuroblasts in the middle.

B. Unipolar neuroblasts of second stage of a duck embryo of the third day of incubation. Held. The first development of the neurofibrils is noted in the region of the process and here also are to be seen the diplosomes.

C. Neuroblast in vitro from a lymph culture of Rana palestris ; the neuroblast on the left after 52 hours of culture, and that on the right after 56^ hours of culture. Harrison.

D. In the upper figure, the cell body of a Purkinje cell of an adult rat, showing the location of the centrosomes opposite the dendrite. In the lower figure, the cell body of a pyramidal cell, showing the centrosome opposite the main dendrite. Halai.

The form and size of the neurofibrils vary under varying conditions. Thus in invertebrates, at least, they appear to be finer in the sensory than in the motor neurons {Apathy, ’97 ; see also ’98). They become less numerous and thicker

during cold and hunger and during hibernation {Ramon y Cajal, ’04, ’09 ; Tello

/ / ’04 ; Marinesco, ’06 ; Donaggio,

y ’06; and others), and in general show an increase in number and are finer during functional activity (hg. 11 ■ see also Dustin, ’06).

^ \ Various pathologic conditions also

' affect the neurofibrils and may lead I to their disappearance. For such changes, texts on neuropathology A should be consulted.

^ Nissl granules {Nissl, ’84) —

y' ^ chromidial or tigroid substance {von

n Lenhossek, ’97) — consist of nucleo ” proteids which contain iron {Scott,

0 ’99 ; Macallum, ’05 ; Nicholson, ^ J ’23). These disappear on treat ment with ammonia and, in accordance with their acid character, are stained by basic dyes. They are

^ present in the larger nerve cells, but

\ have not been demonstrated satis VuS B * factorily in some of the smaller cells

^ % * (granular types) of the cerebro Fio. 11. The form of the neurofibrils in a lizard; A spinal nervoUS system. The gran and a, during hibernation ; B and b, in the awakened ules are present in the Cell body animal after it had been warmed for several hours at j i j -i n j. j. • ., 0 ,,

30’ c. Ramdn y Cajal. dendrites but not m the neu raxis nor at its place of attachment to the nerve cell (the axon hillock or implantation cone, fig. 12). They tend to form clumps or masses and vary in number, appearance, and size in the different cells. Using these morphologic differences, Nissl (’03) worked out an elaborate classification of this substance, for the details of which, reference is made to his work. It may be stated here that he subdivided nerve cells into two main groups, those in which the cell body was well developed and distinctly outlined, the somatochrome nerve cells, and those in which the cytoplasm was either very poorly developed or contained little stainable substance. This second group fell into two classes : the granules or cytochrome cells, with small nuclei approximating in size those of neuroglia cells and the caryochrome cells with larger nuclei approaching in size that of the usual neuron. The majority of nerve cells, of course, belong to the first group, the somatochrome cells of Nissl. These somatochrome cells were thrown into various subgroups, these being based on the types and arrangement of the Nissl or tigroid substance. It is now known that, to some extent, the size and character of the Nissl bodies in a given cell are dependent upon the fixation employed {Cowdry, ’24, and others), but in similarly fixed material or in cells side by side in the same material and con^quently subjected to precisely the same conditions, differences in the size-nisaftHS

Fig. 12. To the left, a normal pyramidal cell from the motor corte.x (area gigantopyramidalis) of an adult man ; to the right, a tigroly tic cell with scalloping of the nuclear membrane.

appearance are evident. That these morphologic differences apparently have a basis in functional differences in the cells has been shown by the studies of Jflcobsohn (’08) and of Malone (’13, ’23). This latter worker has shown that differences in size of cell and in general characteristics of the Nissl substance could be demonstrated in cells supplying voluntary, heart, and smooth muscle. His work also indicated that the functions of various portions of the nervous system could be predicated from their cell types.

In spite of their characteristic appearance in properly stained material, formed Nissl granules have not been demonstrated satisfactorily in living cells {Cowdry, ’24, and others). There is every probability that the form which they take in the fixed material is the result of a coagulation of the protoplasm due to the use of fixation fluids. The work of MoU (’15) appeared to indicate that the substance is quite different in dead cells than in the living neuron. H. C. Voorhoeve ('26) explained its non-appearance in the living cells as due to its having a light refracting index in ordinary or ultra-violet light not unlike that of the rest of the cytoplasm. However, the so-called axon reaction, the chromatolysis or tigrolysis (fig. 12, to the right) of the Nissl substance after injury to the neuraxis, the disappearance of this substance wholly or in part after fatigue or after toxins either administered or produced by disease, and the reappearance, under favorable conditions, of these granules within the cell appear to establish the existence of a substance within the living cell vital to its effective functional activity and indicated — although not directly represented — by the stainable Nissl substance of ffxed material. Macallmn (’05) regarded this substance (a nucleoproteid) as the greatest iron-containing protein \vithin the cell. iVIicrochemical tests (Scott, '99 ; Macallum, '05 ; Nicholson, ’23) indicate the stainable substance of Nissl to be an iron-containing protein. Nicholson (’23) showed further that an actual loss of iron and consequently a real chemical change can be demonstrated where chromatolysis has occurred following an injury to the neura-xis.

The origin of the Nissl substance is still in question. The nucleoproteids of these cells are supposed to originate in the nucleus ® (Holmgren, ’99, ’99a, '00, ’00a; Scott, ’99; Cameron, ’06, and others). In a nerve cell of Lophius, Holmgren (’99) figured a wide gap in the nuclear membrane opposite the centrosome and the apparent formation of Nissl granules in the region. Various authors have favored the theory of such a migration of nucleoproteins from the chromatin material and used it as a basis for explaining the small amount of basichromatin present in the nucleus of the neuron (fig. 12, on left). It is true, certainly, that more chromatin is present in the nuclei of the caryochrome cells of Nissl (those which do not contain tigroid bodies) than in other neurons. Also, both chromatin and Nissl substance are fermented by nuclease (van Herwerden, ’13, ’13a) and both react positively to the nuclear reaction of Feulgen and Rossenbeck (Redenz, ’25, and Voorhoeve, ’26). Consequently, it seems to be established reasonably well that nucleoproteids migrating from the nucleus play a part in the formation of the Nissl substance of the nerve cell. That they form all of this substance is at least open to question, for the amount of Nissl substance appears to be too great to have been formed entirely from such migratory material. The fact that Nissl granules appear first at the periphery of the cell (van Biervliet, ’00 ; Marcora, ’ll) favors the idea that the cytoplasm may take part in their formation. Emil Holmgren (’00) believed that lipoid substance contributes to this. Muhlmarin (’12), working with young embryos, reached the conclusion that the substance contributed must be a neuroglobuline, since the Nissl granules, when treated with a methyl-green pyronine mixture, stained only with the pyronine.

The function of the Nissl substance is not known with certainty. Evidently it is related to the metabolism of the cell. There is a considerable body of evidence suggesting that its importance in metabolic activities is due to the ironholding properties of its nucleoproteid. Presumably the iron serves as a catalytic agent in accelerating oxidation within the cells {Warburg, T4 ; see also ’28). A. P. Mathews (’24) says that “iron catalyzes reactions in which hydrogen peroxide or ozonic acid takes part ; in the system, oxygen-water and its action in the cell are no doubt connected with this property.”

Holmgren (’99, ’00) and Page May and Walker (’07) speak of nucleoli migrating through

the nuclear membrane. It is possible they may be chromatic substance.

Thus it would seem that the Nissl substance is related directly to the passage of the nervous impulse.

The facts mentioned before — that it disappears after injury to the neuraxis and exposure to toxins and upon fatigue — support this interpretation.

Mitochondria are present in neurons as well as in other cells of higher forms. They are regarded as phospholipins, possibly in combination with a small amount of protein {Regaud, ’08 ; FaureFremiet, ’10 ; Cowdry, '18, ’24, and others). Microchemical tests show that, unlike Nissl granules, they contain practically no iron. Morphologically they may be either granular or filamentous in type, but usually they have the latter form in the nerve cells. The numerical variation is great, but mitochondria appear to be more abundant in younger, more active cells, and to decrease in senescence. They are more numerous in cells that have little fat and fewer where the amount of fat is increased appreciably. All these facts suggest that there is a direct relation

between the rate of oxidation within the cell and the amount of mitochondria . Attempts have been made, by means of a special apparatus, to count the number of mitochondria in nerve cells. The material used was the cranial nerve cells of white mice. From a study of such cells, Thurlow (’17) arrived at the conclusion that, per unit volume, a reasonably constant number of mitochondria is present.

It is not possible to enter here into a discussion of the various functions attributed to mitochondria. The literature which has accumulated on the subject is very great. Those interested may find very suggestive bibliographies in the papers of Duesberg (’12) and Cowdry (’18 and ’24). This latter author has collected a list of about eighty substances which are regarded as being affected in some way by mitochondria during their formation. The work of Kingsbury (’12) and Mayer and Schaeffer (’13) suggests that mitochondria may play some part in protoplasmic respiration.

The so-called Golgi apparatus (fig. 14) was first described in nerve cells by Golgi (’98 ; see also ’01) and Held (’02). Since that time, through the work of many experimenters, it has been shown to be present in all normal hving cells, although evidence is lacking that it is either structurally or functionally the same in all cells. It is regarded as lipin hnked with protein material, being similar in constitution to mitochondria {Gatenby, ’20). It hes around the nucleus and only enters the dendritic processes of a nerve cell on rare occasions {Sanchez, '16). It never enters the neuraxis. Penfield (’21) beheved that it is displaced to the periphery of the cell on section of the neuraxis (retispersion) and then soon disappears (retisolution). Students of invertebrate material (Hyman, ’23, for example) have conceived of it as consisting of two constituents, differentiable through their affinity for stain. It has not been observed clearly in unstained hving cells of vertebrates, nor has it been stained differentially through the use of vital dyes (Cowdry, ’24). The microdissection methods of Kite and Chambers (see Chambers ’24, for bibhography, quoted also by Cowdry, ’24) and the centrifugation experiments of Cowdry appear to indicate that, in the hving cell of vertebrates at least, the Golgi apparatus does not differ greatly in density from that of the remainder of the cytoplasm. In fixed material stained by silver-impregnation methods, the Golgi apparatus has the appearance of a reticulum, consisting of more or less densely arranged black threads. There is a certain amount of evidence — as yet not particularly clear cut or convincing — which indicates that the Golgi apparatus is affected by certain pathological conditions.^

Fig. 14. Golgi net in the spinal ganglion cell of a dog. Golgi.

m, mitochondria; n, Nissl granules.

Note the accumulation of the mitochondria around the axon hillock.

Holmgren ( 04, 04a, ’14, ’15, and elsewhere) described a canalicular system in cells (including neurons) which consists of so-called lymph-canaliculi into which processes of surrounding cells (trophozyten) extend, forming a network which he termed the trophospongium (fig. 15). That the canalicular system is present seems to be well established, but whether or not it is to be regarded as identical with the Golgi apparatus is still in dispute. Thus Ramon y Cajal (’09 and ’15) appears to have regarded it as identical, and used the term “appareil tubuleux du protoplasma” or Golgi-Holmgren canals. Duesberg (’14) regarded the systems described by Golgi and Holmgren as the same in all neurons and in some (but not all) non-nervous^cells, while Misch (’03), Bergen (’04), Sjdvall (’06), and Penfield (21 , see also 20) considered them quite independent structures. Cowdry ( 24, p. 342) stated that “observations are not lacking that there is often a close coriespondence between systems of clear canals and blackened networks in normal nerve cells. ”

Pigment containing lecithin is present in some nerve cells (Muhlmann, ’01 ; Obersteiner, ’03, and many others). It is usually found in a mass near the nucleus and may be in sufficient amounts to give color to the cell mass, as in the substantia nigra. It is more plentiful in older than in younger cells and in human than in lower forms.

Fig. 15. Spinal ganglion cell of a rabbit showing trophospongium and trophocytea extending into the cell. Holmgren.

'•eticular nets over certain neurons. According to ^ f e ^ these nets are sometimes regarded as terminal

pr<.ce.ssc.s of the neuraxes of other neurons, fonning thus a pericellular synapse, and sometimes arc considered to l>c of neurogliar origin. j i >

prGCC.*v>C.S \jt viit.. «tui44i4At;o UJ ULUUX iiuun

arc considered to l>c of neurogliar origin.

Oxidizing enzymes, occurring as very small granules within the cell, have been described by Katsanuma (’15), Marinesco (’19 and ’19a), and Ariens Kappers (’20). The presence of these oxydases (fig. 16) or oxydones (von Gierke) in the cell protoplasm (perikaryon) and in the dendrites is further evidence that these parts of the neuron play the more important role in the metabolic and particularly

Fig. 16. Reaction to a naphthol and paraphenylin diamine to show the oxydases within ■ three nerve cells (A and B from the telencephalon, and C from the mesencephalon of a bony fish). Ariens Kappers.

the anabolic functions of the cell. Still further confirmation is given by the work of Unna (’16), who demonstrated, through the use of nongalit and potassium permanganate staining, that a larger amount of oxygen is present in the dendrites and cell body than in the Nissl substance. The morphologic effects of the anabolic function of the dendrites are seen in such parts of a nervous system as have no entering blood vessels. Examples of these are found in the horizontal cells of the developing cortex and in the motor cells of the spinal cord of Ammocoetes (Tretjakoff, ’08). The dendrites of such cells have a tendency to approach the vascularized surface, ending there in thickenings.

The foregoing account has indicated repeatedly that the dendritic processes of the neuron usually have the cytoplasmic structure of the cell body and that they are vitally concerned in its metabolic- functions. Their direction of conduction of impulses is afferent with respect to the cell body. Dendrites within the central nervous system usually are relatively short and branched and do not carry myelin sheaths. The peripheral process of a spinal or cranial sensory neuron is long and has the structural characteristics of a neuraxis. Such a process is regarded as a dendrite because it conducts toward the cell body (see the account of spinal ganglion neurons).

The neuraxis, that process which conducts impulses away from the cell body, is specialized for conduction. That it also has metabolism is indicated by the production of CO 2 by a fiber even at rest, with an increase in the CO 2 when the impulse passes (Tashiro, T3, ’13a, ’15, ’17, ’22). Nissl substance is absent from it and from the axon hillock, but neurofibrils are continued through it into its finest branches. It varies in length from a millimeter or so to nearly a meter. It may or may not have a myelin sheath or medullary sheath about it ; outside, but not inside of the central nervous system, it will carry a neurolemma sheath.

In medullated peripheral nerves (whether the neuraxes of efferent or the dendrites of afferent nerves) the structure of the fiber is as follows :• The central portion, or axis cyfinder, consists of neurofibrils embedded in a fluid material, the neuroplasma. Around this portion is the myelin, separated from the neuraxis, according to some observers, by a thin, structureless membrane, the axolemma (sheath of Mauthner). The myelin sheath itself is composed of lecithin ( a phospholipin) , cholesterin, kephalin, and protagon. Its morphologic structure, as seen in fixed material, appears to vary with the fixing reagents used. Apparently on treatment with certain reagents, a keratin-like, coagulable substance separates out from the sheath and is laid down as a neurokeratin net. Funnels of Golgi probably are precipitated substances. Oblique interruptions of the myelin sheath, which Bruno (’31) regarded as of the same character as the neurolemma but which numerous observers have regarded as artifacts, are usually described under the name of Schmidt-Lantermann segments, although this is a misnomer according to Diamare (’32), who stated that they were described first by the Italian, Wladimiro Zawerthal. Perhaps the myelin, which is known to have a crystalline character, consists of oblique crystals, responsible for the appearance of the above-mentioned structures. Since the pattern of the net varies with the fixing fluid used, it appears probable that the structural patterns described for myeUn are largely artifacts (Huber, ’27). Nageotte (’09a), however, believed the neurokeratin net to be formed of mitachondria. Doinikow (’ll) regarded the myelin substance as deposited in a protoplasmic meshwork, produced by the cytoplasm of the neurolemma cells (the plasma cells of Schwann) . He thought that the more dense portion of the cell, together with the nucleus, remained on the outside as the sheath cell ; Nemiloff (’10) considered that the protoplasmic network associated with the neurolemma extends into the myelin sheath. At intervals along the fiber, the myelin sheath becomes discontinuous, forming the so-called nodes of Ranvier. At such nodes the neuraxis and the neurolemma sheaths remain continuous.® Such nodes occur at intervals of about 1 mm. on fibers of 10^ diameter. The branching of medullated fibers occurs at the

Sometimes (ATemtio#, 10; see figures and accounts in Bailey’s Histology, Bailey, Strong, am Mwyn, 25) the sheath cells are regarded as terminating at the nodes in such a way that the axolemma and the so-called neurolemma become continuous with each other. Thus the axolemma IS regarded as the inner boundary of the cell, the neurolemma sheath as the outer boundary, and the neurokeratm net as a fibrillar network within the cell. Observers, who take this point of view regarding the relations of the myelin to the sheath cells, consider certain of the neuroglia cells of t^ central nervous system as directly comparable with the neurolemma cells of the peripheral nodes in higher forms, but in some invertebrates, such as crustaceans, the division may take place within the internodal segment (Nageotte, T6). One sheath cell nucleus is found between every two nodes. In vertebrates such a nucleus lies external to the myelin sheath, but in arthropods the nucleus is inside of it.

The varying points of view regarding the structure of the myelin raise the question as to its embryological origin. Appearing, as it does in development, after the formation of the neuraxis and its enveloping membrane, the neurolemma sheath, and between these two ectodermal structures, the possibility of its mesodermal origin (which was taught earlier) appears to be definitely excluded. It may be safely concluded that it is ectodermal in origin, but the question as to whether or not it is derived from the neuraxis or from the neurolemma sheath

Fig. 17. A. Nerve fiber from the popliteal nerve of a fetal calf of 45 cm. length, showing the formation of the medullary sheath.

B. Preparations from the ventral white funiculus of the spinal cord of a fetal calf of 32 cm. length with glia cells with myelin droplets.

is less easily decided. Ranvier (’78) regarded the neurolemma as forming the myelin sheath and this conclusion has had considerable support ; Bardeen (’03) and von Kdlliker (’04) believed that the myelin is formed by the neuraxis. In his 1927 paper, Huber (pp. 1095-96) stated that evidence, though at present inconclusive, is at hand to support the interpretation that the myelin sheath is a part of the neuron.

It is certain that the myelin first appears during development (figs. 17A and 17B) as a thin, continuous layer around the nerve fiber, with no nodes of Ranvier; also, in regeneration of cut or injured nerves, no internodes and nodal segments are present at first. This would appear to indicate that it is related to the axis cylinder rather than to the neurolemma sheath. Also, myelin sheaths are present in the central nervous system where there are no neurolemma sheath cells and where only very rarely are neuroglia cells with myelin droplets found (fig. 17B). Furthermore, Ambronn and Held (’95) showed that within the fila olfactoria of the pike, a doubly refracting substance, probably a sort of myelin or lecithin, is demonstrable. Therefore, the present evidence appears to favor the theory that the myelin is a differentiation of the peripheral portion of the neuraxis (cf. Apathy, ’97, and Gothlin, ’17). Particularly favorable is the recent work of Speidel (’33). He studied in great detail the process of myelinization and myelin adjustment in living nerve cells over a period of several months, noting the selective myelinization which occurred under the influence of sheath cells in non-myelin emergent and myelin emergent fibers, and concluding myelin is “ an adjunct of the axis cylinder,” not part of the sheath cell. (For myeliniza^ tion within the central nervous system, see pages 1660 to 1662.

With regard to the function of this sheath, one theory is that the medullary sheath serves as an insulator, making possible more efficient conduction of the nervous impulses. In support of this contention are the facts that the myelin sheath is a poor conductor, that the passage of the nervous impulse is much more rapid in medullated than in non-meduUated fibers, that the majority, at least, of peripheral nerves which have highly specialized terminations and many of the longer tracts of the central nervous system have medullary sheaths, and that these sheaths develop, ortogenetically and phylogenetically, with the differentiation of the various fiber systems. Moreover, myelin is lacking in regions where insulation is undesirable ; it is not present at the synapse where the impulse passes from one neuron to another nor on the dendrites (with the exception of those of peripheral sensory neurons) nor on the telodendria of the neuraxis. Usually it is not found on the cell body, although there are a few exceptions to this, as, for example, around the bipolar cells of the spiral ganglion and sometimes around spinal ganglion cells in sharks. However, all these facts which seem to indicate, in one way or another, that the myelin has a protective and insulating function do not solve the question as to how the accumulation is effected. So far as its constituents may arise from the nerve fiber itself, it is probable that this secretion by the fiber is due to the passage of the nervous impulse. The researches of Ambronn and Held (’95), referred to previously, show that myelin formation is greatly affected by the functioning of the tracts, apparently influenced by the impulses passing through them. Lecithin, which, as was stated previously, forms the chief component of the myelin sheath, in physiological salt solution shows striking kataphoretic properties. This has been shown by Hermann (’97), who described its passage to the anode as one of the most astonishing microscopic phenomena he had ever witnessed. Placing a part of a peripheral nerve of a frog in line with the electrodes (but not touching them), and passing a constant current, he saw a great outflowing of the nerve contents — particularly, but not exclusively, the myelin — toward the anodal pole of the nerve. Here the myelin heaped up as curl-like particles, but, on reversal of the current, was reabsorbed by the nerve, while the myelin at the opposite pole (now anodic) collected in heaps at the end of the nerve. Such an experiment shows clearly the tendency of the myelin to be carried in the direction of the anode. _ In the living nerve, then, the action current, which implies considerable galvanic potentials at the surface of the nerve, might cause the myelin constituents (in so far as they originate from the neuraxis or from the sheath cells) to gather at the surface, thus forming a sheath about the fiber. The above facts offer a reasonable solution of the problem regarding the production of myelin and Its appearance at the periphery of the fiber {Ariens Kappers). However, these explanations do not make clear the reasons why the telodendria are unmyelinated.

In connection with the accumulation of myelin about the neuraxis must be mentioned a fact which comes to the attention repeatedly in the study of certain fiber tracts of lower animals {Ariens Kappers, ’20). In the conunissura superior habenularum of plagiostomes, medullated fibers are frequently arranged at the periphery of non-meduUated ones.

The same is evident in the fasciculus retroflexus. It suggests that, through induction, the periphery of the bundle is strongly anodic, and so is responsible for the formation of myelinated fibers. Whether this is to be regarded as analogous to the peripheral accumulations of myelin around the individual neuraxes is problematical but at least is worthy of consideration.

Synaptic Relations between Neurons

Telodendria of the neuraxes of neurosensory cells are generally in s3Tiaptic connection with the primitive ganglion cells. Sense cells, or neuroepithelia, support the terminal fibrils of sensory fibers but are not in themselves neurons. Primitive ganglion cells may be discrete (Bozler, ’27) or may appear to be connected by processes, the cells forming a non-polarized, or at least a transiently polarized, syncytium in which

the neurofibrils pass from one part to another {Apathy, '97). A distinct barrier exists between neurons of the higher nervous systems, a region which is spoken of as the synapse, which is demonstrable physiologically and, in some cases, anatomically.

