Talk:Paper - On the development of the hind-brain of the pig 2

ON THE DEVELOPMENT OF THE HIND-BRAIN OF THE PIG. By O. CHaRNock BRADLEY, MB. DS$Sc. FRS.E, Royal Veterinary College, Edinburgh. (PLATES XIX-XXIV.)!

PART Il.

THE RHomgic Lre.

IN 1886, His (13) called attention to a folding over of the dorsal edge of the alar lamina which he named the “ Rautenlippe” and to which he attached great importance as a factor in the development of certain portions of the medulla, and especially of the cerebellum of Man. He stated that the rhombic lip begins to form, in the human embryo, at the beginning of the fifth week, and that it extends from the cervical flexure to the isthmus rhombencephali; in some places being larger, in others smaller.

Since the publication of His’ paper several observers, working on the development of the hind-brain of different mammals, have arrived at diverse conclusions as to the formation