According to certain observers, actual protoplasmic continuity is often, if not always, present in the region of the synapse. Apathy (’97, '98, ’07, and elsewhere), Bethe (’01, ’03, ’04, and ’08), Wolff (’03), Prentiss (’04), Dogiel (’05), Bielschowsky (’05, ’28), London (’05), Schultze (’05), Oudendal (’12), Held (’09a, ’29), and others considered that neurofibrils may pass from one cell to another cell without interruption (fig. 19). Beccari (’07) suggested a similar condition where the terminal fibers of the crossed neuraxis of the Mauthner cell in teleosts synapsed with the cells of the ventral horn. Marui (T8) claimed a similar continuity of neurofibrils in his study of the Mauthner cells of teleosts. He thought that the neurofibrils of one neuron may be continuous with those of another but that the perifibrillar protoplasm is very poor near the synapse, the fibrils being surrounded closely by glia. Tiegs (’31) believed himself to have demonstrated neurofibrillar continuity across the synapse in various nerve cells, including Mauthner’s cells. Bartelmez (’15, ’20, and, with Hoerr, ’33), working with the Mauthner cells of fishes, believed that his material demonstrated clearly that in these cells actual cell membranes intervene between the regions in synaptic relation with each other (fig. 20). Direct evidence of an anatomical barrier at the synapse has been presented only in rare cases. However, a considerable body of observers regard the synapse as a region where the cell processes are in contact with each other but are not continuous — “ contiguity without continuity.” Based on the embryological work of His (’90) — who showed that the nerve processes are outgrowths of the nerve cell and who regarded the neurons as an entity — and on the confirmation and acceptance of this observer’s work by various embryologists (see Streeter, ’12), the idea of contiguity but not continuity has found strong support in the histologic and cytologic studies of Golgi (’82, ’83, ’85, 06, 07, etc.), Ramon y Cajal (’06, ’07, ’09, etc.), and many others. Indirect but supporting evidence for the integrity of the neuron is to be found in the work of Harrison (’06, ’07, ’10, and elsewhere), of Lewis and Lemis (’12), of evi { 17), and of their associates, and in some of the experimental and neurosurgical work on nerve degeneration and regeneration (Waller, ’52 ; Ramrier, ’78 ; Howell and Huber, ’92; Stroebe, ’93; Huber, ’95, ’00, ’16-’17, ’19, ’20, ’27; Perronnto ’07; Poscharissky , ’07 ; Ramon y Cajal, ’08, ’08a, and ’28; Ranson, 12; Boeke, ’16 and ’17; Dustin, ’17 ; Huber and Lewis, '20, and others), since the results of their work in general favor the development of the neuraxis as a do^vngrowth of the nerve cell.

Fig. 19. The continuation of the terminal fibrils of the neuraxes of the basket cells into the intracellular fibrils of the Purkinje cells. Oudendal.

Fig. 18. Cells from the nucleus trapezoideus of the cat. Veratti. Different types of end baskets (from the Edtnger textbook, ’08) .

Fig. 20. Mauthner cell of a bony fish. Barlelmez.

Note the axon cap surrounding the axon hillock and the end feet of Auerbach along the lateral dendrite.

Toxins are particularly effective at the S 3 mapse and the susceptibility to fatigue is greatly increased. There is considerable difference of opinion as to the way in which a synaptic membrane (or membranes) might function. It has been regarded by some observers as semipermeable in character and many physiologists favor the theory that at the passage of a nerve impulse, some substances, possibly ions thus dissociated, are able to pass in one direction and in one direction only.

Whether or not there is a continuity of nerve substance at the S 3 mapse, there is strong evidence of physiological differences in the region, which indicates the presence of a physiologic if not an anatomic barrier. Whether or not neurofibrillar continuity may occur across the synapse (and it is conceivable that this may vary in different animals, or even in different regions in the same animal), it is probable from the developmental history and from the work on nerve degeneration and regeneration that each neuron is fundamentally a morphologic and trophic unit.

A study of the sequence of the phylogenetic and ontogenetic development of the nerve processes and the direction of their growth affords some suggestions regarding the factors underlying the polarization of the S 3 mapse. Thus neurosensory cells have no dendrites. Likewise neuroblasts, from which the true neuron arises, form their neuraxes first by an outgrowth of the cell protoplasm, this process growing in the direction along which the current is passing {Bok, ’15). Its growth, then, is stimulo-concurrent and begins at the side of the neuroblast opposite the receptive pole, as it does also in the neurosensory cell. Considerably later, at about the time that the tigroid substance appears in the cell body, the ordinary protoplasm of the cell shows a tendency to form processes toward the source of its stimulation (stimulopetally, Ariens Kappers, ’07, and elsewhere). “ The difference in development of these outgrowths is very striking, since the neuraxis grows away from its source of stimulation, while the dendrite tends to develop in the direction from which it receives its stimuli.’" The outgrowth of these processes in opposite directions has a suggestive resemblance to the polarized growth in the electric field, and indeed may have its basis in polarized bioelectric conditions (see the discussion of neurobiotaxis). It seems quite possible, then, that where two different bioelectric poles lie in close relationship to each other, as at the synapse, a double surface membrane (in the sense of Helmholtz and Quincke) may be formed, through which only such a current may pass as agrees with the bioelectric polarization of both surfaces ; that is, with the stimulo-concurrent bioelectric character of the neuraxis and the stimulo-petal character of the dendrite. Thus, although the neuraxis or the dendrite stimulated along its course may conduct in either direction — because such a fiber is homogeneous in itself — yet where two different polarized surfaces lie in contact, the transmission of the impulse can take place only in a direction in accordance with the polarizations in the region. The above explanation of the condition at the synapse, on the basis of the oppositely polarized character of the offshoots, does not necessarily exclude the presence of some substance such as the so-called junctional substance or the synaptic membrane of Sherrington (’06). Such a substance, however, if it is not a product of the glia, which is highly improbable, may be produced by, or be a part of, the neuron itself. Its formation at this region may be due to the meeting of the two differently polarized layers.

It is to be noted that the cell body of the neuroblast itself, up to the time that it has fully

developed Nissl substance, tends to keep its original position and so to behave like a neuraxis. After the development of the Nissl substance, however, the cell body tends to shift along the dendrites in the direction from which it receives its more important stimulation.

It is evident that the stimulo-concurrent character of the neuraxis and the stimulo-petal character of the dendrite and cell body involve their approaching at the synapse (see fig. 46), and each transmission of conduction tends to increase the proximity of their mutual approach.

Fig. 21 The arch of Frommann, showing intramedullary relations on the right and extramedullary relations on the left.

It is well known that at the synapse the rate of conductivity lowers, and also that this place is more susceptible to fatigue and to drugs. This is due, perhaps, to the fact that the most peripheral fibrils of the telodendria are closely surrounded by a glial reticulum {Marui, ’18), the glia being very susceptible to metabolic changes and to drugs. Textbooks of physiology should be consulted for further accounts of the characteristics of the synapse. An excellent discussion of the problem of nerve conduction and of the synapse, from the physico-chemical standpoint, is to be found in the work of R. S. Lillie (’18, ’19, ’23).

Individual neurons are joined into larger units which are termed cell complexes (coelenterates), nerve strands (worms), ganglia (worms, arthropods, and mollusks, as well as vertebrates), and central and autonomic nervous systems (vertebrates). Cell complexes, formed of single primitive ganglion cells, are found, in lower invertebrates. Those plexuses which are not formed of single ganglion cells and their offshoots, but the trabeculae of which contain bundles of nerve fibers and many nerve cells, as is the case with most invertebrates, are termed cell strands or cords. These strands may contain primitive ganglion cells as well as neurons and processes of neurosensory cells. A somewhat similar arrangement is seen in a sympathetic plexus — such as the coeliac — except that the cellular elements of such plexuses are typical neurons.

By ganglia aie understood accumulations of nerve cells. They are present in invertebrates as far down as worms. Spinal ganglia are examples of them in the vertebrates. Such ganglia may consist of cell bodies, but they become more complicated with the increase in neuropil, which is composed of the processes of the cells and especially the finer branches which weave backward and forward among the cell bodies of the neurons. The term neuropil is synonymous with the intercellular gray of Nissl and refers to a diffuse meshwork of dendrites and

Fig 22 Neuron of a sympathetic chain ganglion surrounded by its capsule Ramdti y Cajal A, small subcapsular dendrite ; a, postgangbomc neuraxis; 6, a dendrite surrounded by the spiral fibrils of a preganglionic neuraxis; c, capsule cells.

neuraxes. Such a meshwork has only the semblance of being diffuse. Actually it consists of fibers which establish precise connections, since only such an arrangement could explain the sharply defined conduction which occurs within it. These ganglia tend to join into larger groups — to centralize. This is particularly evident in the ganglia of arthropods, mollusks, and insects, and leads to the formation of a type of central nervous system.

The term central nervous system is generally applied where not only anatomic and histologic, but physiologic relations as well, indicate a high degree of centralization of nervous function. This centralization is present during the entire ontogenetic development in vertebrates, where the nervous system is a large unit from the beginning. Centralization may arise gradually during ontogeny in invertebrates, through the development of separate primordia. The term central nervous system is usually confined to that of vertebrates. Neuropil, somewhat more evenly distributed, is present in the vertebrate central nervous system.

The autonomic nervous system is considered on pages 233 to 242, and will receive only brief mention here. It consists of chain ganglia (Grenzstrang) situated on either side of the vertebral column, of large sympathetic plexuses called collateral or prevertebral ganglia, and of small, scattered cell masses on.

28 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

in, or near the organs receiving innervation from them, and termed peripheral ganglia. All such ganglia consist of the cell bodies of postganglionic or sympathetic neurons (figs. 22 and 23), the neuraxes of which, frequently, but not invariably unmedullated, supply heart muscle, smooth muscle, oi glands. All such ganglia, wherever situated, are related to the central nervous system through preganglionic neurons, the cell bodies of which lie in brain or spinal cord and the medullated neuraxes of which terminate in pericellular, subcapsular synapses around the cell bodies of postganglionic neurons. There would appear to be some question in the minds of certain observers with regard to the type

of synapse between pre- and postganglionic neurons. Pericellular, subcapsular endings have been demonstrated by Dogiel (’99a), Huber (’99a), and Ramon y Cajal (’09). The prevalence of this type of neuron synapse in man has been questioned. Stohr (’27, ’28) believed them to be of common occurrence in the superior cervical ganglion, but to be rare in other ganglia in man. The evidence appears to indicate that in frogs only pericellular terminations are found.

The autonomic system, in higher vertebrates at least, falls into a craniosacral or parasympathetic portion, with preganglionics through cranial (III, VII, IX, X, XI) and sacral nerves, and a thoraco-lumbar or sympathetic division, with preganglionics from the thoracic and lumbar levels of the spinal cord. Most organs are known to receive innervation from both systems, the results of such innervation producing different, and sometimes diametrically opposite, effects. Thus in the innervation of the heart, the two neuron, cranial chain — the preganglionics of which run in the vagus to synapse on the heart wall with the postganglionic neurons — produces inhibition, while the thoraco-lumbar

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEjVIENTS 29

innervation — with preganglionics from the uppermost thoracic segments synapsing with postganglionic neurons, the cell bodies of which lie in cervical sympathetic and stellate ganglia — produces acceleration.

The chain ganglia are connected with the ventral nerve roots by so-called white rami communicantes, through which the neuraxes of the preganglionic neurons and the visceral sensory fibers pass. The strand by which fibers leave a chain ganglion for other sympathetic ganglia is called a gray ramus, while the strand which connects it with the nerve root is termed the gray ramus communicantis. Gray rami communicantes are present on all of the spinal nerves of man.

The sympathetic system itself is an efferent system, but visceral sensory fibers, with cell bodies in spinal and cranial ganglia, accompany the pre- and postganglionic neurons. Such visceral sensory neurons have their cell bodies located in spinal or cranial ganglia and are comparable to other sensory neurons except for their peripheral and central distributions.

The Connections of Nerves WITH Other Tissues

SENSORY endings

The most primitive sensory

apparatus is found in the neuro sensory cells described in the sensory nerve endings m the skin of Petro preceding pages. These cells are myzon marinus, Retzius. c., cutis ; ep , epidermis, numerous in invertebrates, particularly in the lower types, where they are concerned with general tactile sensibility. In man, neurosensory cells are found in the olfactory epithelium and in the retina. Bipolar sensory cells, with free sensory endings in the skin, are present also in invertebrates and are numerous in vertebrates.

The peripheral endings of sensory nerves, as seen in higher vertebrates, may be either free or encapsulated, and the encapsulated fall into three main subdivisions : those ivith thin capsules, those with thick capsules, and those in which the capsule contains tissue elements. This classification of sensory nerve terminations follows that of Huber (T9).

Of such terminations, the free sensory endings appear^ to be phylogenetically the oldest. In such a free sensory termination, the fiber, if medullated, branches repeatedly at the nodes of Ranvier. The smaller branches lose their medullary

30 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

sheaths and the finer telodendria distribute throughout the area, which may be relatively large. The figures presented are from Retzius (’92) and Huber (’00) (see figs. 24, 25). In the preparation from which the latter figure was made, the

Fig. 25. Free sensory ending in the mucosa and epithelium of the urethra of a cat. G. Carl Huber.

peripheral area of distribution was approximately a millimeter square. According to Vitali (’06) and Stefanelli (’15 and ’16), these are not really endings but form an anastomosing, unmedullated network. However, other observers do not agree with this interpretation. Heringa (’18) often found annular endings between epithelial cells. In the lowest vertebrates, these simple sensory endings are the only endings in the skin, as Retzius (’92) demonstrated for the lamprey.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 31

Johnston (’09) found similar endings in the intermuscular septa in fishes. They are found in various regions in higher animals, as for example, in the cornea, meninges, gingiva, adventitia of the blood vessels, and intestines, and in general on surfaces which are only sensitive to great differences in temperature or to painful stimuli, or show general tactile sensibility. Thus free sensory endings are found particularly on those fibers directly concerned in the conduction of such primitive perceptions as deal directly with the preservation of the life of the animal and which are termed protopathic {Head, Rivers, and Sherren, ’05) or vital perceptions {Fabrilius, ’10 ; Ariens Kappers, ’20). These stimuli are often disagreeable ones, being concerned with an appreciation of stimuli more or less injurious in character; consequently the reflexes produced by them are often negative reflexes. The free endings {Sherrington, ’06) act principally as noxireceptive endings {nocere — to injure). However, it would be an exaggeration of this function to consider them only as noxireceptive endings, for lower animals, as well as higher ones, receive stimuli which are agreeable to them and which lead to positive reactions. Thus lower animals often exhibit positive reflexes to stimulations from skin surfaces having free sensory endings ; such terminations must, therefore, be, in part, gratoreceptive.^^ Generally speaking, however, such endings carry impulses in which the element of personal welfare (euphoria) is an important factor ; thus the term protopathic *- or vital sensibility may be applied to all of this group. The work of Ranson (’15, ’30 ; but see Sheehan, Anat. Rec., vol. 55, ’33) and others has indicated that free sensory endings, at least in so far as they receive painful stimuli from body surfaces, are, for the most part, endings of unmyelinated nerve fibers. The work of Windle (’26) and others indicates that endings of this type distributed to the head may be terminations of myelinated nerve fibers. In addition to painful stimuli, a poorly localized (dyscritic, Parsons, ’27) sense of touch is transferred by such fibers and probably also the appreciation of very high or very low temperatures, which, from their importance for the welfare of the body, fall into the category of vital perceptions.

Beginning at least as far down as amphibians and reptiles, more complicated sensory terminations make their appearance. This greater complexity of structure goes hand in hand with a finer differentiation of perception. It implies the termination of nerves in relation to other structures, such as special epithelial cells, connective tissue or other tissue elements, specifically arranged to further in some way the specialized endings of the nerves and thus assist perception.

In forms below mammals, the most highly specialized terminations are found in the tactile end-organs of birds, which are known as the corpuscles of Grandry {Grandry, ’69) or Grandry-Merkel {Merkel, ’75), the corpuscles of Herbst (’48), and those of Key-Retzius (’75-’76). The terminations of Grandry, which are present in the skin of the bill of such birds as the goose or the duck, are composed of two or more cells, surrounded by a connective tissue capsule. The cells are

"This word, introduced by Ariens Kappers (’20), is derived from gratus, meaning useful,

'^’"““From protos, meaning that which appears first, and pathos, meaning that which affects. This nomenclature originated with Head, Rivers, and Holmes.

32 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

regarded by some observers {Izquierdo, 79) as of epithelial origin ; by others {Szymonowicz, ’97) as derived from the connective tissue. Such cells are placed side by side within a capsule and have the opposed surfaces hollowed out so that a space intervenes, in which is the so-called tactile disk, where the nerve fiber comes into relation with the cells. Such cells measure loy. X 50jii according to Slohr (’28), and have a fibrillar structure which has been studied by various observers {Nowick, ’10, and others). The nucleus of each cell lies at the inner border near the tactile disk. To these disks, trabeculae of connective tissue extend from the capsule. Dogiel (’91, ’04), Dogiel and Willanen (’00), Heringa (’17a), and Boeke (’25a) believed that the terminal unmedullated fibers break up into finer fibrils in the disks and penetrate the cells. These become continuous with the intracytoplasmic fibrils of the tactile cells {Heringa, ’17a; Boeke, ’25a; Lawrenijew, ’26, and others) . Other workers considered that a fine, unmedullated fiber forms a pericellular plexus inside the capsule {Dogiel, ’04; Botezat, ’06). Degeneration involves both cells and fibers {Schafer, ’12). The corpuscles of Herbst (’48), similar to the Vater-Pacinian corpuscles {Valer, 1741 ; Pacini, 1836 and 1840) of mammals, are found in the skin of the bill region and in the tongue and palate of water birds (see fig. 24C). Such corpuscles have a thick lamellar capsule of connective tissue and a central core of cubic cells. The fiber passes through the central part of the core to end in an enlargement at its outer end. It may or may not show branching. The Key-Retzius corpuscle {Key-Retzius, ’76), intermediate in type between the Herbst and the Vater-Pacinian, is found in the bill of certain water birds.

In mammals there is a great variety of sensory nerve terminations and only a brief account of certain more generally recognized types can be given here. A primitive type of connection in relation with the epithelium is found in the tactile menisci of the mouse (fig. 26A) and the pig. Three well-differentiated terminations {Dogiel, ’92, ’93) bear great structural resemblances to each other, the differences being mainly in their distribution and size. These are the genital corpuscles, the spherical end bulbs of Krause, and the tactile corpuscles of Meissner (’53; see fig. 26B). All three of these terminations have a thin lamellar capsule into which the nerve fibers enter. Within this capsule, at least in Meissner’s corpuscle, lie cells {Krause, ’82) which are oriented at right angles to the length of the corpuscle and which are termed either tactile cells or “Kolbenzellen ” by various authors (see Stohr, ’28). The number of nerve fibers varies with the size of the corpuscle ; thus the smaller spherical end bulbs of Krause and Meissner’s corpuscles receive only one fiber, larger corpuscles of these two types and the smaller genital ones receive two or three such fibers, and the larger genital corpuscles may ha.ve eight or ten medullated fibers entering them. There is difficulty in determining positively the extent of division of a nerve fiber before entering a large genital corpuscle ; the numbers here given, therefore, are not above question. The medullated sheaths disappear either before they enter or at their entrance into the spherical end bulbs of Krause, but are retained by fibers passing to tactile and genital corpuscles until after their entrance into the corpuscle. In all three types the fiber (or fibers, as the case may be) forms two or three spiral turns within

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 33

the corpuscle and then breaks up into numerous fine branches which certainly interlace and possibly anastomose. Dogiel (’91, ’92, ’93) appears to have shown that terminal branches of the nerve fibers form a periterminal network which is continuous with the intracytoplasmic fibrils. The genital corpuscles {Dogiel, ’93 ; Huber, ’19) are the largest of the three, but vary in size from .04 to .1 mm. in breadth and .06 to .4 mm. in length. They are distributed to the external geni

Fig. 26, A. Tactile disks and tactile cells associated with a tactile hair of a mouse,

B. Meissner’s tactile corpuscle from a human finger tip,

C. Herbst corpuscle from the bill of a duck,

D. Karobshaped, richly looped terminations of the neurofibrils in a Pacinian corpuscle from the mesentery of a cat, E. van der Velde.

talia, such as the glans penis, prepuce, and clitoris. They are sometimes lobulated. The tactile corpuscles of Meissner (Wagner, '52 ; Meissner, '53 ; Dogiel, ’92 ; von Kolliker, ’89-’02; Szymonowicz, ’95; Ruffini, ’02; van der Velde, ’09; Ramon y Cajal, ’09; Botezat, ’12; Schafer, ’12; Heringa, ’17, ’17b, ’18, ’20; Htiber, ’19; Boeke, ’25a, and others) are an irregular peanut shape, varying from .02 mm. to .03 mm. in breadth and averaging approximately .08 mm. in length. They are found in the connective tissue papillae under the epidermis of the skin, being particularly plentiful in the skin of the hands and feet, especially that of the index finger. They also occur at the tip of the tongue, around the lips and eyelids, on the outer surface of the forearm and in the nipple region. The end bulbs of

34 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

Krause also are found in the lip region and in the oral cavity, in the conjunctiva of the eyes, around the cornea, in the region of the external genitalia, and possibly elsewhere. They vary from .02 to . 1 mm. in length ; an average width is .02 mm., although some of them may attain four times that diameter. Larger fibers from the network inside of the genital corpuscles, and from the corpuscles of Grandry and Meissner as well (Dogiel, ’92), may occasionally leave one corpuscle. Such a fiber may terminate in other corpuscles (at least with the genital terminations) and in the skin (fibers of Dogiel). Meissner’s tactile corpuscles, and perhaps other encapsulated nerve terminations, may show an unmyelinated nerve fiber (fiber of Timofeew) as well as the usual myelinated nerve fiber. Dubrenil (Ariens Kappers) advocated the theory that the fibers of Timofeew have to do with painful overstimulations of such corpuscles. It is supposed that their overstimulation in cases of causalgia (Weir Mitchell) causes excessive pain. As this pain disappears after periarterial sympathectomy, it would appear that they carry general visceral sensibility (pain) and are not concerned in higher perception (Le Riche). This, however, has not been confirmed as yet. In the human finger tip, Perez (’31) found peculiar, complicated endings with fibrils to the basal stratum of the skin near a tactile meniscus. It is probable that Meissner’s tactile corpuscles serve for finer discrimination and thus are concerned in epicritic or gnostic sensibility (eucritic sensibility. Parsons, ’27), since they are most abundant in places where such discrimination is best developed.

Examples of sensory terminations with thick capsules are the corpuscles of Herbst and Key-Retzius and the Vater-Pacinian corpuscles (see fig. 26), all of which are more deeply situated than the ones just described. A brief accoimt of the Herbst and Key-Retzius corpuscles has been given earlier. The Vater-Pacinian corpuscle (Vater, 1741 ; Pacini, 1836 and 1840) has a very thick lamellar capsule, the lamellae numbering between twenty and sixty and consisting of connective tissue fibers arranged in concentric layers with a small amount of lymph between each two lamellae. Schumaker (’ll) was of the opinion that an actual capsule was formed around the fluid and that the lines indicating the lamellae were, in ordinary preparations, really double walls where two capsules came together. Plate-like cells, sometimes regarded as connective tissue cells (Huber, ’19) and sometimes as endothelium (Schwalbe, ’87), lie in interlamellar spaces, in which lymph is found also. P acini showed that the outer capsule layers represent a continuation of the connective tissue sheath of the nerve fiber. The inner lamellae have been added later. A nerve 6ber — large and medullated and surrounded by a little endoneurium — enters each corpuscle and retains its medullary sheath until it reaches the core. Here the sheath is lost and the fiber runs through the core, which consists of a dark staining protoplasmic mass, and, after branching several times at the end, forms terminal enlargements consisting of a dense neurofibrillar network and end disks. Sometimes, in passing through the core, the fiber divides into large branches and a modification of the capsule occurs. In preparations from the pancreas of the cat, Relzius (’98b) described small side branches on the main fiber of the Pacinian corpuscle as it passed through the core, each branch terminating in an enlargement. Sola (’99) studied these corpuscles in the mes

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 35

entery of the cat and found that there the fiber breaks up into branches which ascend and show enlargements near the peripheral pole of the corpuscle. Great variations are foimd in the final termination of the fiber within the core. At the end of the main fiber may be a simple enlargement or it may break up into ramifying branches (Sala) ; also, it may continue through one corpuscle, pass out, and enter a second. Dogiel (TO), van der Velde (’07), and others were able, by the use of various special methods, to demonstrate neurofibrils within the main fiber and its branches. Numerous observers (Eohner, ’05 ; vander Velde, ’09 ; Dogiel, ’10) Boeke, ’25a, and others) described fine fibrils leaving these enlargements and entering into the cytoplasm of the core. A satellite fiber (Sokolow, ’99), quite independent of the main fiber, forms a plexus about the core. A rich capillary plexus lies in close relation to the nerve fiber at its place of entrance into the corpuscle. According to Stohr (’28) there are no capillaries within the core. The Pacinian corpuscles are visible to the naked eye and were first described from gross dissection {Valer, 1741). They are widely distributed, being found in the subcutaneous fat, in the deeper parts of the dermis (particularly of the hands and feet), aroimd bones and joints, in the septa between muscles, and even in muscles and tendons. They sometimes occur on nerve plexuses such as the solar plexus, and they are very plentiful along the nerves in the abdominal mesentery and peritoneum (for the course of these fibers to the spinal ganglion see Sheehan, ’32). They have been demonstrated on the nerves to the clitoris, penis, urethra, mammary glands, and nipples, on the intercostal and sacral plexus nerves, and cutaneous nerves to the upper extremities. These corpuscles probably are concerned with the perception of pressure and tension and possibly with stereognostic sense.

Muscles and tendons have (1) free sensory endings, (2) muscle spindles or neuro-muscular terminations, and (3) neurotendinous terminations. Simple inter-muscular endings are present in petromyzonts {Johnston, '08) and comphcated end-trees and nets have been described in the muscular coats of the trachea, stomach, and intestine (Ploschko, ’97 ; Carpenter, ’18). Basket-like sensory endings on muscle were seen by Retzius (’91) in Myxine and by Giacomini (’98, ’98a) in sharks, bony fishes, and amphibians (“terminaison en panier”) ; still more complicated brush-like endings occur in certain fishes. Most workers have not seen muscle spindles in forms below tailless amphibians, although Allen (’17) found them in the caudal heart of cyclostomes. Ranidn y Cajal (’88), Sihler (’95), von Kdlliker (’96), Huber and DeWitt (’98), Dogiel (’02), and Hines (’30) have described muscle spindles in tailless amphibians. Such spindles are typically encapsulated endings containing intrafusal muscle fibers and receive a medullated nerve fiber (or rarely 2) breaking up in the usual fashion and also an unmedullated fiber {Huber and DeWitt, Hines, and others) which is sometimes thought to be motor and sometimes sympathetic in function. Hines (’30) stated that in the sartorius muscle of the frog “the non-medullated fiber is found lacking only after the removal of the abdominal sympathetic chain. She found a motor type of polar ending in certain spindles of the frog pectoralis abdominis. Ranvier ( 78), Sihler (’95), Perrondto (’01), Huber and DeWitt (98), Kulchitsky (24), Boeke

36 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

(’22, ’27, ’30), and Hines (’30) described muscle spindles in reptiles. The dense, two-layered, Wous tissue capsule has from 1 (python, Kulchitsky; boa, Hines), 2 to 5 (alligator, Hines), or 2 to 8 (tortoise, Huber and DeWiit) intrafusal muscle fibers, striated throughout, although with increased nuclei in the equatorial region. A heavily medullated proprioceptive fiber, after entrance to the capsule, divides into two branches which coil around the fiber. A second thinner fiber, unmedullated or thinly medullated, forms a polar ending within the spindle. This latter has been regarded as sympathetic by Kulchitsky (’24) and motor by Perroncilo (’01), Hines (’30), and others. Boeke (’27) believed that the intrafusal fiber of certain reptilian muscle spindles receives both motor and sympathetic innervation. The muscle spindles of birds have been studied by Giacomini (’98a), Huber and DeWitt (’98), and others.

Kerschner (’88), Ramon y Cajal (’88), Ruffini (’92, ’93, ’98, ’98a), Huber and DeWitt (’98, ’00), Baum (’00), Dogiel (’02, ’06), Tello (’22), Langworthy (’24, bibliography. Chap. V), Hines (’27, ’30, ’30a), and Hines and Tower (’28) have described mammalian muscle spindles. Each consists of a small bundle of intrafusal muscle fibers (3 or 4 to 20) surrounded by a connective tissue sheath. In man this ending measures from .08 to .25 mm. in width and from 2 to 10 mm. in length (Baum). These spindles are said to be more numerous in the extremities than elsewhere and to be lacking in certain muscles (for distribution see Hines, ’30). Proximal polar, equatorial, and distal polar regions have been recognized. In the polar regions the muscle is striated and in the distal polar region the fibers appear smaller and more numerous — possibly because of division of the fiber (Schafer, ’ 12) . In the equatorial region the striations are less clear and the nuclei more numerous and the fibers resemble more nearly embryonic muscle. The axial sheath which surrounds the intrafusal fibers is separated from the main capsule by a periaxial lymph space. The main capsule, formed of several concentric layers of fibrous connective tissue, is continuous with the connective tissue over the muscle fibers and fasciculi. These spindles receive an unmedullated fiber (arising from a medullated fiber) which terminates in the polar region as a “terminaison en grappe” (1 to 4 to a spindle). The Henle sheath around such a medullated fiber becomes continuous with the capsule, the myelin sheath extending to the inner axial sheath. The fibers divide several times in their course and terminate in spirals or annulo-spirals or in disks or flower-like endings, the latter representing terminal branches of annulo-spiral fibers. According to Kerschner (’93), Huber and DeWitt (’98), and Huber (’19) they are the “ terminaisons en forme de fleur” of Ruffini (’98). The sensory function of these neuromuscular endings was proved experimentally by Sherrington (’94), who demonstrated that such fibers did not show Wallerian degeneration when the ventral roots, carrying motor nerves, were cut in the monkey and cat. The “terminaison en grappe” (Dogiel, ’02), sometimes described as sensory, sometimes as motor, and again as sympathetic, is considered later (p. 42).

Neurotendinous endings (fig. 28), like neuromuscular endings, contain tissue elements within the capsule. Golgi (’80) first described them, and the terminations are often called the organs of Golgi. According to von Kolliker (’89-’02)

Fig. 27. Neuromuscular terminations. r> j.

^1. Very simple neuromuscular spindle in the cat. oc *c. r j e * i

B. LuromuLuIar nerve end organ from the intrinsic plantar muscles of the dog, from teased

reparation of tissue stained in methylene blue. Hu an

38 NERVOUS SYSTEMS OP VERTEBRATES AND OF MAN

such terminations in man are from 1.28 to 1.42 mm. in length, while their width varies from .17 mm. to .25 mm. That they may be even larger is indicated by

Ciaccio (’90, quoted by Huber, ’19), who

Fig. 28 . Compound neurotendinous sensory end organ from the fascia of the back muscles of the albino rat. Huber and DeWill.

described such a termination with a length of between 2 and 3 mm. The capsule, consisting of several connective tissue lamellae, is continuous at its poles with the connective tissue sheaths around the tendon fasciculi. As in neuromuscular terminations, an axial sheath and a periaxial lymph space are present. The inclosed tendon fasciculi are smaller than elsewhere in the tendon, number from 8 to 15 {Huber and DeWitt, ’00 ; Huber, ’19), and appear embryonic in staining characteristics and the arrangement and number of the nuclei. The medullated fibers branch before and after entering the capsule. After they lose their myelin sheath, they divide still further and then spread out over the inclosed tendon fasciculi and terminate in end disks. In their course over the tendon fibers, short branches are given off which may partly surround the fasciculi. Golgi rSO), Cattaneo(’88), von Kdlliker (’89), Huber and DeWitt (’00), Dogiel (’06), Cilimbaris f’lO), and many others have added to our knowledge of these terminations. It appears probable that the neurotendinous terminations maybe phylogenetically younger than the neuromuscular endings, since tendons, as such, appear to be of more recent evolutionary origin than are muscles. According to Pansini (’89), however, neurotendinous terminar tions are not entirely absent in sela

chians and teleosts, and similar end organs (the end organs of Sachs, ’75, and Rolletl, ’76) have been observed in amphibians and reptiles. Their structure is shown in fig. 28, It is evident that neurotendinous and neuromuscular endings are of great significance as organs for the stereognostic sense ; they make possible a determination of the position of the body and its extremities.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 39

Other sensory terminations in relation to muscle and tendon have been described by Giacomini (’98), Ceccherelli (’04), Dogiel (’06). Such consist of fine branches to the region near the tips of the muscle fibers and to the tendons near their attachment to the muscle. Huber (’99) described a special type of sensory nerve-ending in the extrinsic eye muscles of the rabbit. Huber (’00a) also described a special type of sensory nerve-ending in the tendons of the extrinsic eye muscles of the cat. Small Pacinian corpuscles, approaching in form and structure the cylindrical end bulbs of ICrause; are found in the intermuscular connective tissue septa and joint capsules.

MOTOR AND OTHER EFFECTORY ENDINGS

The motor termination on skeletal muscle is termed the motor plate or soleplate ending. Medullated neuraxes of ventral horn neurons pass out from the central nervous system to the muscle, and, after repeated branchings, terminate as unmedullated fibers within the muscle substance under the sarcolemma, the ectodermal neurolemma of the nerve fiber giving the appearance of being continuous with the mesodermal sarcolemma. The region of penetration, frequently termed Doyere’s elevation, or the sole plate, is characterized by a sarcoplasma containing many nuclei (sole nuclei), which are large and clear and contain one or more nucleoli. Small granular nuclei can also be seen along the terminal fibers (Schafer, ’12). Henle’s sheath appears continuous over the ending and has been called the telolemma (Kuhne, ’86). A single sole-plate ending is found customarily on each fiber. Under the sarcolemma the nerve fiber may break up into smaller branches, and the neurofibrillar elements (first demonstrated by Ram6n y Cajal, ’ll) of the entering fiber may spread out. The amount of branching varies. Around the neurofibrils is the periterminal network described by Boeke (’ll, '21, ’26, ’27, etc.) and also seen by Stefanelli ('ll), Erlacher f'15), Agduhr (’16), Murray (’24), and Iwanaga (’26). Boeke (’26) and Heringa (’31) regarded this substance as transitional or receptive substance (in the sense of Langley) between the nervous and muscular substance. According to Boeke (’26) the periterminal fibrils approach the anisotropic disk of the muscle; however, Heringa (’31) believed he had shown that it is connected with the Y-granules of the isotropic disk. Neither Roefte nor Heringa regarded the periterminal fibrils as neurofibrils (though they stain differentially) but as products of the sarcoplasma.^^ According to Wilkinson (’30a), the periterminal network of Boeke is probably an artifact “due to chemical alteration of the cytoplasm of the sole plate, produced by prolonged fixation in formalin.’’ He presented as evidence studies of these endings by various techniques and WeiVs results (’29) on the effects of formalin fixation on lipoids of the central nervous system. Occasionally a delicate network is formed around a muscle fiber by the terminal branching of a delicate unmedullated nerve fiber which has separated from the sole-plate ending. Such nearlying little nerve fibers are called ultraterminal fibers. Sometimes the network

“This might be considered as additional proof that fibrillar structures may arise in other than nerve cells, as is shown by the neurophanes of ciliates and fiagellates by the Kofoid school {Ariens Kappers).

40 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

may be very rich, as in snakes {Boeke, ’22), but it is found very seldom in man {Boeke, ’ll, and Iwanaga, ’26). Ultraterminal fibers have been seen by Perroncito

(’01), Ruffini (’00), Crevatin (’01), and Cilimbaris (’10).

Bremer (’82 and ’83) traced unmedullated nerve fibers into the sole-plate endings of frogs and lizards. Grabower (’02) noted the entrance of thin, unmedullated nerve fibers into the soleplate ending, but showed that the fibers which he was describing were branches of motor nerve fibers. Perroncito (’02 and ’03) traced immedullated fibers which entered the motor ending and broke up into a number of branches. He was not able to discover their final termination. They had approached the sole-plate ending within the Henle’s sheath of the motor fibers. Perroncito (’02) regarded them as sensory, but later suggested for them a sympathetic character ('03, quoted from Boeke, not available). Gemelli (’05) believed he could trace these fibers of Perroncito (’02) to their ultimate termination where they became continuous with branches of the motor fibers. Botezat (’06) described both medullated and unmedullated fibers to the voluntary striated muscle fibers of birds. In his series of studies on the innervation

«. rectua muscle of a caf t

motor ending (m/) and accessory nerve fil>er (a/.). Lower (*09, '10a, '10b, H;

Iigure from the tongue muscle of a mouse. Boeke, *12, '13, '15, '16, '17, '21, '22,

Motor nerve terminations in striated voluntary

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 41

’20, ’27, ’30) described accessory nerve fibers, unmedullated and with small hypolemmal nerve endings. These he regarded as sympathetic fibers. He did not regard them as homologous to the Perroncito-Gemelli fibers (Boeke, ’13). Boeke’s results are based on studies of a considerable range of material, including that from mammals and forms below mammals and from both embryos and adults. In his work he has employed both normal and experimental methods. Among his attempts to establish the sympathetic character of the accessory fibers by physiologic experimentation, are Boeke' s (’13) operations on eye muscle nerves in the eat. In normal preparations of these eye muscles, Boeke identified sole-plate endings, epilemmal sensory endings, and hypolemmal terminations of his unmedullated accessory fibers, which he regarded as sympathetic terminations. Three and a half to four days after cutting the eye muscle nerves, these latter endings remained intact, although the motor and sensory endings had degenerated. Three weeks after a similar operation, not only had the motor and sensory endings disappeared, but also most of the terminations of the accessory fibers as well as their fibers, although some unmedullated fibers remained. Removal of the superior cervical ganglion, with the eye muscle nerves intact, appears to have led to a decrease, but not to a total disappearance, of the accessory fibers. Soleplate and sensory terminations, of course, were intact in this second type of experiment. These experiments upon the extrinsic eye muscles of the cat are somewhat inconclusive, for when sufficient time had elapsed after resection of the oculomotor, both medullated and unmedullated fibers suffered degeneration, while removal of the superior cervical ganglion, in his opinion, appears to have decreased but did not eliminate the accessory fibers. With regard to the work on the oculomotor, the results of Hines, reported at the 1930 meeting of the American Association of Anatomists, are of interest. She found, in a study of the extraocular muscles of the rabbit, that “when the oculomotor nerve is severed at the base of the brain, only nerves supplying blood vessels remain.” Thus the extravascular innervation of these muscles apparently is from the oculomotor alone. This is substantiated further by the fact that in the rabbit, at least, removal of superior and middle cervical ganglia affected no terminations in these muscles except certain ones on the blood vessels. Boeke and Dusser de Barenne (’19) showed intact accessory fibers to the intercostals along with degenerated motor and sensory fibers, following extirpation of the roots and spinal ganglia of the sixth to ninth thoracic segments on the right side of a cat. Corroborative evidence was offered by Agduhr (’19a) and by Kuntz and Kerper (’24). These latter observers used dogs and studied the eighth intercostal muscle four weeks after the seventh to ninth thoracic nerves were sectioned proximal to the rami commimicantes. They found the motor and sensory fibers degenerated while the unmedullated fibers (accessory fibers) and their terminations remained intact. Various other observers {Aoyagi, ’12 ; Terni, ’22 ; Iwanaga, ’26 (in a few cases) ; Kuntz, '27 ; Hines, in skeletal muscle according to Weed, '27, and others) have described accessory fibers to voluntary striated muscle.

But while a considerable number of workers favor Boeke s idea of a sympathetic innervation of striated muscle fibers by means of his accessory fiber and

42 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

its teniiinations, an almost equal number are opposed to such an interpretation, or at best are unwilling to accept it as proven, Wilkinson (’29) questioned Boeke’s results, basing his criticisms, to a considerable extent, on a study of the latter observer’s preparations. He (’30 ; see also ’30a) followed this by later experimental work on the innervation of the eye muscles of the cat, using in all some twent 3 '-one animals, and varying the time permitted for nerve degeneration from 3 to 55 days. He found that the motor endings degenerated in about three days, while the sensory endings, which were more resistant, persisted for at least five

days and four hours after the operation. Wilkinson interpreted certain small endings described by Boeke (’27) as present on the eye muscles after the cutting of the nerve, as remains of terminations of proprioceptive fibers. Wilkinson (’29) stated that, in his opinion, sympathetic innervation of voluntary muscle is only for the supply of the blood vessels of that muscle. Boeke (’30) rephed to 11 ilkinson s 1929 paper, emphasizing again the presence of accessory fibers. Certain other observers have failed to verify the presence of the accessory nerve fiber of Boeke. Neither Slefanelli (’12) nor Tello (’17) were able to confirm the presence of these fibers. Ramon y Cajal (’25) could not demonstrate such an inner\ation and emphasized particularly the difficulty of distinguishing an unmedullated branch of a motor neuraxis away from its origin from the unmedullated sjmpathctic fibers. Woollard (’27), who studied a great range of normal, pathologies , and operated material by various methods, obtained negative results with regard to a dual innervation of voluntary striated muscle, except in the case of eye muscles ; there he believed he was able to demonstrate unmedullated sympathetic 1 ers o snia n^usc e fibers, while the large muscle fibers were innervated by solep ate endings Thus his results are unfavorable to Boeke’s idea of a sympathetic ° striated muscle. They favor, rather, the idea of Kul snindles of° fho t t i' Tower (’28), in their study of the muscle

to the intnf / to support a sympathetic innervation

Itriat dfinH the innervation of

the blood vessel Postganglionic fibers from the chain ganglia to never sel , : %K but stated that “the author has

muscle fibers A. furth ^ P^oxus to end hypolemmally in skeletal

votonrv Itriateil f f ^^^®tion of the dual innervation of

bttsRd panieuhTv '/i! 241 to 242. Those readers

should refer to the mn “^ question of the existence of the accessory fibers to their illustrations. ^ above, to their bibliographies and, particularly,

“terminaison en^^grapp" ”^has°h sole-plate ending, another termination

’79; //aitrand DeWilt ’’OS- n ^^"7 ^^^‘^"bed by various observers (Tschiriew, tain workers (A'ZSa ’02, and others). By cer

tain workers (A'ldc/iite/-,, 'OA n 1 ’ 1 / ’ 02, and others). By cer rogarded as terminations’ of «’ ’25, “terminaison en grappe’’ were

them is certainly inconclusive^^Otll^^’'^ neurons, but the evidence offered by motor endings and D/W.,; 7>r\o\ ’ have regarded these terminations as

forms of the motor end nlst f’29) believed them to be immature

as. ndmgs, at least very similar or possibly iden

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 43

tical with these, have been described in certain muscles — as for example, in the extrinsic eye muscles — as sensory {Huber, ’99 ; Wilkinson, ’29). It is not impossible that in certain muscles such terminations may be sensory and in others motor (see Hines, ’27) ; if sensory, their position is epilamellar, if motor, hypolamellar.

The above account of the motor or sole-plate ending is based almost entirely on conditions as found in mammals. However, such terminations are present not only in vertebrates below mammals but even in invertebrates. In fact, motor terminations were observed first in the muscles of insects by Doyere (’40), and it was not until about twenty years later that they were described in amphibians by Kiihne (’62) and in reptiles, birds, and mammals by Rouget (’62). A considerable amount of study has been devoted to these endings in invertebrates and lower vertebrates, of which only the briefest mention can be made here.

In crustaceans, usually the unmyelinated fibers branch and terminate in free endings, but may have more highly differentiated terminations suggestive of those in mammals (Rctefus, ’90). In worms, the fibers terminate in very simple, small plates on the muscle fiber, each terminal nerve fiber supplying a large number of muscle cells. Hansen (’81), Heymans (’89), and Burger (’91) have contributed to our knowledge of these terminations. Methods employed in the study of motor endings in mammalian muscles have not been used successfully, for the most part, in the study of insect material and, although perimuscular plexuses (R. Monti, ’91) have been stained by Ehrlich’s methylene blue method, certain of the finer details of the terminations are as yet unknown. In the leg muscles of insects, endings similar to those in mammals have been described ; the innervation of the wing muscles shows marked peculiarities, the branches of the nerves forming a latticework about the whole muscle cell.

The terminations in the voluntary muscle of lower vertebrates have been studied in representative forms by various observers. Retzius (’91 and ’98a) found them to be relatively very simple in Amphioxus lanceolatus. Here the thorny, unmyelinated nerve fibers, often without division, pass along the muscle fibers, bifurcating once or twice near their terminations, and then each fiber supplies a large number of muscle fasciculi. In lower fishes in general, the motor terminations approach in type those found in higher vertebrates, although there is considerable variation in type even in the same animal, as Retzius ( 91) showed in his work on Mjrxine glutinosa. In this cyclostome, he found an elongated type of termination in the more central portions of the muscle bundle, true terminal motor plates toward the ends of the bundle. Cartilaginous and bony fishes have true motor end plates.

Sillier (’95), Ramdn y Cajal (’88, '09, and elsewhere), Cuccati (’88), Dogiel (’90), Retzius (’92a), Huber and DeWitt (’98), Garven (’25), Hines (’27), and Lawrentjew (’28) have studied the motor end plates in amphibians. Ramon y Cajal and Dogiel both described terminations, not only at the ends of the fibers but following the bifurcation of unmedullated collaterals given off the main fiber during its course. The former observer (’09) regarded the peculiar terminations described by Cuccati as fixation artifacts and the terminal arborizations described by him

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 45

knobs (as is the case with the depressor nerves which in part reach the auricle, Woollard, ’26), or may merely divide and subdivide until they disappear from view{WooUard, ’26). Single fibers may twist and turn to orm curious snarls or ball like terminations {Dogiel, ’98), and encapsulated endings have also been demonstrated (Michailow, ’08, and others). Similarly, in the endocardium and in the valves of the heart, exceedingly richly branched, free sensory endings have been seen by Smiriiow (’95), Dogiel (’98), Michailow (’08), and Woollard (’26). Encapsulated endings may be found (Michailow, ’08) in the endocardium.

The sympathetic innervation to smooth muscle is by way of lateral branches from an unmedullated fiber, which branches terminate in small granules (Huber and DeWitt, ’98; Stohr, ’28, and others). Secretory fibers break up into very fine terminal fibrils which often show distinct varicosities and which come into very intimate relations with the gland cells. There is still difference of opinion among workers in this field as to whether or not the ultimate terminations are intraprotoplasmic. It is entirely beyond the scope of the present account to attempt a discussion of the details of their distribution in the various glands. Those desiring such details are referred to the review by Stohr (’28), in Mollendorf’s “Handbuch der Mikroskopischen Anatomie des Menschen,” where brief accounts of the innervation of various glands and a helpful bibliography are to be found. Reference is made here to the work of Anderson (’92) and Rhinehart (’12) on the thyroid, to the accounts of Retzius (’92b), Korolkow (’92), and Huber (’96) for the salivary glands and that of Dogiel (’93a) for lachrymal glands, and to the descriptions of the terminations in the pancreas as given by Muller (’92), Peiisa (’05), and de Castro (’22), and of the endings in the kidney as figured and described by Sjnirnow (’Ola) and Stohr (’28). Pines (’31) reviewed the histologic details of endocrine gland innervation.

The Ectodermal Supporting Tissue of the Central Nervous System

The central nervous system contains, in addition to neurons, certain elements, largely of ectodermal origin, which are not conductive but are supportive and secretory in character and possibly have other functions as well. These nonnervous elements are more important in vertebrates than in invertebrates, and are better developed in higher than in lower vertebrates. They are distinct from the connective tissue, which is mesodermal in origin. For an account of the nonnervous elements in the invertebrate nervous system, reference is made to the recent excellent book by Hanstrom (’29).

The non-nervous tissue within the central nervous system differentiates along three lines, leading to the formation of three types of structural elements which will be considered in the order named. These are the ependyme, the choroid plexuses, and the neuroglia.

In the fetus, certain ectodermal supporting elements of the central nervous system send processes from cell bodies near the ventricle to the periphery of the cord. These processes branch near the periphery and their terminations anastomose or interlace to form the external limiting membrane. These cells are termed spongioblasts, and they are the anlagen for both ependyme and neuroglia. In

46 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

lower vertebrates, such as fishes and amphibians (Huber, ’03, and others), the supporting elements of the nervous system retain this radial arrangement, but in higher forms, during development, certain of the spongioblasts lose their connections with both the ventricular surface and the external limiting membrane and become neuroglia. Others of the cells retain their position along the ventricular wall. These are the forerunners of the ependyme. At first the processes of such cells extend to the periphery but later this connection, for the most part, is lost. The ependymal cells have one or more cilia on the side towards the ventricle.

Fig. 30. To the right of the figure, ependyme; to the left, glia, from the spinal cord of a human fetus of 14 cm. length, von Lenhossek.

The base of the cell is branched but such branches can be traced only a short distance and are soon lost in the gray of the nervous system. In the region of the posterior median septum and the anterior median fissure the processes still reach the surface (Ranson, ’30) in the adult. According to Ramon (’30), the cilia are lost in the adult human. It appears quite certain that the ependyme may have a secretory function, at least in certain regions. Thus, along the ventricular wall of the thalamus in certain fishes, reptiles (fig. 31), birds, and even mammals, there are patches of tall ependymal cells, overlying a rich capillary plexus and often giving evidence at their surfaces of an albuminous deposit (Ariens Rappers, ’21 ; Rendahl, ’24 ; Holmgren and van der Horst, ’25 ; Huber and Crosby, ’26 ; Hocke Hoogenboom, ’28; Charlton, '28, and others). Granules

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 47

can also be demonstrated in ependymal cells, particularly in developing animals. Wislocki and Putnam (’21) have showed that in the area postrema fluids will penetrate from the blood vessels into the ventricle. Frederikse has demonstrated intercellular substance between the ependymal cells similar to that between choroid cells. All of these characteristics show the close relationship between the ependyma and its specialized derivatives, among which may be included the choroid epithelium, which will now receive consideration.

Certain parts of the brain wall — the roof of the fourth and third ventricles and a part of the walls of the lateral ventricles — contain neither nerve fibers nor nuclear masses and only consist of a single layer of epithelium.

This layer, with the vascular pia, constitutes the tela choroidea, from which infolded highly vascular tufts project into the ventricles and form the so-called choroid plexuses. The choroid plexuses formed by these vascularized tufts of choroid epithelium are relatively larger during later embryonic development (Loeper,

’04) than during adult life. This is in conformity with the fact that choroid plexuses never attain as great a size in higher animals as they do in certain lower forms.

The cells of the choroid epithelium are simple cuboidal in type and are held together by a homogeneous intercellular substance (see fig. 32,

Hexanchus). In embryonic or young stages, they are provided, as are embryonic ependymal cells, with active cilia {Studnicka, '00 ; Brookover, ’10, and others; Kramer, ’ll). In older individuals these cilia become less evident and often disappear {Ariens Kappers, ’20). The ventricular part of the cell often is hyalin in character, and the secretory function of the cell is evidenced by the appearance of striations in the cytoplasm and by the frequent appearance of a layer of precipitated albumin on its surface. The protoplasm of the cell shows fine granulations, which first appear around the nucleus. According to Galeolti (’97), these arise from the nucleus but pass secondarily into the cytoplasm, where they are surrounded by a membrane. These basophilic granulations have been termed globuloblasts by Schnopfhagen (’82), and are said to have a delicate lipoid membrane. Besides these granules, acidophile granules {Goldmann, ’13 and ’13a) are present, containing oxydases which are very abundant in choroid cells {Pighini, ’12).

Fig. 31. A highly vascularized region of the ependyme in the diencephalon of a reptile; probably secretory.

48 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

The capillary plexus overlying the choroid epithelium is very rich ; the capillary vessels are rather large, and their endothelium, particularly at the top of the villi, often lies close against the choroid cells (see fig. 32 of Acanthias and Aeipenser). This latter condition is illustrated when the vessels retract through shrinkage, leaving only an empty space between the endothelial lining and the choroid epithelium. In some cases a small amount of mesenchyrnatous tissue from the

Acanthus

Fig. 32. Choroidal epithelium from Acanthias, from the roof of the fourth ventricle of Acipenser, and the roof of the third ventricle of Hexanchus. Note the intimate relation of the capillary walls to the choroidal .epithelium in Acanthias and Acipenser and the lightly stained upper portion of the choroidal cells of Acipenser.

overlying membrane may accompany the capillaries (see Hexanchus). In the meningeal tissue overlying the choroid villi, or even on the ventricular side, are large mononuclear cells (Kobner, ’21). According to Sundwall (’17) these constitute a type of “mast” cell. Their positive staining reaction to pyrrol blue led Ooldmann (’13a ; see also ’13) to term them pyrrol cells. They show a similar positive reaction toward Weigert stains (Ariens Kappers, ’20). They are very clear in lower animals (Ceratodus). Asa Chandler (’ll) found many of these cells, with picric stainable granules, in Lepidosteus. In Amia, Acipenser, Polyodon, and ganoids in general, large masses of these granular cells, together with

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 49

certain pigment ceils, form a gland-like mass in the region of the calamus scriptorius and behind it {van der Horst, ’25, and Tilney, ’27). This glandula myelencephalica {van der Horst, '25) is well provided with blood vessels and is probably concerned with some sort of interchange between the ventricles and the blood.

The cuboidal cells of the choroid epithelium (separated by cement substance) appear to be secretory in character, and many observers regard their function as that of secretion of the cerebrospinal fluid. Moreover, the choroid epithelium may serve as a semipermeable membrane. It is probable that the so-called foramen of Magendie {Magendie, 1825 and 1842), which was once supposed to permit the flow of the cerebrospinal fluid into the subarachnoid space, is merely an artifact,*'* although Rogers and IFesZ (’31) described it in man as a complete defect of the lower part of the ventricular roof. It is lacking in lower vertebrates and recent evidence seems fairly conclusive that normally it is not present in higher mammals and probably not in man {Bland-Sutton, ’23 ; Huber and Huber, unpublished ; and Ariens Kappers, ’29). Whether or not the foramina of Luschka, situated one on each side in the region of the lateral recess of the fourth ventricle, are present is still questioned by some observers. The work of Strong, Greene, and Oliveira (’26) and Rasmussen (’27) appears to favor their presence in mammals. Thus it is probable that the choroid plexus permits the cerebrospinal fluid, and possibly other substances, to pass through it into the subarachnoid spaces and so ultimately to reach the vascular system. It is thus a part of the mechanism for regulating intraventricular and intracranial pressure.

The choroid plexus plays an important part as a protective mechanism, not permitting the passage into the ventricles of certain substances which may be present in the blood, such as some antitoxins (for tetanus and diphtheria), gall pigments, and certain medicinal substances {Meyer and Ranson, ’13). In this respect choroid tissue bears some resemblance to the placenta and has been termed “placenta cerebralis. ’’ Loeper (’04) and Goldmann (’13) have shown that the choroid epithelium, particularly in the fetus, is well supplied with glycogen, which is known as a reserve food.

The greater extent of the choroid plexuses in fishes and in the fetus probably is due to the fact that the ventricular fluid develops earlier in phylogenetic and ontogenetic history than do the subarachnoid spaces. Consequently the secretion of the fluid into the ventricles precedes the transudation of this fluid through the choroid plexuses into the subarachnoid spaces. The glandular character of the choroid is proved by the action of such drugs as pilocarpine upon its secretion. This action is indirect, being brought about by the effect of the drug upon the sympathetic innervation. Where the choroid plexuses have been removed experimentally, as in the frog, the animal soon dies under spastic conditions {Pellizzi, ’ll). Thus it would seem that the choroid plexus is a selective and secretory

“ The choroid ple.xus in the region wherein the foramen of Magendie is thought to occur, situated in front of the calamus scriptorius, is covered by the cerebellum which is attached to the choroid plexus by the pia and arachnoid. On lifting up the cerebellum so as to see the foramen of Magendie, the choroid plexus at this place is easily torn and a foramen is made. In three human brains, carefully examined in this way, the torn-out part of the choroid plexus could be seen attached to the meninges (Ariens Kappers).

50 NERVOUS SYSTEMS OF VERTEBRATES AND OP MAN

membrane, interpolated between the liquor cerebrospinalis internus on the one hand and the blood capillaries of the pia and the extracerebral fluid (liquor cerebrospinalis externus) on the other hand.

Mestrezat (Tl- 12) produced a fluid with a high chloride and a small protein content, similar, at least, to the cerebrospinal fluid. He showed that this fluid placed in a collodion sac showed no change when the sac was immersed in plasma. Weed and McKihhen (T9) found that an increase in the pressure of the cerebrospinal fluid followed intravenous injection of hypotonic solutions while a decrease of pressure followed the use of hypertonic solutions. Fremont-Smith (’27), commenting on the experiments of Mestrezat, emphasized the fact that if the choroid plexus had properties similar to the collodion walls of the sac, it too might serve as a semipermeable membrane, and showed further that variations in the chloride concentration of the cerebrospinal fluid is correlated with variations in the plasma proteins. Moreover, he pointed out that “only methods which affect the capillary pressure in the plexus or the osmotic pressure in the plasma affect the amount produced or the pressure of the cerebrospinal fluid.” Wislocki (’28, p. 1076) also reached the conclusion that the cells of the choroid plexus formed a semipermeable membrane “which serves as a mechanism interposed between blood stream and ventricles.” Very recently Clark (’28), in reviewing the question in connection with his work on the innervation of the choroid plexus, reached the conclusion that “from an unbiased view of the literature, one can safely say that it has not been proven that the epithelial cells of the plexus actively secrete the cerebrospinal fluid. On the contrary, the evidence thus far agrees as well, if not better, with the hypothesis that the choroid plexus is only an elaborately formed semipermeable membrane” (p. 13). Foley (’23) and Forbes, Fremont-Smith, and Woljf (’28) were able to reverse the direction of flow of the fluid through the plexus, although the attempts of Wislocki and Putnam (’21) and of others to do this had been unsuccessful.

In the cat, Clark (’28; compare Slohr, ’28 and earlier) described nerve fibers with sensory terminations to the choroid plexus, arising directly from the dorsolateral part of the medulla. These are the fibers described earlier by Benediki (’73) and are sometimes known as Benedikt’s thirteenth nerve. They supply the lateral tufts of the plexus, according to Clark, while the medial tufts receive fibers from the medulla by way of the taenia. These latter fibers, while sensory to the choroidal epithelium, differ in type of termination from the sensory fibers supplying the lateral tufts, and there is marked difference in the terminations of the adult as compared with those found in new-born animals. All the terminations demonstrated by Clark in the plexus, with the exception of sympathetic endings on the smooth muscle of blood vessels, were sensory in type.

Spongioblasts, as has been stated, form not only the aniagen of ependymal cells but also of another of the central nervous system supporting tissues, the neuroglia cells (fig. 33), under which term are included both astrocytes and oligodendroglia. Those cells which are to become astrocytes lose their cilia. Their cell bodies shift to a greater distance from the ventricular surface, keeping in contact with it only by means of a centrally directed process. A pial ex

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 51

pansiou is present, and consequently bipolar elements are formed which, according to de Castro (’20), may produce other bipolar elements by mitotic division. The centrosome and the Golgi net, originally located toward the central canal, lie opposite the central process {de Castro, '20). When the connection with the central canal is lost, the cell is termed a glioblast or an astroblast {von Lenhossek, ’95a) ; this is the displaced epithelial cell of Ramdn y Cajal (’09). A loss of its connection with the pial surface converts the astroblast into an astrocyte. Penfield (’2S) called attention to the fact that all the various developmental stages of the spongioblasts into adult neuroglia and ependyma are to be found in the adult human nervous system. Thus the primitive ependymal cells or spongioblasts are found in the region of the ventral sulcus of the cord and the median raphd of the medulla oblongata, while spongioblasts with pial attachments occur in the cerebellar astrocytes (the process being termed the fiber of Bergman) and in the subpial neuroglia {Penfield, ’28).

Germinal cells (or medulloblasts), which have shifted away from the ventricular surface during development, may form not only neuroblasts but spongioblasts as T^ell. They may remain for a long time as indifferent cells and during later development become either of these cellular elements. According to Bailey and Cushing (’26), they may retain their indifferent form in the adult. Thus astrocytes may arise from more deeply situated medulloblastic elements. These astrocytes are usually unipolar in type. During development the cells undergo further transformation. The process (sometimes more than one) grows out in the direction of the capillaries and forms trumpet-like endings or sucker-like feet around the vessels. The developing neuroglial cells now acquire smaller processes which pass out in all directions from the cell bodies. As they develop into adult cells some of the astrocytes retain their protoplasmic processes, others develop neuroglial fibrils and still others have both protoplasmic processes and fibrils. The first are called a protoplasmic type and the second a fibrillar type {von Kdlliker, ’89-’02, and Andriezen, ’93). The third type is said to be mixed, since fibrils are found in the more superficial expansions, the deeper expansions remaining typically protoplasmic. The neuroglial fibrils are fine, straight, and unbranched, and are always somewhere in relation to a cell {Huber, ’03, and others) and probably covered with cytoplasm under normal conditions. Retjnolds and Slater (’28) have pointed out that this covering is exceedingly thin “little more than a prolongation of the cell membrane.’’ Such fibers do not pass from the cytoplasm of one cell to that of another. According to da Fano (’06) and Penfield (’28), under exceptional conditions the fibrils may be free from the cell. The fibrillar type is found chiefly in the white matter of the brain and cord ; the protoplasmic type in the gray. There are exceptions to this, however, Spielmeyer (’22, quoted from Penfield, ’28) having demonstrated fibrous astrocytes in the thalamus. . Certain of this type which are partly wrapped around neurons belong to the satellite cells. Large cells with oval nuclei showing little chromatin occur among the protoplasmic type and are called giant cells. Perivascular astrocytes and marginal glia cells represent specialized forms of the fibrous type, while the astroblast, as was mentioned before, finds representation

52 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

in the subpial astrocyte of the adult cerebellum. Both protoplasmic and fibrillar types are said to multiply by amitotic division.

The adult astrocyte, or so-called common neuroglia cell, is an irregularly shaped cell with many branching processes (hence the term spider cell). Its cytoplasm is reticulated, the neuroglial fibrils, according to Del Rio Hortega (T6, T6a), being formed from the reticulum. Granules or gliosomes (see AMcarro, T3, and Del Rio Hortega, T6b) are present in the cell cytoplasm. These respond to certain special stains for mitachondria and so are believed by Nageotle (’20) to be of that character. Eisath (’06) regarded them as responsible for the formation of the fibrils, an opinion with which Fieandt (’10) was in agreement. Pigment granules, due to cell degeneration {Penfield, ’28), are found in astrocytes as in nerve cells. Ramon y Cajal (’13) described the Golgi apparatus as present in young mammals and suggested its probable persistence in a perinuclear position in older individuals, where by present methods it is unstainable. Practically invariably a centrosome can be demonstrated in astrocytes. The nucleus, which may be vesicular {Huher, ’03), has scattered chromatin granules and no nucleoli {Penfield, ’28).

Before closing this very brief summary of the structural relations of the astrocyte, the perivascular and subpial types must be considered somewhat more fully. The terminal enlargements of the astrocytes where they lie up against the pia were beheved by Held (’04) to form a “membrana limitans gliosa superficialis,” and he thought that the sucker-like feet of the neuroglial cells (astrocytes) formed a similar “membrana limitans gliosa vascularis” around the vessels (figs. 33A and B ; see also AriSns Kappers, ’29). These are regarded as shutting off the ectodermal nervous system from the mesodermal supporting and vascular tissue, and the layers between the brain parenchjona and the perivascular spaces form the pia-glial membrane of Schaltenbrand and Bailey (’27-’28). Between this latter membrane and the vessels, a narrow, perivascular lymph space remains — the space of Virchow-Robin. This is the only perivascular space in the central nervous system, except where larger vessels carrying a considerable amount of adventitia have, in addition, periadventitial lymph spaces associated with the vessels. Particularly at the line between the gray and the white matter, the spaces of Virchow-Robin show some enlargement ; these are known as the accessory pial spaces of Held (’04).

Held based his discussion of these membranes on the supposition that the neuroglial tissue forms a syncytium {Held, ’04 and ’09). A somewhat different interpretation of the relations is to be found in the work of Alzheimer (’10) and Ramon y Cajal (’13), where the evidence indicates an independence of the astrocytes. Such cells, according to the latter observer, merely show terminal expansions along the capillary walls and remain independent.

The astrocytes, both protoplasmic and fibrous (for cytogenesis, see Jones, ’32)

Near the membrana limitans gliosa, the neuroglia tissue often has the appearance of containing spaces, and since the nervous tissue is more scarce here, an impression is often given of the presence of fluid spaces. These are probably due to shrinkage but have been termed lacunae marginales and lacunae perivasculares.

’c.'MaUo“of processes of neuroglia cells to blood vessels. Bou,mn.

54 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

are of ectodermal origin and represent the chief supporting tissue within the central nervous system. Since astrocytes do lie in such intimate relation to the vascular supply, the suggestion of Held (’04) that they may be of importance in furthering the nutritive exchange of the nerve cell is pertinent. Reynolds and Slater (’28) have suggested that the protoplasmic type may be more efficient in facilitating the nourishment of the nerve cells and the fibrillar type afford better supporting tissue. Astrocytes have been regarded as serving as insulators. Mawas (’10), Achucarro (’ll), NageoUe (’20), and others have regarded neuroglia cells of this type as providing internally secreting tissue. There is a slowly accumulating body of evidence (see Del Rio Hortega, ’17 ; Penfield, ’28, for example) which would apparently favor such conclusions, but the evidence is far from complete as yet. It has been suggested that'such a secretion may exercise an influence over the general nervous morale.

A special type of interstitial cell is the oligodendroglia, which formed a part of the third element of the nervous system as the term was applied by Ramdn y Cajal (’09). Del Rio Hortega (’21) separated this third element of Ramdn y Cajal into two types, the oligodendroglia and the microglia. Frequently now {Penfield, ’28) the oligodendroglia are placed as a specialized type of neuroglia, and the term “third element” is limited to the microglia. In development, oligodendroglia develop from migratory spongioblasts which do not take on recognizable form until fairly late in embryonic life, although, according to Del Rio Hortega (’21), they are present before microglia appear and are found in both gray and white matter at birth. (For cytogenesis, see also Jones, ’32.)

Oligodendroglia are termed interfascicular where they lie between bundles of fibers over which their processes form a plexiform arrangement, while those that lie close to the cell bodies of neurons are perineuronal satellites, which belong to the general group of satellite cells. According to Penfield (’28), the position of the interfascicular oligodendroglia is in rows between the nerve fibers ; these may be regarded as homologous with the neurolemmal sheaths of peripheral nerve fibers and as concerned in the production of myelin within the central nervous system {Del Rio Hortega, ’22). Oligodendroglial cells, while forming the majority of interstitial cells of the nervous system, according to Reynolds and Slater (’28) are particularly numerous and most granular during the time when myelinization of the nerve tracts is at its maximum. Penta (’31) noted the close relation of oligodendroglia and myelin sheaths.

Oligodendroglial cells are not so large as astrocytes and they have but few processes (none of which terminate in vascular feet, Penfield, ’32) and no fibers. The chromatin within the small nuclei is densely packed. For further details, the papers of Del Rio Hortega (’21, ’22), Penfield (’24, ’25a, ’28, ’32), and Reynolds and Slater (’28) should be consulted.

Oligodendroglia have been regarded as concerned with the formation of the myelin sheaths within the central nervous system and their preservation. Reference has been made in this review to Del Rio Hortega’ s suggestion that the oligodendroglia of the central nervous system are homologous to the neurolemma of the peripheral nerves.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 55

Other specialized cells belonging to the general group of interstitial cells of the nervous system are the microglia or mesoglia cells of Del Rio Hortega, often termed “Hortega cells” since they were first stained completely by his method (Del Rio Hortega, '20). They are small cells, soraefmes oval but sometimes elongated or irregular in outline, the form depending upon the position of the cell. They have small, irregular, darkly staining nuclei, a granular cytoplasm and thin processes which run in all directions and which usually have perpendicular spiny e.xcrescences. The processes do not end in terminal e.xpansions. The cells have no centrosomes and no Golgi apparatus. Although they may contain granules of various sorts, these do not seem to be gliosomes and the cells contain no fibrils. Microglia appear to be migratory elements which occur as satellite cells around capillaries or neurons. They have been referred to as “tercer” elements by Del Rio Hortega, and are supposed to be derived, not from spongioblasts, but from fibroblasts which have migrated into the central nervous system from the pia (Del Rio Hortega, '21 ; Marinescu and Tupa, '25 ; Del Rio Hortega and Penfield, '26 ; Penfield, '28 ; Reynolds and Slater, '28 ; see also Zand, '30 ; Ishikawa, '32), and thus to be mesodermal in origin. Metz and Spatz ('24), however, held them to be ectodermal. In embryonic development the microglia cells do not occur first near the central canal or the ventricles as they might be e.xpected to do if they were of spongioblastic origin. Instead of this, they make their first appearance at the periphery of the central nervous system, particularly in those regions where masses of white substance lie in relation to the pia mater — in the brain, in the regions of the tela choroidea of the third and of the fourth ventricle and the pes pedunculi, and in the cord, beneath the pia in the dorsal and ventral sulci (Del Rio Hortega, '21 ; see also '21a). The microglia enter the white substance first, and first reach the gray substance a few days after birth ; twenty days after birth they are already more abundant in the gray matter than in the white matter (Strong, '25, in Bailey, Strong and Elwyn). Such evidence is regarded as indicating a pial origin for the microglia. Bergman (’27), who has made an e.xtensive study of the microglia, did not express himself with certainty as regards their origin. Metz and Spatz (’24), working with pathologic material, believed them to be ectodermal in origin.

Microglia are phagocytic in function, at least in the amoeboid form (Penfield, '25 and '28 ; Reynolds and Slater, '28 ; Zand, ’30). “Whether or not the ramified form of mesoglia in the normal brain serves any function is purely a matter of conjecture” (Peiifield, ’28).

Amphioxus, which possesses no blood vessels within its central nervous system and has no myelinated fibers, has only ependymal cells and fibers within its cord. In Petromyzon, which likewise lacks intraspinal vessels and myelin sheaths, similar conditions exist, for although forerunners of glia cells without connection with the central canal are present, the peripheral processes extend to the surface to form the limiting membrane of the cord. Real autonomic neuroglia cells do not make their appearance until the plagiostomes, where the cord is richly provided with vessels and with myelin sheaths. Above the plagiostome level, neuroglia elements become progressively better differentiated.

56 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN The Mbsodebmal Supporting Tissue of the Central Nervous System

THE MENINGES

The meninges in lower vertebrates are very different from those in mammals, including man. Although formerly certain observers, misled by superficial resemblances, supposed a dura mater, arachnoid, and pia mater to exist in cyclostomes and plagiostomes, later work has shown this to be incorrect. In 1884 Sagemehl pointed out that a real arachnoid does not occur in fishes, and Sterzi (’00-01) showed clearly that in cyclostomes and plagiostomes only one undifferentiated meninx is to be found, which he termed meninx primitiva. He considered this to furnish the source of the pia, arachnoid, and dura of higher animals. It appears more probable, however, that the real dural membrane of higher animals develops from the mesenchymatous blastema, immediately adjacent to the meninx primitiva. A brief summary of the meninges in the various classes of vertebrates follows.

Among cyclostomes, the relations in Petromyzon fluviatilis are essentially those described by Sterzi (’OO-’Ol). The cord is surrounded by tissue, which, by this observer, was called the meninx primitiva. This is continuous with the sheath over the nerve roots. From this membrane strong lateral ligaments extend laterally into the perimeningeal tissue. The membrane does not send septa into the spinal cord and consequently is easily detached. With this absence of intramedullary connective tissue septa is associated an absence of intramedullary blood vessels, and the food material for the cord must reach it through the superficial glial layer (the limitans gliosa superficialis). Between the endochondral layer of the vertebrae and the meninx primitiva is a broad layer of round or oval mucoid cells which form the perimeningeal tissue.

In the selachians, meningeal septa of connective tissue with accompanying blood vessels grow into the spinal cord from the surrounding tissue, but separated from the nervous elements by the development of a membrana limitans vascularis (membrana gliosa limitans). Thus a real penetration of the meningeal tissue into the nervous system does not occur although the nervous tissue and vascular system are brought into closer relation. The gray substance has a richer blood supply than does the white substance.

“ The external or periosteal dural membrane originates from the endosteal (or endochondral) connective tissue, which, in lower vertebrates, usually lies at a considerable distance from the meninx primitiva and separated from the origin of the real dural membrane by the peridural or perimeningeal tissue. In our opinion, it is better not to consider the so-called external or periosteal membrane of the spinal dura (which follows all the sinuosities of the bone) a part of the dura proper, since, although it fuses with it in the cranial cavity of the adult, in the embryonic condition the two are differentiable from each other (see Gegenbaur, '96 ; Poirier and Charpy, '01 ; Testut, ’ll , Sterzi, '00, and Rauber, ’03). The separation into periosteal and internal layers of the dura spinalis only leads to confusion. This confusion disappears if the so-called periosteal dura is left, where it belongs from nature and origin, with the connective tissue of the endochondrium or endosteum, while the term dura is restricted to the internal dural membrane of other authors.

As a matter of fact, spaces occupied by these septa are comparable to the fissures in the forebrain, with this difference — the former are much smaller and are filled up in greater part by the penetrating tis.sue, while the arachnoid cavities are larger and penetrate more deeply into the brain fissures. A further resemblance is to be found in the fact that in higher animals tlic dura remains outside of the brain fissures and the septa of the spinal cord.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 57

A single sheet of tissue — the meninx primitiva (Sterzi, ’OO-’Ol) — is present ; this is illustrated in Scy Ilium (fig. 34B), in which only the one meninx (d) was found, without differentiation into layers. The four spinal hgaments, already

a b

/

I

h

B

Fig. 34. A. Spinal cord of Petromyzon in situ; xx, space between meninx primitiva and cord, caused by shrinkage j a, perimeningeal tissue j 6, meninx primitiva ; c, lateral ligament.

B. Spinal cord of Scyllium cam’cula, tn siCu; a, lateral ligament; b, endochondrium; c, perimeningeal tissue; d, menin.x primitiva; c, perimeningeal vein; /, radix posterior; g, vertebra; A, arteria ventralis anterior.

described by Sterzi, are very evident in the shark. These consist of two strongly developed lateral ligaments (fig. 34B, a) and a very poorly developed dorsal ligament, as well as a somewhat better developed ventral one. The last two ligaments are merely thickenings of the meninx primitiva ; the lateral ligaments extend out for some distance. Outside of this meninx, between it and the

58 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

endoi’hachis or perichondrium, is a large amount of perimeningeal tissue (c) which, on the whole, has rather looser meshes than in cyclostomes, although it becomes somewhat more dense toward the endorhachis. It is mucoid in character.

The relations in ganoids (Acipenser and Polyodon) are similar to those just described for selachians. They will not receive further consideration here.

Such accounts of the meninges in bony fishes as are to be found in the literature are not in accord. In part, this may be due to actual differences within the various highly specialized groups of fishes. That different descriptions are not due entirely to differences in animals is illustrated by the varying accounts of Sterzi and Sagemehl, which are based in part on the same material, Bachus. According to Sterzi, the membranes in teleosts are similar in character to those in other fishes. There is a single meninx primitiva (which includes the leptomeninx and the dura in an undifferentiated state). This single meninx is separated from the endorhachis by a loose perimeningeal tissue of fatty character.'® Often this primitive meninx can be divided further into two leaves, an outer more or less pigmented portion formed of flattened cells and an inner part, A thickened bundle, the ligamentum ventralis, connects the meninx with the endorhachis at the level of the fifth to the eighth intervertebral disks, while the ligamentum laterale, lying between the anterior and posterior roots, passes from the meninx to the endorhachis through the perimeningeal space {Sterzi). The meninx primitiva has numerous capillaries which run into the cord, especially into the gray substance, and which are accompanied in course by fibrous connective tissue strands.

Sagemehl, unlike Sterzi, distinguished two membranes around the cord — (1) a dural membrane and (2) an underlying tissue — separated by a fissure, which he regarded as the anlage of pia and arachnoid. This latter is a meninx secundaria (Gefasshaut of Sagemehl). It is differentiated into inner and outer portions only in certain places and this differentiation is not comparable to that of the arachnoid and pial membranes of higher forms.

Ariens Kappers (’25 and ’26) called attention to the fact that the relations in teleosts vary with the animals studied. He compared the relations in the small teleost, Girardinius, with those in Lophius piscatorius and found them to be very different in the two forms. In Girardinius the meningeal tissue around the cord and in the medulla oblongata region and the cranium shows no differentiation into two layers and consequently a meninx primitiva, comparable to that of Sterzi’s account, was recognized here. In the lateral regions of the cord he found this membrane continuous with the periosteum with scarcely any intervening space. Dorsally a wider space occurs, filled in by an exceedingly thin and exceedingly wide-meshed perimeningeal tissue carrying large veins particularly on its dorsal side. The relations of the meningeal membrane are essentially the

Sterzi (and also Sagetnehl) regarded the perimeningeal tissue in elasmobranchs and ganoids as mucous in character but as adipose in teleosts. This is not always correct. An Acipenser sturio in the Amsterdam collection has, for instance, a large quantity of perimeningeal fat but mucous tissue has also been seen by us in several teleosts. Both of these tissues are fitted to serve as a buffer substance in a movable inclosure and they may replace each other as such (Ariens Kappers).

c

a 5 c

Fig. 35. A. The cervical cord of Lophius surrounded by meninges, a, dural layer; b, perimeningeal tissue; c, supramedullary spinal ganglion cells; d, internal leptomeningeal layer of the meninx; e, external leptomeningeal layer; /, leptomeninx (meninx secunda).

B. Enlarged photograph of the meninges in Lophius. a, spinal cord; b, internal layer of leptomeninx; c, external layer of leptomeninx; d, dural layer; e, fissure.

59

60 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

same in the medulla oblongata region and in the cranium of Girardinius, except that the relatively large cranial cavity permits the differentiation of a much larger amount of perimeningeal tissue.

Other relations exist in a large specimen of Lophius piscatorius (figs. 35A and B), which was available for study. Here there are large quantities of widemeshed perimeningeal tissue, but the structure of the meningeal tissue lying under it is very different from that in Girardinius. The tissue immediately under this perimeningeal layer (6) forms a fibrous layer (a) which is better developed in some places than in others, but which is always recognizable as a distinct layer. If this layer were separated from the underlying meningeal tissue by a continuous cavity, one might speak correctly of a well-differentiated dura mater. However, such a continuous separation as that described by Sagemehl as a "pericerebral lymphraum” and considered analogous to the subdural cavity of mammals is not demonstrable in Lophius. The relations in this animal are similar to those described by van Gelderen (’24) for early human embryos. This latter author found that the inner layer or the ectomeninx consists, in human embryos of 19.6 mm. length, of a tissue which, because of its greater compactness, contrasts distinctly with the overlying leptomeningeal tissue, although not separated from it as yet by a distinct space. Such a separation has not occurred in 25 to 30 mm. embryos. It is making its appearance as localized separations in embryos 35 to 40 mm. in length. Conditions similar to this latter stage are found in Lophius. In Lophius, the wide-meshed leptomeningeal tissue, although surrounding the whole spinal cord on all sides, is especially evident at the lateral and ventral sides of the medulla oblongata (a fact in agreement with the results of Weed (’16a), who found that the meningeal differentiation occurs first in the basal regions in ontogenetic development). In this animal, the tissue is not a receptacle for the liquor cerebrospinalis extemus as it is in higher animals, but probably is only supporting in character.

The presence of this wide-meshed leptomeningeal differentiation in Lophius and not in Girardinius may be associated, in part at least, with the occurrence of a much larger vertebral canal in the latter animal. In larger fishes there is a greater development of the skull and of the vertebral canal than of the nervous system itself, and a consequent increase in the tissues intervening between the brain and the bony wall. This increase, which is more evident in the perimeningeal than in the leptomeningeal tissue of Lophius — although present in both — indicates differentiation to a stage of development just preceding the appearance of an arachnoidal layer. A large quantity of perimeningeal mucoid or adipose tissue is present, this serving as a buffer tissue, thus permitting great flexibility of movement on the part of these animals. The thin perimeningeal adipose tissue which is present in man, in the space between the actual dural membrane and the endosteum of the vertebral column, may be a phylogenetic remnant of this buffer tissue. Such fatty tissue is lacking in the cranial cavity, which changes relatively less in form relations {Poirier and Charpy, ’01).

The fibrous membrane lying on the leptomeninx is regarded as dural tissue, since the fibrous condensation proves that there is development in the direction

EVOLUTION AND MOKPHOLOGY OF NERVOUS ELEMENTS 61

of a strongly fibrous dura mater. Van Gelderen (’24a) found that this dural lamella develops in Lophius in connection with (and so probably from) the meningeal tissue itself. The open-meshed character of the leptomeningeal part of the meninx is very striking (figs. 35A and B). In many places it is possible to distinguish an external layer (e) from an internal layer (a) (figs. 35A and B). In the former, the cells are almost perpendicular — in palisade arrangement — to the external layer of flat mesenchymal epithelial cells with which it is covered (figs. 35A and B). The meshes of the inner part (a) are less regular than those of the outer (e). The inner layer extends into the septa. It has more blood

Fio. 36. The fourth ventricle with its high choroidal roof in Petromyzon

fluviatilis.

vessels than does the outer part, particularly where it lies directly upon the cord. Although the tissue is fairly wide meshed, particularly in the region showing palisade arrangement, nevertheless it does not appear to be comparable to the trabecular tissue of the arachnoid. True arachnoid trabeculae, that is, narrow, connective tissue bands covered with mesenchymal epithelial cells, are not present. The pseudotrabeculae are branchings of single cells and consequently might well be designated as monocellular trabeculae. They are somewhat similar to the reticular connective tissue of lymph glands. In typical arachnoid tissue, the meshes are wider and the trabeculae less numerous.

There is no doubt that actual arachnoidal cavities are lacking in the lowest vertebrates such as cyclostomes, plagiostomes, ganoids, and teleosts. Consequently no liquor cerebrospinalis externus, such as fills the mammalian subarachnoidal cavities and which in man considerably surpasses in volume that of the liquor cerebrospinalis internus, is present ; but, although this former fluid is absent, it is a noteworthy fact that the liquor cerebrospinalis internus — that is, the ventricular fluid — is very frequently of considerable volume in lower fishes. The amount of this latter fluid is evidenced in plagiostomes (especially sharks)

62 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

and cyclostomes not only by the wide ventricles but also by the great expansion of the choroid plexuses. This choroid membrane may bulge out very considerably over the fourth ventricle in the roof of the midbrain and rhombencephalon, as observed in Petromyzon (fig. 36). Similarly protruding choroid membranes are found in Ceratodus {Bing and Burckhardl, ’04 and ’05 ; N. Holmgren and van der Horst, ’25), in Lepidosteus and in Amia (see Ariens Kappers, ’26) ; the choroid roof of the third ventricle (the so-called parencephalon) evaginates to such a degree that the choroidal sacs, filled with a liquor cerebrospinalis internus,

extend far frontalward as well as caudalward along the outer side of the brain wall (fig. 37). In higher an’mals, especially in mammals in which the arachnoidal cavities and the liquor cerebrospinalis externus are markedly developed, the choroidal membranes no longer have the form of outwardly protuding sacs but, with few exceptions, are folded into the ventricle. Thus a large volume of liquor cerebrospinalis internus may be present in lower animals where the arachnoidal cavities and the external fluid are lacking. This relationship in lower forms is not accidental. The liquor cerebrospinalis externus does not originate in the arachnoidal spaces but from the ventricular fluid, which diffuses secondarily through the choroid membranes into the arachnoidal spaces. Consequently the appearance of a liquor cerebrospinalis externus and of arachnoidal and subarachnoidal cavities is due to the greater development of the functioning of the choroid plexus as a semipermeable membrane in these forms, while its relatively less permeability in lower forms explains the strong protrusion of the choroidal sacs in lower fishes, as well as the lack of proper arachnoidal cavities in these animalsThis phylogenetic process is repeated in the embryological development as has been shown by Weed (’16), who proved that the liquor cerebrospinalis externus is found in the arachnoidal cavities of the pig for the first time in an embryo of 14 mm., although there is fluid within the ventricle in the first stages of ventricular development. Moreover, Loeper (’04) called attention to the fact that the choroidal sacs are larger in the fetus than in the adult.

The meninges are more highly developed in amphibians than in fishes, at least two membranes being demonstrable. The inner of these membranes is

Fig. 37. Cross section through the frontal portion of the thalamus, showing dorsal, lateral, and ventral recesses of the third ventricle in Lepidosteus osseus.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 63

pigmented. Slerzi called them the dura mater and the meninx secundaria. Such a division is only indicated in the tailed Amphibia, but the two are well differentiated in the frog. The dura mater contains lacunae, the further development of which appears to be dependent upon an increased metabolism. The membranes are better developed in the cephalic regions ; caudally in urodeles, only one membrane is found, and this is formed by the union of the two more cephalic layers, being held closely to the endorhachis (periosteum of the vertebrae) by means of connective tissue trabeculae. A large perimeningeal space is found outside of the meninges. This space is not filled with mucus nor with fat, as in fishes, but consists of a series of peculiar little tubes filled with a white substance. They are supposed to be continuations of the saccus endolymphaticus (see Chapter IV) which enters the cranial cavity and reaches the vertebral canal through the foramen magnum, extending as far as the eleventh spinal nerve.

At the level of each spinal nerve, little sacs arise from the major sac and surround the spinal ganglia. The contents of the organ depend upon the condition of nutrition of the animal. The epithelial lining consists of cuboidal cells which may become greatly flattened when the organ is distended. An analogous structure is found in Dipnoi and in teleosts frontally near the fourth ventricle. The significance of the arrangement in any of the forms is not understood thoroughly

Fio. 38. The well-developed dura mater and subdural spaces m Athena (the owl). A, subdural space; B, leptomeninx : C, dura mater.

as yet. , , , . ,

In reptiles the dura is fairly well separated from the underlying leptomemnx or meninx secundaria of Sierzi. This latter does not show, as yet, differentiation into pia and arachnoid and consequently no arachnoidal cavities containing liquor cerebrospinalis externus are present. A wide perimemngeal or peridural space occurs in reptiles. This space contains a large amount of tissue in which are large epimeningeal veins with endothelial walls. The denticulate ligaments are well developed in snakes (Slerzi). Smaller dorsal and ventral ligaments are

^'^ThLura in the avian brain is more differentiated (fig. 38) and the subdural space is more evident than in lower forms. A dura and a secondary meninx are present, and in the latter there is an indication of the beginning of arachnmdal spaces ;hich, although still small, allow injected flmd to spread over a considerable area of the cervical and into the thoracic region, as has been shown by Hansen Pruss (’23). Slerzi regarded the secondary meninx as consisting of an outer endothelial (or mesenchymal epithelial) covering, a middle v^cular, and an

inner portion lying close to » LvVedtVsVnd a few trabecuke"

64 NERVOUS SYSTEMS OF VERTEBRATES AND OF ^N

and a ventral ligament are present. In the lumbar regions there is a fibrous thickening between the two denticulate ligaments and the ventral ligament which is called the ponticuli interligamentarii and which lies in the fissures between the eminentiae ventrales of the anterior horns.

The meninges of the cord show a distinct advance in differentiation in mammals as compared with birds, since the meninx secunda first differentiates definitely into arachnoid and pia in the mammalian forms (marsupials and placentals). The pia lies directly upon the spinal cord and consists of fibrous connective tissue containing blood vessels but not a capillary net {Weed, T4). Pigment cells occur in certain regions of this layer in manamals, including man. Frequently in older individuals, concretions of lime are found. The inner layer of the pia, the membrana intima piae of Held (’09), consists of large endothelial (or mesenchymal epithelial) cells. It lies immediately upon the membrana gliosa perivascularis.

There is no general agreement as to the exact place where the line between pia and arachnoid should be drawn. According to certain observers, the arachnoid may be compared to a spongy sac, the walls of which are interconnected by trabeculae of fibrous connective tissue. Walls and trabeculae alike are covered by a thin layer of simple pavement epithelium, which is variously termed either endothelium, mesenchymal epithelium, or mesothelium {Weed, ’16a). The inner wall lies against the pia, the outer wall against the subdural space, and the spaces between the trabeculae are termed the intraarachnoid spaces. Like the pia, the innermost layer of the arachnoid and some of the larger trabeculae carry vessels which run to the brain and cord.

Other observers {Weed, ’23, for example) regard the arachnoid as consisting of merely the outer layer of the above account and the arachnoid trabeculae, while the inner layer is counted with the pia. In such a case, the openings between the trabeculae and above the inner layer are usually termed the subarachnoid spaces and the arachnoid is considered a non-vascular membrane.

The intraarachnoid or subarachnoid chambers are continuous with the perivascular spaces of Virchow-Robin in the cord, so that there is communication between the perivascular lymph spaces and the cerebrospinal fluid. Consequently, substances injected into the subarachnoid spaces may pass into the perivascular spaces and reach the spinal cord from there {Goldmann, ’13), if they are able to penetrate the membrana intima piae and membrana limitans gliosa. Weed (’23) found it possible to inject the entire perivascular system with hypertonic solutions tlirough the subarachnoid space. This space in the cord is continuous frontally with that at the base of the brain, which is also connected with similar spaces above the cerebellum and the cerebrum, although this latter connection is less easy to demonstrate {Goldmann, ’13). Key and Retzius (’75 “ .V ca-^.c came under obi-crvation where the pia was entirely covered with sucli concretions, yet tlie man, who died of pneumonia, had never complained of headaclic or of pain from the cord region and liad Ki'’en no intimation that he was aware of any .stimulation of the meninges which might have ari'-en from ^uch particle.s (Ariens Kappers). According to mo.st ob-'crver-s, thc.'-e concretioms ari.'c through tlie calcification of cartilaginous plates (.see Obcrslcvier’n Arliciten dcr Neurologic, ’03).

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 65

’76) were the first to demonstrate definitely this continuity of these spaces of the cord and brain.

A considerable number of observers agree that the subdural and subarachnoid spaces do not interconnect under normal conditions. Substances introduced into the latter space do not appear in the subdural spaces [Key and Retzius, ’75-76; TFeed, ’14; Cushing, ^ »

’14). However, Quirwke (’72)

the subdural space entered

Quincke ^ were correct, it would

tion it may be stated that

Leary and Edwards (’33) re garded the subdural space as formed by the apposition of two structures which were developmentally unlike, the lining being formed by ectodermal arachnoidal and mesodermalfibroelastic dural tissue.

In so far as it has been possible to judge, the consensus of opinion appears to be that the subdural space, in reality a

potential space, is anatomi cally closed, and that it is not essential to the outflow of the cerebrospinal fluid.

The dura mater is formed B

of fibrous connective tissue Fia. 39. A. The spinal cord of a newborn cat in siCu.

•ii. XT. nu A .4 dura mater: B, perimeningeal adipose tissue; C, ligamen Wlth both white fibrous and fj^denticulatum; P, arachnoid region,

yellow elastic fibrils. Usually B. The spinal cord of a newborn cat in situ. A, epimenin it is regarded as consisting of 5 ^™”;*' g'rSSUSra 5 .“ VS.?”'"" two layers, but of these only ... , . • i t.

the inner is true dura mater. The outer, which lies in close relation with the

Fig. 39. A. The spinal cord of a newborn cat in situ. A, dura mater; B, pcrimeningeal adipose tissue; C, ligamentu’m denticulatum; D, arachnoid region.

B. The spinal cord of a newborn cat in situ. A, epimeningeal veins; B, perimeningeal adipose tissue; C, ligamentum denticulatum; O, subdural space ; F, spinal veins.

the inner is true dura mater. The outer, which lies in close relation with the skull, is to be regarded as periosteum. In the vertebral canal the so-called intradural space occurs between the two layers. This space, also lined with mesenchymal epithelium, is really a remnant of the perimeningeal tissue and contains many fat cells and the dural sinuses. Arteries and veins are found in the dura, in addition to the great sinuses of the so-called intradural space. The dura

66 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

passes out on the roots, becoming continuous with the perineurium of the nerve trunks.

The fluid of the subarachnoid or intraarachnoid spaces is called the liquor cerebrospinalis externus ; that inside the ventricles of the brain and cord, the liquor cerebrospinalis intemus. The chemical difference between the two is slight (perhaps a difference in the percentage of dextrose). Both fluids, according to Halliburton (’16) and others, contain but little protein, small quantities of salt, and traces of dextrose. They are clear, have a low specific gravity, and contain few cells. They differ from the l 3 nnph of the body in having a smaller percentage of lipoids and fewer cells.

The source of the cerebrospinal fluid has been a matter of much dispute. Early workers {Magendie, 1825, 1842) believed that it was formed by the leptomeninges. Faivre (’53) suggested first that the cells of the choroid plexuses of the ventricles were concerned with its formation. Since then, many observers have brought fonvard evidence favoring these plexuses as a source of the cerebrospinal fluid. Among such workers are Cappelletli (’00), Pettit and Gerard (’02), Meek (’07), Mott (’10), Weed (’14b, ’17a, and elsewhere), and others. The work of Weed and of others suggests that perivascular tissue within the nervous system may also contribute to the formation of the fluid. There is evidence that ventricular ependymal cells in regions other than those of the choroid plexuses may secrete cerebrospinal fluid. This question of the probable secretory function of the choroidal epithelial cells has been discussed earlier (see p. 49) and does not require further discussion here (see pp. 47 to 50). The cerebrospinal fluid which enters the subarachnoid or intraarachnoid spaces collects particularly in the cisterna cerebellomedullaris. The flow is relatively rapid in the region of the cord and to the ventral side of the brain, but slower and less efficient to the upper portions of the cerebral hemispheres (Weed, ’23) as seen in injection experiments.

There has not been general agreement as to the course of this fluid from the intraarachnoid or subarachnoid spaces into the general circulation. In an effort to solve this problem. Key and Retzius (’75-’76) injected a gelatin mass, colored by Berlin blue, under low continuous pressure into the subarachnoid or intraarachnoid spaces of a cadaver. Their results led them to believe that the fluid reached the cerebral sinuses by way of the Pacchionian bodies (arachnoid villi), although a limited amount escaped into the lymphatics associated with the nerve roots and the intervertebral ganglia. Difficulties in accepting this theory arose from the fact that in lower animals and in infants the large Pacchionian granulations are lacking. However, the results of Key and Retzius have been corroborated by Weed, who found that the major drainage occurs along the Pacchionian bodies (arachnoid villi), while a slower drainage into the lymphatic system takes place along certain emergent nerves. In the brain, where there are large venous sinuses and Pacchionian bodies or arachnoid villi, according to the experiments of Quincke (’72), Reiner and Schnitzler (’94), Hill (’90), Spina (’00, ’00a), Lewandowsky (’00), and Weed(’\i, ’14a, ’17a, ’32), the major escape of the cerebrospinal fluid is directly into the venous sinuses of the dura. Small quantities undoubtedly pass along the cranial nerves, particularly the olfactory

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 67

and optic (TFeed, T4a, T7, etc.). In relation to the olfactory the fluid collects first in a perineural cul-de-sac on the lamina cribrosa and then finds an outlet into the lymph vessels of the nose and those associated with other regions of nerve distribution. In the spinal cord region, the cerebrospinal fluid escapes chiefly along the nerve roots into the lymphatic system (Weed, ’14a).

Weed (’17, ’32) and van Gelderen (’24, ’24a) have studied the development of the meninges carefully and reached the conclusion that they are mesodermal derivatives. Harvey and Burr (’26)-® considered that they are partly of ectodermal origin. Leary and Edwards (’33) considered that the subdural space is bounded by ectodermal arachnoid and mesodermal fibroblastic tissue. On the whole the evidence for a mesodermal origin for these membranes seems more conclusive at present, particularly in view of the more recent work of Flexner (’29), in the Contributions to Embryology (110, Publ. 394) of the Carnegie Institute. The first meninx to develop is the so-called entomeninx or leptomeninx which corresponds to meninx secundaria (pia and arachnoid) of Sterzi (’00). Later the ectomeninx differentiates from the surrounding connective tissue, and eventually becomes separated from the endomeninx by the appearance of a subdural space. Fatty tissue and dural sinuses then separate the dura from the periosteum. Finally the entomeninx differentiates into pia and arachnoid. For details of this development the papers of Weed (’17, ’32) and van Gelderen (’24, ’24a) should be consulted. The matter is reviewed in the 1932 account of Weed to be found in “Cytology and cellular pathology of the nervous system” edited by Penfield (Hoeber, New York).

Supporting Elements of the Peripheral Nervous System

THE ectodermal SUPPORTING TISSUE OF THE PERIPHERAL NERVES

The supporting elements of the peripheral nervous system fall into two main groups — one of ectodermal, the other of mesodermal origin. The former group will be considered first. It includes the neurolemma sheath cells or lemnocytes and the capsules of the spinal and sympathetic ganglion cells. To these must be added the myelin sheaths of peripheral medullated fibers, particularly if they are to be regarded either as derivatives of the neurolemma sheath cells or as parts of these cells, as certain observers suppose to be the case. The structure of the myelin and the problems concerned with its development and function have been discussed earlier, and reference is made here to the previous account (pp. 20-23).

The neurolemma sheath (nucleated sheath of Schwann) is usually described as a thin and apparently homogeneous membrane surrounding the myelin sheath of the peripheral medullated fiber and lying next to the axolemma of the unmedullated fiber. Huber (’16, ’17) suggested a delicate fibrillar structure for the neurolemma ; Bruno (’31) described it as singly refractive, isotropic, and having

Harvey and Burr (’26) believed that in amphibians the entomeninx (or leptomeninx) arises from the neural crest cells. Flexner (’29), studying amphibian material, could not confirm their results but derived this meninx from mesoderm.

68 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

some elasticity. One (and in some lower vertebrates more than one) oval or somewhat flattened nucleus may be found in each internodal segment. This nucleus is surrounded by a small amount of granular cytoplasm which shows a Golgi net. As was stated previously, certain observers regard the neurokeratin net, and even the axolemma, as a part of the sheath cell, the latter forming the inner boundary and the neurolemma sheath the outer boundary of the cell. To such workers, the node represents the place of fusion of adjacent neurolemma cells. (A more extended account of this is given on page 20, footnote.)

There has been considerable difference of opinion as to the embryologic origin of the neurolemma sheath cells. Carpenter and Main (’07) and Held (’09a) believed that usually they arise from the neural tube, but certain observers are of the opinion that, in certain cases at least, they may arise from peripheral epithelium such as that of the mucous membrane surrounding the fila olfactoria {Disse, ’97, and Held), or the supporting cells of sensory corpuscles (as, for example, Elmer’s organ, Boeke and de Groot, ’08). Indeed, according to Heringa (’17), they may sometimes be of mesenchymal origin. However, the mesenchyme thus giving origin to sheath cells is probably developed from ectomesoderm, derived from certain regions of the neural crest, and thus in reality of ectodermal origin. Bailey and Cushing (’26) regarded them as derived, at least in part, from the neural crest; Kuniz (’22, ’29) thought them to be partly of neural crest derivation. Harrison (’06) found that when the neural crest is ablated at an early stage in the developing tadpole, development proceeds and the ventral horn neurons send out their neuraxes into the near-lying somites. Such neuraxes are naked fibers, lacking the neurolemma sheaths present in the control. Therefore, Harrison concluded that here, at least, the neurolemma sheaths are from the neural crest.

In normal development the sheath cells grow out with the developing nerve fibers. At first they are not arranged in a single layer along the axis cylinders, but entwine among the bundles of fibers (fig. 40A) in a more or less irregular way. Then they penetrate the bundles (fig. 40B) and finally become arranged around the single nerve fibers (fig. 40C). Only after such an arrangement of the neurolemma cells has occurred does the finer connective tissue, the endoneurium, extend into the funiculus among the nerve fibers. Ml peripheral nerve fibers including those of the sympathetic system — are surrounded by neuroleimna sheaths until such fibers approach their terminations. In the region of spinal and sympathetic ganglia the neurolemma sheaths become continuous with the nucleated capsules over these cells. Such capsules arc composed of a single layer of flattened cells, often termed amphicytes or trophocytes (fig. 22). These are ectodermal in origin. iVs the ncurolemma sheaths approach the central nervous .system, they terminate in such a way that their central ends form a curved Hue along each root, the so-called arc of Frommann (see fig. 21) — not to be confused with Frominaim's lines or crosses, obtained by silver nitrate treatment of peripheral nerves. In the lumbar region, this arc lies at some distance from the cord, while in the cervical region it lies more or less inside of the cord {Rcdlich, ’97 ; i.evi, ’06). 'I'he region of the roots between the termination of the sheaths and their entrance to the cord is relatively less well protected. This fact has been

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 69

used by Redlich as an explanation of the greater predisposition of the lumbosacral cord for developing tabes. According to Michailow (’09a), there is considerable individual variation in the position of the arc of Frommann in man, a fact which

may have clinical significance.

Of late years there has been special interest in the problems associated with the

degeneration and regeneration of peripheral nerves. In connection with this, there has been much interest as to the function of the sheath cells or lemnocytes. Practically all observers would grant that they were a supporting tissue, but there has been, and still is, much difference of opinion as to whether or not they have any further function.

The monophyletic theory of nerve fiber formation regards the nerve process (neuraxis or dendrite, as the case may be) as the outgrowth of a single cell ; the polyphyletic theory considers that such a fiber is produced by the end-to-end arrangement and fusion of a number of cells. In its extreme form, it regards them as autonomous links of a chain, but in its more modified form it regards them, during development, as under the influence of

Fig. 40. Series of drawings illustrating the development of the neurolemma sheath.

A. Intercostal nerve from a 30 mm. sheep embryo, showing perifunicular sheath cells.

B. Sciatic nerve of a 70 mm. sheep embryo, showing wandering of sheath cells into the nerve funiculi.

C. Sciatic nerve of a 24 cm. sheep embryo with intrafunicular sheath cells. To the left, sheath cells amongst the primitive nerve fibers devoid of myelin sheaths; to the right, nerve fibers with myelin sheaths.

those more centrally placed

neurons of which the nerve fibers are to constitute the dendrites or neuraxes in

the fully developed peripheral nerve. Certain observers, who favor the polyphyletic theory, regard the neurofibrils as derived from the protoplasm of the sheath cells or the “Bandfasern” and speak of peripheral autoregeneration {von Biingner, ’91 ; Galeotti and Levi, '95 ; Kennedy, ’97 ; Bethe, ’03, and others). In its extreme form, however, the polyphyletic, or chain theory, is regarded by most observers as disproved, but there are still those who regard the influence

70 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

from the more centrally placed neurons as purely functional in character. Thus it has been thought that under the stimulative influence of central cells (which may send processes into them for a short distance), the sheath cells or lemnocytes may form neurofibrils and thus cause growth of a nerve fiber from other sources than the tip of the neuroblast. Held ('09a ; see also ’29) believed that he could demonstrate that neurofibrils arise in the central neuroblasts and that primarily all neurofibrils arise from these cells and become embedded secondarily in the syncytial cell mass of neurolemma cells. However, he believed it possible that fibrils of this origin, once embedded in the protoplasm of the sheath cells, might show independent regeneration for a short time and for a short distance, even if severed from the central neuron, and that by such local degeneration a nerve might heal per primam, if the ends are inamediately sutured. Held emphasized the importance of the neuro blasts, and unlike Beihe (’03) and Apathy (’08), did not regard the function of the sheath cells as that of neuroformation.

Heringa (’17) believed that the neurofibrils occur in the protoplasm itself of the neurolemma cells, and that the axoplasm or neuroplasm around the neurofibrils is continuous with the protoplasm of these cells. In cross section, this neuroplasm has a reticular aspect, which to Heringa’ s mind indicated an alveolar or foam-like structure, with the more fluid protoplasm filling the minute alveoli. Whether such a structure actually exists in life or whether it is the result of fixation is still a disputed question. Many observers are inclined to regard the neuroplasm as a colloidal mass. In this are more or less dense, gel-like portions which form an irregular anastomosing reticulum, similar to that demonstrated for colloids, rather than a strictly alveolar or foam-like arrangement such as Butschli predicated as the structure of protoplasm. Heringa accepted the idea that the axoplasm is in the form of a syncytium, in the sense of Sedgwick (’95) and Rohde (’16), with fibrils derived from different cells running through this syncytium. The neurofibrils occur in the denser part of the neuroplasm. Traced peripheralward, this latter decreases in amount. After the loss of the myelin sheath, some observers regard the neuroplasm as directly continuous with the protoplasm of the sheath cells, and this is used as evidence that the neurofibrils are formed in and from these cells. The results of Spielmeyer (’17) on regeneration of nerves appear to indicate the local formation of neurofibrils in the protoplasm of the neurolemma sheath cells. Likewise the researches of various workers on nerve terminations (cells of Grandry, Meissner’s tactile corpuscles, sole-plate endings, etc.) suggest that neurofibrils may penetrate other cells and that the neuroplasm of the nerve process may become continuous with the protoplasm of these cells.

In contrast to the views of the polyphyleticists are those of the observers who believe the nerve fiber to be an outgrowth of the neuron only, and the neurolemma to be incapable of forming neurofibrils. Many prominent scientists have favored this view since the time of His (’90). Among the later contributions in support of this view must be mentioned particularly the experimental work of Harrison (’06, ’07, ’07a, ’08, ’10, ’10a, ’24, etc.) and his school and some of the work on nerve regeneration and nerve transplantation carried on during the World War.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 71

Harrison’s work has already been mentioned in connection with the origin of neurolemma. His results also indicated that, in the absence of neurolemma, the nerve process grows out to its termination in the somite, and that it is the direct outgrowth from a single nerve cell. The work on nerve degeneration and regeneration is so important in confirming the monophyletic theory of neuron development that a brief review is included.

The very brief review given here of the process of nerve regeneration is based chiefly on the extended account of Huber (’27). The tips of the central neuraxes show degenerative changes within 24 hours after the injury, as indicated by silver staining {H uber, ’27) . Such changes resemble those found in the degenerating central stmnp. Within this time also, as indicated by the work of Perroncito (’07), Ranson (’12), and others, evidences of regeneration appear in the form of deUcate branches on the sides of both medullated and unmedullated neuraxes. For the most part, these branches disappear secondarily and are to be regarded chiefly as abortive attempts at regeneration. The effective regeneration of myelinated fibers has not gone far before the end of the first week following the injury, at which time many new branches and subdivisions of the neuraxes — as high as fifty per medullated fiber (Ranson) — have made their appearance. The unmyelinated fibers (Ranson, Huber) begin regeneration within about two weeks. 'These new neuraxes terminate in end disks or incremental cones, the size of which varies, perhaps with the amount of resistance encountered by the tip during its growth (Htiber). Such neuraxes may follow a relatively straight course through the old neurolemma sheaths or may form elaborate spirals, the spirals of Perroncito (’07). Through the wound region the fibers are not parallel ; they have an irregular zigzag course, but beyond the wound, if they reach the distal degenerating stump of the nerve, they may assume again a regular parallel course and, if the degeneration of the severed portion is not complete, the downgrowing neuraxes may penetrate the old neurolemma sheaths, several of such fibers sometimes lying within a single sheath (Huber, ’27). Others of these downgrowing fibers may be found in the endoneurial, perineurial, and even in the epineurial sheaths of the nerve.

While these processes have been going on in that portion of the nerve fiber retaining its attachment to the cell body, active degenerative processes are occurring in the severed stump. Several days (2 to 3 in human) after section of a peripheral nerve, structural changes appear in the severed portion, first in the form of granulations or swellings of the neurofibrils (Monckeberg axid Bethe, ’99) or in silver impregnation material, as staining irregularities (Ranson). Then changes occur in the myelin sheath leading to fragmentation of it and then of the neuraxis. The sheath cells increase in size and multiplication of their nuclei (by mitosis) occurs (von Biingner, ’91 ; Huber, ’92). Gradually the sheath cells acquire a phagocytic action toward the broken-down myelin. These sheath cells form the syncytial protoplasmic bands termed “Bandfasern by the German writers (von Biingner). Although they have been variously regarded as of mesodermal, of ectodermal, or of mixed mesodermal and ectodermal origin, the results of modem experimental and embryological investigations appear to

72 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

indicate their ectodermal derivation. Huber stated that their protoplasm is undifferentiated and possibly may bfe embryonic in character. There has been much controversy with regard to the part which these “Bandfasern" play in the regeneration of fibers and the question is not settled as yet to the satisfaction of all. For the details of this dispute and for a discussion of the various theories, reference is made to the works on nerve degeneration and regeneration listed in the bibliography at the end of this chapter. Only a few of the more recent views can be mentioned here. Boeke (’16, ’17) and Ranson (’12) regarded the neurofibrillar strands as always intraprotoplasraic, lying within the “Bandfasem,” and in fact the tendency at present is to regard the growing neuraxes within neurolemma sheaths as having such an intraprotoplasmic position. By certain observers {Kirk and Lewis, ’17), they were regarded as serving as conduits' for the growing nerve fibers, although their presence is not regarded as necessary for such growth. In his monograph on nerve regeneration, Huber said of these fibers; “Faint, longitudinal striation is now and again seen in the ‘Bandfasem’ in silver preparations, but transition stages between the syncytial protoplasmic bands and developed neuraxes have not been demonstrated.’’ Preparations obtained from experiments on nerve transplantation, in which the sheath cells of the transplanted fibers do not proliferate, and where regenerating nerve fibers may grow for very considerable distances through regions from which sheath cells are absent, has led Huber to confirm Harrison’s results — that the presence of sheath cells is not necessary to the growth of the nerve fiber. The weight of evidence at present seems to us to be in favor of regarding the nerve fiber as the outgrowth always of a neuron and the sheath cell as concerned in protective and supporting functions, rather than in the production of conductive elements. Although not directly concerned with the problems here under discussion, the topic of nerve degeneration and regeneration cannot be dropped without some tribute to the great significance of the work carried on in this field both in America and abroad in the period preceding and during the World War. As products of the experimentation and observations of that time have come improved methods of preventing amputation neuromas and valuable contributions to the surgical treatment of nerves severed with loss of substance. The contributors have been many, of whom may be mentioned : Perrondto (’07), Poscharissky (’07), Ramon y Cajal (’08, ’08a, ’08b), Ranson (’12), Huber f’OOb, ’16-’17, ’19, ’20, ’27, ’27a), Boeke (’16, ’17), Dustin (’18), Ingehrigsten (’16, ’16a, ’18), Kirk and Lewis (’17), Elsberg (’19), Huber and Lewis (’20), and others. For a later presentation of his views on nerve degeneration and regeneration, the reader should consult the 1925 contribution of Ram6n y Cajal.

THE MESODERMAL SUPPORTING TISSUE OF THE PERIPHERAL NERVES

The peripheral nerves, like the central nervous system, are surrounded by mesodermal tissue. The bundles of nerves, or funiculi as they are called technically, are surrounded by a dense fibrous connective tissue sheath, continuous centrally with the dura and with the capsules of the ganglia. This perineurium

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 73

forms the most definite sheath and it is through this that the stitches are taken in suturing severed nerves.

The perineurium is continued into the funiculus and between the various nerve fibers as a thin connective tissue lamella, spoken of as endoneurium. The endoneurium also enters the spinal ganglia, forming a binding and supporting tissue for the cells and fibers. Its lymph spaces are said to be continuous with subarachnoid spaces, and substances in the lymph stream may filter into subarachnoid spaces which extend out for some distance with the roots. Various toxic agents may thus enter subarachnoid spaces. In some regions these endoneurial lymph channels, the spaces inside the “guaina sussidiaria” oi Ruffini (’05) or the endoneurial lymph sheath of Retzius (’98), appear to correspond with relatively definite regions of subarachnoid spaces without being in open communication. Recently Kazue Yuien (’28) showed that the lymph current in these endoneural lymph spaces is in a direction opposite to that of the nerve current, running centrally with motor roots and peripherally with sensory roots.

Between and over the funiculi, holding them together and binding them into a nerve trunk, is a looser areolar connective tissue, carrying smaller blood vessels and lymph vessels and containing scattered fat cells — the so-called epineurium. This looser connective tissue relates the nerve trunk to the surrounding structures.

The number of fibers in the funiculi decreases peripheralward until single fibers can be traced. These are surrounded by the neurolemma and a single thin connective tissue sheath with flat cells, forming the sheath of Henle. In terminations, such as the cells of Grandry, where the sensory fiber enters a cell, the sheath of Henle terminates shortly before the point of entrance. Where the sensory fiber enters the core of a sensory corpuscle, this sheath frequently becomes continuous with the capsule of the corpuscle. The Henle sheath of certain sympathetic neurons is believed to become continuous at times with the basement membrane of glandular cells.

Structural Laws of the Nervous System

THE PRINCIPLES OP NEUROBIOTAXIS

Before dealing with the comparative anatomy of the nervous system in vertebrates, we wish to discuss briefly certain principles which appear to deterniine the arrangement of the nervous elements. For many years the factors which have determined the structures of the nervous system — the form of its neurons and their positions and connections — have puzzled the minds of neurologists. Embryologists first gave the matter consideration, but were interested chiefly in the connections between the central nervous system and the periphery, that is, in the factors determining the course of nerve roots. Thus Hensen (’03) assumed that “all nerves originated by an insufficient separation in the primary connections between ganglion cells and their peripheral organs during evolution.” This assumption was the forerunner of the conception that a real separation of the cellular constituents of the body never occurs but that

74 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

its elements remain connected with each other. A similar conception of syndesmism was defended in England by Sedgwick (’95), who stated that “nerves are developments of the reticulum, elongated strands of the pale substance composing this reticulum with some of their nuclei.” At a later time reference will be made to this conception which may contain some truth, .although it certainly does not explain the peculiar selectivity of neuronal connections.

In contrast with the views just quoted are those of Balfour (’76) and His (’89), who showed that the connections of nerves with their end-organs are secondarily acquired. His (’89 ; see also ’87), who in general regarded mechanical factors as the most important ones in embryonic development, considered that the underlying principles determining growth and arrangement of the nervous elements presented a purely mechanical problem. He attempted to solve this problem by assuming that the direction of growth of the nervous processes is determined by paths of least resistance. Dustin (’10) called this the hodogenetic principle. He pointed out that the presence of such preformed and thus guiding paths explained why peripheral nerves, after severance, grow out along the degenerated nerve sheaths of the peripheral stump, while fibers of the central nervous system, where distinct neurolemma sheaths are lacking, practically never reach their functional end station and consequently do not show functional regeneration. However, the presence later of well-established pathways does not necessarily offer an explanation of their formation.

If it be assumed that inherently the developing nerve cell is capable of sending out processes but that the direction of these processes is dependent upon previously existing paths in the surrounding tissue, then the question remains as to what establishes the typical arrangement in this tissue so that functionally correct nervous impulses — and no others — result. Furthermore, the precise character of the functional connections within the central nervous system, where neurolemma sheaths do not occur, remains entirely unexplained by this theory. Another embryologist. Held (’09a; see also ’06 and ’07), proceeding on the assumption already formulated by Hensen and Sedgwick that the nerve cells are ab origine connected by intracellular protoplasmic bridges, believed that he was: able to demonstrate that the fibrils grow into such bridges. As Held himself: recognized, even such a condition would not explain why nerve fibrils grow into, certain of such protoplasmic bridges and not into others. He thought that the] position of the cells (1. c., p. 47) and the directions of their neuraxes (1. c., p. 68)i might be determining factors but not of sufficient importance to explain the^ typical and precise selectivity evinced in the formation of nerve tracts. HelCi\ stated (1. c., p. 270) that the determining principle had, as yet, escaped scientifi<5-] research. A similar remark was made by Harrison (’10), to whom we owe th(;j first researches on the outgrowth of nerve fibers in tissue cultures. This observe;];, stated that “there is nothing in this work which throws any light upon process by which the final connection of a nerve fiber is established.” Harriso^

Though Penfield (’28) has shown that the oligodendroglia surrounds the nerve fibers witlii'ii; the central nervous system, these cells have by no means such a regular arrangement as the sheal'i^ cells of peripheral nerves.

EVOLUTION AND MORPHOLOGY OP NERVOUS ELEMENTS 75

thought that it must be a form of specific reaction between each kind of nerve fiber and its particular end-organ.

Ramdn y Cajal (’93) was the first to hypothecate that tropistic influences play a part in determining the direction of the outgrowth of fibers. He also believed that the nervous elements of the central nervous system e.xert reciprocal tropistic influences on each other. He thought that the connections of the nervous elements are determined by the secretion of attracting and repelling substances and by the sensitivity of the nerve cells to such substances. The m.aterial thus secreted appears in different parts of the nervous system at different periods of their embryonic development and can be formed by ependymal cells ” as well as by neurons. Ramon y Cajal stated that the stage of attraction “coincides with the evolution of the cell.” However, of necessity, such a statement leads to further difficulty, for Ramon y Cajal did not make clear

A

Fia. tl. The neuraxw of iieuroblasts adjacent to a fiber tract grow out in the direct ion of the por[>endicuIariy irradiatuig currents of tlie latter, as indicated by the arrows in the figure. The arrow drawn with the solid line indicates the direction of growth of the activating bundle. Boh.

what factors underlie the evolution of the cells and consequently the secretion of these specific substances. Thus his theory does not offer an explanation of the causes of the local and temporary selectivity of this chemical process nor the factors that produce the different characters of the axons and dendrites (the so-called dynamic polarization of the neuron). Ramon y Cajal himself remarked (in his work on the retina), “Cette th^orie presuppose des conditions pr6alables chimiques et morphologiques tout h fait inexplicables : on peut dire que cette theoric eioigne la difficulte sans cependant parvenir a la r&oudre.”

More important than Ramon y Cajal’ s chemotactic theory — of greater importance even than he himself realized — is a remark of this author concerning the shift of nerve cells during the embryonic development of the nervous system. This remark (unknown to Ariens Kappers when he began his researches) is in perfect harmony with the latter’s observations, and he is more than glad to be able to confirm Ram6n y Cajal’s statements on this point, since he arrived at a similar conclusion by an entirely different method, that is, not by embryonic but by comparative phylogenetic studies. The remark made by Ramon y Cajal runs as follows; “If, during embryonic development, new axons pass to some

Although we are not inclined to attribute any great part in this tropic phenomenon to the central spongioblasts, it is a fact that certain non-nervou.s elements (chief cells, muscular cells, epithelium, and even cicatrices of connective tissue) are able, at certain stages of their dewlnnment, to affect the direction of outgrowing nervous elements.

76 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

region of the central nervous system, ganglion cells may approach these axons in two different ways, either by sending forth long dendrites, or by a migration of the cell body itself” (translated from his textbook, p. 560). Ramon y Cajal mentioned, as an example of the shift of cells, the movement of the superficial layer of granular cells, which at an early period of development cover the surface of the cerebellum but which later on shift into its depths. He also called attention to the fact that the cell bodies composing the spinal ganglia, which originally lie very close to the neural tube, later on move a short distance peripheralward away from the spinal cord. Comparative researches on the medulla oblongata and the mesencephalon {Ariens Kappers, ’07, ’08a, ’20) indicate that changes in position of the cell bodies are determined by a process of taxis or tropism, due to the stimulation of such cells and the bioelectric consequences of such stimulation which determine the selectivity of the neuronal connections and the differences between the dendrites and neuraxes, the so-called dynamic polarization of the neuron (compare with p. 79). By what means these processes are reproduced engrammatically under embryologic conditions, it is not possible to state at present. A similar statement applies to the entire ontogenetic development. Thus the formation of the extremities for walking and grasping can be explained only by use of engrammatic factors, the specific characters of which are unknown as yet. That the electrical potentials arising during evolution {Child, ’21), the sequence of which may be determined by engrammatic factors, may play a part in this process is possible.

Topographic differences are observed in homologous cell groups in the central nervous system of vertebrates. Such differences are most evident in the nuclei of the motor roots of the oblongata {Black, ’17, ’22; van der Horst, ’18, and Addens, ’28 ; for these references see Chapter V), but may also be seen in cells of the spinal cord, the midbrain, and the forebrain {Herrick, ’10 ; Elliot Smith, ’10 ; Dart, ’20 ; for these references see Chapter IX). These differences appear to be caused by differences in the nervous stimulations which reach the nuclei, the topography of the cell groups depending upon the direction from which the greater number or the more dominant impulses reach the cells. Thus we have to do with the process of taxis or tropism, to which the term “neurobiotaxis” {Ariens Kappers, ’08) has been applied, since it occurs in the nervous system during life. A striking example of this process of neurobiotaxis is seen in fig. 42, where the dorsal position of the abducens nucleus associated with the large medial longitudinal fasciculus (vestibular and optic reflex tract in Acanthias) contrasts strongly with the ventral position of the same nucleus in the bony fish, where the medial longitudinal bundle is small but where the ventral optic reflex tracts that influence this cell group develop to a much greater size (the tractus tecto bulbaris : fig. 43). Cases of this type make it clear that an increase in the amount of stimulation of a certain tract does not lead to the approach of all nuclear groups of the medulla oblongata to this tract but only of such definite groups as have a functional relationship with it. Thus such nuclear groups as the cells of the facial nucleus that innervate the gills do not migrate in the direction of this strengthened reflex field since their function is

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 77

not related to that of these optic reflex tracts. There is, then, a selection, and obviously definite relationships are required to determine the location of the nuclear groups. Further, this relation is a functional one and consists in a simultaneous excitation of the enlarged stimulating tract and the motor cells. If the motor cells and the enlarged center or tract have a stimulative interrelation — that is, if the motor cells are in action at the same moment at which a nervous current passes through the enlarged tract (as is the case with the eye muscle nuclei and the optic reflex tracts) — then the cells are attracted by those

Fig. 42. The medulla oblongata of Acanthias vulgaris, van der Horst Note the dorsal position of the abducens nucleus m association with the marked development of the medial longitudmal fasciculus (f I V-) tracts and not otherwise. Anatomically this is expressed by the fact that the nucleus of the abducens nerve shifts from a position near one path for visual reflexes (the medial longitudinal bundle) to a position near another path for visual reflexes (the tractus tecto-bulbaris ventralis) with an increase in the size of the latter bundle. However, the increased number of taste fibers in the medulla oblongata of certain fishes does not have the slightest influence on the eye muscle nuclei, since a functional relation does not exist between the two, but this increase does cause migration of the nuclei of nerves supplying the jaws and gills which make effectual those impulses carried by the taste buds. Thus the positions and relations of the dendrites and cell bodies of neurons of the central nervous system are regulated in conformity with that law of psychology which has long been known as the law of association. According to this law.

78 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

simultaneousness of excitations or their successive occurrence is the leading factor. The early work {Ariens Kappers, ’07) on motor cells and their dendrites led to a more complete study of the course of the neuraxes, and it was supposed (’08, ’08a) that electric conditions (potential differences) existing between the regions where the fibers begin and where they terminate may explain this law,

Fig. 43. The medulla oblongata of a bony fish (Mugil chelo). van der Horst. Note the ventral position of the abducens nucleus in association with the marked development of the ventral optic reflex path (tractus tecto bulbaris,

Ir.t.b.).

namely, that the potential relationship between two regions always underlies the establishment of eonnections between such regions.

The above discussion shows that associated stimulation was found to be the determining factor in both dendritic and neuraxonic outgrowths. In the following chapters, many examples of this phenomenon will be mentioned.

It has been possible (Ariens Kappers) to formulate the following laws :

(1) If several centers of stimulation are present in the nervous system, the outgrowth of the chief dendrites and eventually the shifting of cells takes place in the direction whence the greatest number of stimulations reach the cell.

(2) This outgrowth or shifting, however, only takes place between stimulatively correlated centers.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 79

(3) Temporarily correlated excitation plays a part also in establishing the connections of the neuraxes.

Fig. 44 shows the outgrowth of the dendrite and the final shifting of the cell body in a stimulo-petal direction and the stimulo-concurrent course of the neurite.

The comparative anatomy of the fiber tracts of the central nervous system gives much evidence in support of these laws as leading principles in the formation of tracts. However, the question arises: If associated excitation causes the formation of dendrites and the shift of ganglion cells, as well as the formation of neuraxes, how, then, are to be explained the differences m character of the dendrites and neuraxes ; that is, the dynamic polarization of the neuron?

This is no easy problem. The migration of the dendrites and cell bodies of the neurons toward the center of excitation is a stimulo-petal tropism. The case is different and more difficult with the neuraxis, since this process apparently does not grow toward the exciting center but in the same direction as the nerve current that irradiates from that center and consequently away from the exciting center itself (fig. 46).

That the neuraxis does grow in the same direction as the exciting current and that this current plays an important part in its formation was proved by Bok (’15). Bok formd that when a bundle of unmedullated nerve fibers within the central nervous system grows out and passes neuroblasts in Fig. 44. Changes in the position of the facial

its course, these neuroblasts become nucleus with shortening of the dendrites and length . ^ , ,, „ , enmg of the axons. A, shark ; B, lizard; C, mouse,

activated by the fiber bundle. Such a

neuroblast sends out a neuraxis in a direction perpendicular to the bundle and this neuraxis apparently grows in the direction of the current that irradiates sidewise from the growing nerve fibers (see fig. 47).

Further proof of this is found in the fact that neuroblasts lying in the region of the growing bundle are only activated if the bundle has reached their level. Thus the outgrowth of the processes is like that of the dendrites, where the shift of the cells is determined by the passage of the nervous current. However, the neuraxis grows away from the region of stimulation, its direction of growth

80 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

being stimulo-fugal, or better, stimulo-concurrent (i.e. with the current), while the growth of the dendrite indicates a stimulo-petal tropism. Attention should

be called here to the fact that both the neuroblasts and the neurosensory cells which have no dendrites may shift with the nervous current away from the center of excitation. This is contrary to the shift which occurs later with the adult ganglion cells.

It is clear, however, that the functional connection of the outgrowing neuraxis cannot be determined by this process of irradiation alone. Boh also reaUzed this and came to the conclusion that the final connection or end point of the neuraxis is determined by the chief law of neurobiotaxis, namely, by a

Fig. 45. Cross section of the spinal cord of a larva of stimulative relationship between Acanthius of 3 cm. length. Reiaius. c, commissural ceU; the

m motor cell. •'

neuraxis receives its activation and the neuron with which the new neuraxis connects. The irradiation of side currents from naked neuraxes is unquestionable. An example of it is found in

Fig. 46. The growth of the dendrites (upper figure) and the shifting of the cell body (lower figure) in the direction of the impulses. The course of the neuraxis corresponds to the direction of the nerve current (centrifugal or stimulo-concurrent).

the relation e.xisting between the dendrites of the Purkinje cell and the parallel fibers of the cerebellum (see next page).

The question of selectivity on the part of the termination of the neura.xis will

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEIVIENTS 81

be considered later. When the stimulo-concurrent character of the neuraxis and the stunulo-petal character of the dendrite and adult ganglion cell were once established, the difficulty then arose of finding the physicochemical basis for these phenomena. It may be asked in the first place how it is possible for two opposed tropisms to occur in one and the same cell. Ariens Kappers is inclined to believe that bioelectric influences of the nature of galvano-tropisms have here the chief influence. That these bioelectric factors are carried by chemical substances in the form of ions is evident. Thus the process has an important chemical aspect, as is always the case where electrical phenomena are associated with organic substances. However, these bioelectric influences are not to be regarded as the equivalent of chemotropisms (in the sense in which that word is generally used), since the electrical property of the ions is the determining factor rather than the chemical properties and chemical conditions which accompany these special electrical conditions. The dissociated or ionized stages play the most important part in these growth phenomena just as they do in stimulation and conduction (see also Lillie). Pure chemical or hormonic conditions are not the determining factor because a formation of chemical substances generally leads to more permanent chemical conditions while physiological changes in stimulation and conduction are temporary and of short duration. Moreover, introspective observations of the activities of our own brains compel the conviction that they are primarily dependent upon processes of short duration and that more constant relations are made possible only by frequent repetition.

It is possible, of course, that during embryonic development the bioelectrical conditions are of longer duration than they are in later life. This seems possible (1) because of certain electrical phenomena well known in nerve physiology,

(2) because of the exactly opposite and antipolar character of the tropisms, and (3) because certain collaterals of neuraxes in the beginning very often run exactly perpendicularly to the motor neuraxis. An illustration of this last point is found in mitral cell neuraxes, and likewise in collaterals of peripheral nerves {Speidel, ’32) gro%ving out perpendicularly at the nodes of Ranvier.

The perpendicular position of the dendrites of Purkinje cells with respect to the parallel fibers within the cerebellum (fig. 48) is highly suggestive of bioelectrical fields in connection with stimulative activities, the more so since

Fig. 47. The activation of the neuroblasfs (at the right) through the irradiation of an unmedullated but growing nerve bundle (at the left) is indieated. (See Boh.) Note the horizontal course of the newly formed neuraxes, which grow in a direction corresponding to the irradiation of the impulse. The most proximal neuroblasts have grown the most in correspondence with the growth of the activating bundle. The vertical arrow indicates the direction of the irradiation.

82 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

Addison (’ll) showed that the perpendicular orientation of the Purkinje dendrites, originally diversely spread out, is only completed 10 days after birth in the rat. Other examples may be found in the spinal cord of the lamprey, where the dendrites of motor cells are orientated at right angles to the unmedullated longitudinal tracts (Treljakoff, ’08). The fact that certain of these dendrites reach the periphery of the cord, where they end in thickenings, suggested to Treljakoff that their arrangement is due to metabolic influences, since the spinal

A B

c

Fia. IS. niiistration of the dendrites of the Purkinje cells. From the cerebclhar cortex of the cat. A, section parallel to the fissure; D, section perpendicular to the fissure; C, cerebellar cortex of young bird. Golgi. Note the peripheral thickening of the dendrites and their relation to the pia mater.

cord of the lamprey does not contain blood ve.ssel.s and food materials for the nerve substances mu.st come from the pcrimedullary vessels. Doubtles.s their clo.se relation to the surface of the cord may be explained in this way (see p. 152). It does not .‘■cem probable, however, that the perpendicuhir position with respect to the axis of the cord can be attributed to the cfTcct of the peripheral blood ve,-^‘ls alone, since contact with the surface might ejuite as well be obtained if the dendrites should extend out at different angles. In fact, these dendrites might most ea-ily reach tlu; dr)rsal and ventral surfaces if they were to spread out in a fan-like manner parallel to the longitudinal axis of the cord, .since the dor.s<>- ventral dimensioas of the cord are very .small in this animal. In thi.s

84 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

of this fact in the formation of the nervous system has been confirmed by Child (’21), who also is a believer in the theory of bioelectric potentials as leading factors in the formation of the neuron. Nerve cells situated in the vicinity of the electro-negative excitation center first produce (probably on account of change in surface tension as Marinesco, ’13, supposed) a positive process corresponding to the direction of irradiation of the nervous current from the excitation center. This first offshoot is the neuraxis. As Child has already emphasized, the region of origin of the neuraxis is electrically determined in each cell by the electrical currents of its environment. It seems probable to us that positive ions, such as potassium, play an iruportant part in the growth of the neuraxis, just as different concentrations of electrolytes are of importance in the passage of the nervous current itself, as has been demonstrated by Macdonald (’02), Sherrington (’06), Lillie (’ll), and others. The neuraxis, more than any other part of the neuron, contains at its periphery large quantities of potassium compounds, as Macdonald (’02), Macallum (’05), and Macallum and Menten (’05) — worldng independently of each other and in different ways — have shown. This high percentage of potassium must favor the stimuloconcurrent growth of the neuraxis, the more so on account of its relaxing or lowering influence on surface tension (Macallum) and its membrane-loosening influence (Hober, ’22 ; Kunio Sato, ’29). Just as Hdber (’22) is inclined to consider the action current of the nerve affected by cationic transport at the seat of action, so we consider the outgrowth of the neuraxes as being greatly influenced by such a cationic transport, the outgrowth of the neuraxis being apparently influenced by the action current. This may explain the favorable influence of slight stimulations on regeneration. This is not so strange after all, for it is generally recognized that the function of an organ and its growth are two different aspects of the same or allied processes. The electric galvano-tropic character of the outgrowth of the neuraxis has been confirmed experimentally in serum cultures of embryonic tissue in Harrison’s laboratory by Ingvar (’19, ’20), who found that such an outgrowth may be determined by a constant galvanic current of the strength of two to four billionths of an ampere, density approximately yoW to WotT) nonpolarized electrodes. In this connection mention should be made of the interesting experiments performed on neuroblasts in vitro by Peterfi _a.nd Kapel (’28). These observers noted that if very young neuroblasts were touched by a microsurgical needle an outgrowth of the neuroblast from the side opposite the injury resulted, thus making it probable that an injury current running away from the injury causes this outgrowth. Further, Peterfi (’32) showed that in somewhat older stages dendrites may grow out and the cell may shift its cathodic direction.

Turning now to a consideration of the dendrites, we find that they arise at a much later stage. Somewhat later still, the cell body itself begins to shift in a direction opposite to that of the growth of the neuraxis, that is, toward the center of excitation (stimulo-petal shifting). The stimulo-petal cathodic tropism of the dendrites and of the perinuclear cell protoplasm coincides in appearance with that of the tigroid substance and consequently only takes place when the

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 85

neuron has reached a much more advanced stage of development. This tropism of the dendrites and of the cell itself is in perfect harmony with the phenomena of excitation or contraction at the cathode as stated in Pfluger’s law and is found in any protoplasm. Thus, for the amoeba, Loeb and Maxwell (’96) demonstrated that the animal tends to move toward the field of excitation. In connection herewith, it is .an interesting fact that a muscle, subjected to a slight galvanic current, shows an excitation and contraction at the cathode and a slight rela.\ation at the anode, the latter reminding us of the lengthening of the neura,xis at the anode. That the galvano-tropism of the dendrite is actually opposite to that of the neuraxis- is evident, and the consideration of this outgrowth of the dendrites and shifting of the adult cell body as a tropism in the direction of the negative excitation field raises the question as to what conditions in cell or dendrites favor such a tropism. In seeking an e.xplanation, it becomes a matter of interest that the cathodic shift only occurs after the appearance of the Nissl substance and in those parts of the cell which contain these Nissl granules, that is, in the dendrites and cell body but not in the neuraxis. It may even be said that the shifting of the cells is most evident in those cells that contain the greatest amount of Nissl substance — the motor cells, in which this process was first realized and most studied. The Nissl or tigroid substance, then, is probably associated with the appearance of this stimulo-petal cathodic tropism. The young neurobUist, which contains no Nissl substance, not only fails to show a cathodic tropism, but may even exliibit, to some slight degree, a tropism of the opposite type as was experimentally confirmed by Peterfi (’32). What, then, is the influence of the chromidial substance on this process? It may be that kataphoretic phenomena {Hardy, ’99) and certain facts of colloidal chemistry, which according to Greeley (’04) and von Herwerden ('13a) may be applied to protophismic colloidal suspensions, furnish the solution of this problem. It is known that the Nissl substance during life {Cowdry, ’16, ’24), particularly during the development of the cells {van Bicrvliet, ’00), is in a more or less fluid condition and that it surrounds the fibrillar substance. This chromidial substance is a very complex substance, but it is certain that it contains acid derivatives (compounds of nucleic acids with iron ; see above). Furthermore, excitation involving oxidation increases the acid content. According to Hardy’s researches, acids favor the shifting toward the cathode of such colloidal matter as is suspended in them. The late appearance of the chromidial substance in the cell body, in which it appears only when the neuraxis has already attained considerable growth, would offer an explanation for the late formation of the dendrites. Thus it appears that the developmental character of the neuron may be explained by bioelectric forces and is in perfect harmony with the bioelectric phenomena known in nerve physiology. The growth of the neuraxis depends on the action current, whereas the formation and contraction of the dendrites is homologous to the cathodic outgrowth and contraction of pseudopodia in a galvanic current and is favored by metabolic cell processes.

The part played by the dendrites and the cytoplasm in the assimilation of oxygen, a part already assumed by Golgi, is confirmed by researches on the

86 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

localization of oxidizing enzymes. These enzymes only occur in the dendrites and the cytoplasm of the cell body — not in the neuraxis. Unna’s (’ 16) experiments “ with “rongalit white” likewise show the presence of a large amount of stored oxygen in the dendrites and cytoplasm and so confirm this view. Consequently it is not strange that the dendrites show a nutritive tropism and that this early nutritive tropism of the dendrites and their early tendency to pass toward nutritive surfaces {Tretjakoff, ’08) can later change into a stimulative tropism. This is easily explained by the fact that stimulation increases the assimilation of oxygen, as has been experimentally proved by L. Hill (’00) and as is in perfect harmony with Hering’s thesis that the autonomic (that is, the unstimulated nutritive) absorption of oxygen is enhanced by an “allonomic” (that is, stimulative) absorption of oxygen at the pole where the stimulus enters the neuron. Thus the nutritive and stimulative tropisms of the dendrites are not opposed to each other. On the contrary, the one t 3 q)e of tropism may be transformed into the other type because of their fundamental relation to each other.

MONOAXONISM AND POLYDENDRITISM

Certain of the characteristics of the nerve cells have yet to be considered. First among these is the fact that only one neuraxis (monoaxonism) leaves the cell body, whereas a large number of dendrites (polydendritism) may grow out from the cell body in any direction toward the several centers of stimulation. To explain monoaxonism, return must be made to the theory of the stimulo-concurrent direction of growth of the neuraxes of neuroblasts (fig. 40). Such neuraxes are perpendicular to the activating tract or center. Also, the collaterals of the axis cylinders attain a perpendicular position and both of these facts point to a condition of perfect polarity. If, now, two (or more) different excitation centers simultaneously activate one cell, it is to be expected that only one neuraxis will grow along the resultant line of the two forces, that is, of the two currents, since it is only in this line that an equal influence on both sides of the growing neuraxis is possible. But what will happen if two or more activating centers exert their influence, not simultaneously but successively, upon the same cell body? One of these activating centers will of necessity be first and will cause the formation of the axon hillock. When, however, such an axon hillock has arisen — that is, when a small efferent pole has been formed on the cell body — it is to be expected that the greater opportunity for conductivity offered by this zone will tend to favor the passage of any new bioelectric current set up in the cell body to this region of the cell rather than tend toward the formation of a new neuraxis at some other part of the neuron. Thus the nerve impulse will follow the path where the conductivity is best. In doing this, it will tend to pass in the direction already laid down by the original bioelectric currents. This is the more possible because the original irradiating character of the nervous currents favors their reaching all

“ Speaking of the formation of T-shaped ganglion cells from bipolar cells, Hanslrom’s (’29) conclusion should be mentioned. He concluded that this is caused by a trophic or nutritive migration of those ceils to the periphery of tracts.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 87

parts of the cell, and such currents necessarily reach the axon hillock.^^ The first zone of efferent fibrils formed at the anlage of the axon hillock thus becomes the point of origin of the neuraxis, which, by its unique conductive properties, is to carry the stimuli away from the cell body. So although stimulations coming from other directions might change the course of the axonic outgrowth, it does not affect its origin, if once established, nor create a new a.xon hillock.

The conditions underlying the formation of the dendrites are altogether different from those producing neuraxis formation, since the whole cytoplasm is sensitive to stimulation. Thus when a stimulus appears in the vicinity of a cell, the part of the protoplasm nearest to such a point of stimulation will receive the impulse and may shift in the direction of the stimulus. Since the protoplasm is much alike throughout the celt body and the Nissl substance is present in the whole cell (with the exception of the axon hillock) this process of shifting is, of course, not restricted to any one field, and is peculiarly favored in no place except the area nearest the stimulation. Centers of excitation situated elsewhere may, and even must, cause new protoplasmic outgrowths in their own directions. In connection with the supposed r61e of the Nissl substance in the stimulo-petal tropism of the cytoplasm and dendrites, it is interesting to note that at places where dendrites bifurcate, a considerably larger amount of Nissl substance is usually found (cone chromidial de bifurcation) than elsewhere in the dendrite.

Thus monoaxonism is found to be a result of the special character and the polar localization of the anodal tropic part of the cell, whereas polydendritism is based on the fact that the cell protoplasm contains no places peculiarly favored for receiving stimulations and everywhere is able to give a cathodic tropism.

SELECTIVITY IN TUB CONNECTIONS OF NEURONS

It has already been shown that the anatomical relations occurring within the nervous system and the factors underlying cell shifting point clearly to the fact that the relationships which determine connections are synchronic or immediately successive functional activities. This fundamental law of neurobiotaxis not only shows that the well-known law of association in psychology is a neurobiotactic law, but it also indicates how wonderfully polarized is the whole process of tract formation and how well this process fits into the class of bioelectric phenomena. In explaining selectivity, the following points must be emphasized. It may be assumed that a state of excitation once set up in a budding neuraxis proceeds rapidly, and that a strong current of internal positive (external negative) potential reaches the budding cone of this neuraxis. That this is more than mere supposition has been indicated by the researches of Scaffidi (’10),“ who proved that if a This place also appears to contain diplosoines. As it does not seem reasonable to suppose that the position of the diplosome (which position is extremely variable) can determine the “working" point of the current, one must conclude that the place of the centrosome is bioelectrically defined by the influence of the radiating current. Such a conclusion is of importance from an erabryological standpoint.

“L. 0 ., p. 345: “Die Schnittflachen der Nerven, welche nach der Durchtrennung m dlu bleiben, sowohl nach wcnigen Minuten als nach verschiedenen Monaten fast immer positivereagicren, u.s.w. Die positive Ladung der Schnittflachen verschwindet rascher nach der einfachen Durchtrennung, d.h. wann Versehmelzung folgt.”

88 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

nerve which has been sectioned starts to regenerate, its budding cone shows a positive potential current which may be called the regeneration current or growth current. That nerve growth and nerve function are closely interrelated has been pointed out by Coghill (’29, and elsewhere). If it may now be assumed that a number of nerve cells are situated in the neighborhood of the budding cone, one of which cells is already functioning while the others are not, it will be evident that the cell which is functioning is the only one that presents a selective point to the budding neuraxis. The potential which runs along the budding neuraxis can find its natural counterpart only in the already ionized cell and not in the cells that are not stimulated and consequently are indifferent objects, not presenting any predilection for stimulation. The raised surface potential, which appears near the cell shortly after a stimulation and which makes its appearance inunediately following the stimulation, probably plays the principal part in establishing the connection between the growing neuraxis and the cell or dendrite with which it is to come into relation (see fig. 46 left side of the cell body). In other words, the growth current of the budding neuraxis will find a favored direction for its growth to a neuron which has been set in action just previously. In the physiology of nervous currents there are several facts which favor the supposition that an immediately prior excitation exercises a direct influence upon the course of other excitations occurring in the nervous system. Thus Sherrington (’06) emphasized “that the threshold of a reflex is lowered by the excitation just preceding its own.” This fact also explains why a connection just established between two neurons (a synapse) “is an apparatus for coordination and may introduce a common path” — that is, of several excitations (1. c., pp. 184-351). This principle of selectivity, based on the influence of a just preceding functional state as a center of attraction for other nervous currents or budding neuraxes, is of great use in making clear the connections of the nervous system with the muscles. Bok (’17) emphasized that the connection of certain muscles with widely separated parts of the central nervous system has to be explained by the fact that the tonic change of the muscle (since the muscle formation precedes the formation of the nerve roots) acts tropistically upon the central nerve fibers. A contraction (or an analogous embryonic condition ; for example, the embryonic growth of a muscle “®) produced by some external non-nervous condition may attract action currents which chance to be present at that moment in the central nervous system. This attraction may lead to the outgrowth of processes toward that muscle. In accordance with this conception is the fact that the first motor roots, as they occur in invertebrates and as Coghill (see bibliography for Chap. II) found them in larvae of amphibians, originate as collaterals of longitudinal tracts within the spinal cord. Only later do the special neuroblasts which lie near such longitudinal tracts become activated and form neuraxes which replace these collaterals and constitute the real motor roots. It follows that originally the myotomes attract action currents, or analogous currents, present in the central nervous system.

As mentioned before, cations, such as potassium, probably play an important

That rapidly proliferating tissue attracts axons or collaterals was shown by Ramdn y Cajal (’00) in proliferating granulation connective tissue.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 89

part in the growth of the neuraxis, just as they do in the action current. In this connection must be emphasized the importance of the researches of Howell (’06), and particularly of Zwaardemaker (’19), regarding the r61e of potassium in the transmission of stimuli and in growth in general {Lewis and Lewis, ’12), It is probable (see also Detwiler, ’26, and Hoadley, ’25) that, in the embryo, proliferation of muscle tissue exerts an influence similar to the functioning of that tissue. Proliferating muscle tissue attracts the irradiations of the nervous currents and thus draws toward itself the outgrowths from the spinal cord. Proliferating connective tissue attracts collaterals of the roots and even of the lateral funiculi (experiments of Ramon y Cajal, ’00, ’ll). Child (’21) and Hoadley (’25) have called attention to the probability that, during evolution of tissue, electrical conditions occur which are very similar to those occurring on stimulation. However, the sequence in which this embryonic muscle proliferation takes place is a problem, the solution of which must be left to the myologists.

It is evident, of course, that if a nervous connection is once established, nervous stimulation must have a great influence over the further development of the limbs and other organs. That such is the case has been proved experimentally by Hamburger (’02, ’04), W eiss (’26), and others. This effect of the establishment of a nervous connection is not confined to motor neurons alone, but is equally true for the sensory cells, as has been illustrated in connection with taste buds and Meissner’s tactile corpuscles {Olmsted, ’20 ; May, ’25). Burr (’16, ’16a, and ’20), Detwiler (’23, ’23a, ’24, etc.), and Stone (’24) showed that nervous tissue, such as placodes, may be transplanted to various regions near the central nervous system of embryos and will establish new connections with centers with which they were formerly entirely unrelated. A transplanted part of the olfactory placode grew out into the dorsal thalamus in one of Burr's experiments. May and Detwiler (’25) have obtained similar results in transplantation of the eye. Thus, in one of these experiments, an eye was transplanted near the medulla oblongata and became connected with the medulla oblongata center. These experiments are of great importance, although they are not to be regarded as leading to the conclusion that under normal circumstances selectivity depends only on proximity. Such experiments prove chiefly that any state of embryonic growth or regeneration may activate and direct the growth of nervous tissue. This power of activation and growth is to be regarded as a general tendency of growing tissues. According to Burr the influence exerted is analogous to that of mitogenic rays. The special problems of brain anatomy, the special relations underlying the distinct selectivity that give it its functional value, are approached more closely in the experiments of Detwiler (’20, ’22, ’23, ’23b, ’24, ’26, etc.) and Hooker (’15, ’16, ’17, ’23, and ’25). Detvnler transplanted a limb a considerable distance (4 or 5 segments) caudal to its natural insertion and even then saw the root fibers to it arise from the normal segments. Detwiler (’23b) and Wieman (’25) cut out a part of the embryonic cord, reset it in the cord in the reversed way or at an angle (sometimes with other tissue in between), and observed the behavior of the formerly descending and ascending tracts or root fibers. The first thing observed here, as in the previously mentioned researches of Burr, Detwiler, and May, was

90 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

that the outgrowth of a bundle was primary to neuroblastic proliferations, a result which appears to confirm Bok’s theory of the stimulating influence of the fibers on neuroblasts. Hooker found further that there was a marked tendency on the part of the regenerating fibers to avoid entering the opposite (that is, the

reverse) wound surface in a reset piece, and Wieman found that the development of the ascending tracts depended on a prior formation of descending ones through the operated segment. Such experiments as these are certain, to show new aspects of the problems of nerve growth.

That funetional fasciculation relationship is an important factor in determining the course of neuraxes and that simultaneous fimction plays a large part in the process of “fasciculation” (joining of neuraxes in one bundle) is most evident from the course of the optic nerve fibers in higher mammals and man. Whereas in fishes and all vertebrates below the mammals there is a total decussation of the optic nerves, in primates there is a hemidecussation, the temporal fibers of one eye running together with the nasal fibers of the other. This change in the course of

Fig. so. Total decussation of the optic fibers in a fish with little more than panoramic vision. Note the convergence in the optic tectum of those optic tract fibers, the visual fields of which join or overlap.

Fig. 51. Semidecussation of the optic fibers in man with binocular, convergent vision. Note that those fibers of the visual fields that overlap join in their course to the lateral geniculate nucleus (Gen.).

the optic nerve corresponds exactly with the collaboration of the nasal visual field of one eye with the temporal visual field of the other in producing convergent binocular vision (see fig. 51), which only occurs in mammals. A more simple example of the influence of simultaneous stimulation on the central arrangement of nerve fibers is seen in the fact that the cutaneous sensory fibers of the vagus.

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEIVIENTS 91

after entering the bulb, immediately join the cutaneous sensory fibers of the descending trigeminal, whereas the taste fibers of the vagus join the taste fibers of the glossopharyngeal in their final course. So it appears that neurobiotaxis is a very active principle also in the collective arrangement of the nervous pathways. It may be of interest to discuss . —

briefly the cellular migrations oc- ^

curring in the sympathetic system. po.g. /

In the ontogenetic development /

of this system various migrations

of cells are observed, for which it 0 is not easy to furnish explanation. ^

According to the recent researches

of van Campenhout (’30, ’30a) and

Terni (’31) on the embryonic de- sp-g. ^ — v.

velopment of the sympathetic /

chain and its ganglia in the chick, ^ /

the cells which probably arise ^ /

from the neural crest (although l—^ /

according to Kuntz, ’29, certain

cells migrate along the ventral Fig. 52. Scheme of the development of the postganroot) first form what is known glionic neurons of the sympathetic nervous system (po.y.)

. , . ., , j 1 from the same primordium as the spinal ganglion cells

as a primary chain situated along (sp.g.) and their neurobiotatic migration as a consequence

cells migrate along the ventral Fig. 52. Scheme of the development of the postganroot) first form what is known glionic neurons of the sympathetic nervous system (po.y.)

. , . ., , j 1 from the same primordium as the spinal ganglion cells

as a primary chain situated along (sp.g.) and their neurobiotatic migration as a consequence the aorta, which location may of f**® postganglionic a.xon reflex (fully drawn arrow). _ .j . , , . , . The central reflex arc over the spinal ganglion cells and

evidence an interaction between preganglionic neurons (pr.g.), indicated by the dotted these cells and the arterial blood, arrow, is used less. The peripheral dendrites of the spinal Thn Ir. ganglion cclls are not drawn.

^ 1 • . , • V X xiic uru uver iiic auniui kuhkiiou cciia anu

evidence an interaction between preganglionic neurons (pr.g.), indicated by the dotted these cells and the arterial blood, arrow, is used less. The peripheral dendrites of the spinal The next step in the development

consists in the formation of the secondary or the final sympathetic chain, initiated by the budding in a central direction of cell groups from the primary chain. According to van Campenhout and Terni, this budding in a central direction coincides with a considerable outgrowth of preganglionic fibers that link up with these buds ; according to van Campenhout this shifting is a neurobiotactic process, the cells growing out into the direction of the impulse that reaches them through the preganglionic fibers. What is left of the primary sjmipathetic chain forms the juxtaneural and other peripheral ganglia of the sympathetic system. These cells do not shift in the direction of the effectors. However, as nerve cells shift in the direction of impulses, this seems to show that the majority of impulses acting on the juxtaneural postganglionic cells come from the effectors with which these postganglionic cells are connected. However, since these connections are axonic connections, this implies, if the explanation be correct, that

the majority of the reflexes acting on the more peripheral ganglia of the sympathetic system are axonic reflexes of the character described by Langley and Anderson (’95). The dominance in the viscera of axonic reflexes over central reflexes would seem to be in harmony with the scarcity of visceral afferent fibers in comparison with somatic afferent fibers, approximately only 5 to 8 per cent of the nerve fibers to the intestine being sensory (afferent) fibers (Ranson, ’31).

92

NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

Aiiothor fcaturo on vvliicih ncurobiotiictie relations per!iai)s may j'ivc some light is the synaptic coiKlilion of the interneuronal eonneetions. In this relation, consideration should he given to the fact that impulses may pass the interneuronal connections in one direction oidy, that is, from axon to cell or dendrite and not from cell or dendrite to axon. In order to explain this f.ninjlcy and Andcrmni (’92) and Shcrrintjlon (’OG) accepted the pre.sence of a synaptic membrane between these two parts of the connection, a membrane that could be piussed in one direction only by nerve impulses. However, the jjre.sence of an irreversible membrane has not been demonstrated in the central nervous system. It would seem that the irreversible character of the synapse may be explained by the opposite neurobiotactic characters of the axon and the cell dendrites. .Since the growth of the axon is stimulo-concurrent and the growth of the dendrites and cell body stimulo-petal, the normal transmission of the impulse must neces.sarily bring both nearer to eacli other, while a reversetl transmission (if possible) apparently would draw them apart and finally l)reak the connection (see fig. .o2). .Although the consideration of these facts may not suHice to explain the irreversible character of the synapse, it at least s1k)ws that the irreversibility of the synaps,e is in perfect harmony witli the opposite stimulative tropism of a.xon and dendrite.

UKSUMK CONCI.USIO.NS

The phylogenetic differences in position of the cells of the motor nuclei suggest that the positions of the dendrites and the cell body are detennined by the impulses which reach them. Further researches show that the determining influence is evident only in such cells as have a previous or indirect afiinity for these impulses or lie in a region where these impulses accumulate. Tliis afiinity consists of simultaneous or successive states of action (stimulative correlation). Consequently a law governing nervous arrangement can be laid down. This law has long since been acknowledged to be one of the major laws governing the development of our mental capacities, that is, the law of mental association.

The acknowledgment of correlative function as the fundamental fact determining the arrangement of tlie cells and their dendrites raises the question as to whether the same law may be in effect in determining the final courses and connections of the neuraxes. A careful comparison of the regions where such paths begin and terminate shows that here, also, an associative affinity can be pointed out and that this affinity determines the place that the neuraxis will end. Under this fundamental law — that neurobiotactic processes occur between correlated systems — the tropisms of the dendrites and cell body take place in a direction opposite to that of the nerve current, that is, toward the center of stimulation. They are thus stimulo-petal, while the course of the impulse over the neuraxis is in the same direction as the direction of the axon current, that is, stimulo-fugal, or more correctly, stimulo-concurrent. That the development of the neura.xis is nevertheless a consequence of the stimulus has been proved by Bok (’15a), who showed that irradiating impulses activate neuroblasts in such a way as to form a neuraxis, so that here also a stimulogenous formation occurs. This correlation of stimuli thus plays a fundamental role in all processes of neurobiotaxis, although

EVOLUTION AND MORPHOLOGY OF NERVOUS ELEMENTS 93

the dendrites and cell bodies grow toward the stimulus while the neuraxis grows away from the stimulating center but under the influence of irradiating impulses from it. How, then, is it possible that a single nerve imit, the neuron, should show such clearly opposite polar differences, that one part of its protoplasm approaches the source of stimulation (the stimulo-petal dendrites and cell body) while the other grows in the direction of the stimulus or irradiation proceeding from it (stimulo-concurrent neuraxis) ?

The solution of this problem is aided by a consideration of other tropisms in nature which are more accessible to experimentation. A study of galvano-tropism reveals phenomena which are forcible reminders of the conditions just described for nervous tissue. Thus the root tips of plants grow toward the electro-negative pole and monocellular animals move in the same direction. This process, however, is reversible. By placing the amoeba, or the root tips of the growing plants, in a stronger solution of potassium or sodium chloride (which increases its conductivity), the tropisms become reversed and the movement or growth, as the case may be, is toward the positive pole. Lecithin also shifts its position in a galvanic current (kataphoresis) , but both it and albumen, under ordinary conditions (that is, under those conditions in which they occur in the animal body), move toward the positive pole. Addition of potassium enhances the anodic character of this process. Similar reversible kataphoretic phenomena are described with albuminoids, bacteria, and yeast cells. There is considerable evidence that the results of these galvanotropic and kataphoretic experiments may be used to explain the formation of the nervous system through the stimuli which act upon it. It is known that the surface of a nervous tract which is stimulated forms a negative pole, a cathode, with respect to the surrounding regions, which regions then represent an anodic field as compared with the center of stimulation. A neuroblast about this electro-negative center forms first an anodic offshoot or neuraxis, which will grow in the direction of the radiating current from the center of stimulation because of the anodo-tropic character of the cell protoplasm. The process thus formed probably derives its chemical and tropic characteristics from the potassium present within it. The potassium enhances the anodo-tropic, in these cases stimulo-concurrent, character of the neuraxis and besides increases its conductivity. In addition, potassium ions have a membrane loosening and surface tension lowering influence on protoplasmic membranes and thus favor its outgrowth.

The stimulo-petal, cathodic tropisms of the dendrites and of the perinuclear protoplasm are probably favored by the appearance of the Nissl bodies, as they do not take place until the neuron has developed its tigroid substance. This cathodic tropism, followed by a gradual shortening (contraction) of the dendrite and a displacing of the cell itself (as in cathodic tropisms with amoeba), occurs in accordance with the phenomena of cathodic stimulation, as stated in Pfliiger’s laws {Loeb and Maxwell, ’96 ; Boruttau, ’08) and as seen in such animal protoplasm as is susceptible to stimulation (e.g. the amoeba under normal conditions).

At the moment that the galvanic potential makes itself felt within the nervous system, there is probably a facilitation of stimulus-transition in the receptive

94 NERVOUS SYSTEMS OF VERTEBRATES AND OF MAN

part of the cell and enhanced sensitivity at the cathode, as is well known in experimental neurology. Thus the first development and lengthening of the stimulo-concurrent neuraxes ” is a consequence of the increased anodo-tropic character of the tissue and is strengthened by potassium salts. The formation, and much later contraction, of the dendrites and the displacement of the perinuclear protoplasm toward the cathode is a special case of Pfliiger’s laws.

It is evident that this explanation of the dynamic polarization of the neuron gives no clew to factors determining the final connections of the neuraxis. This final connection always takes place in a territory or with a cell which has correlated activity, that is, exhibits just previous or simultaneous electric phenomena. Non-stimulated centers are all equally indifferent to it.

Monoaxonism is the resultant of all the forces (or stimulations) acting on a place of predilection (axon hillock). Polydendritism is not only possible but usual because the perinuclear and dendritic protoplasm are ever 3 rsvhere equally sensitive to cathodic influences and may respond at several different places to stimuli of as many different origins, each stimulus affecting the region nearest it. The trophic or metabolic tropism occasionally shown by the cell body or dendrites is not necessarily antagonistic to their stimulative tropism ; stimulation enhancing the metabolism of the cell, they may go hand in hand.

The ability of the neuron to receive at a given time different stimuli over as many distinct dendritic processes and to discharge the resultant of these over a single neuraxis may be considered the material expression of the property of the neuraxis of serving as a final common path.®

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Book - The comparative anatomy of the nervous system of vertebrates including man - 1

Chapter I The Evolution And Morphology Of Nervous Elements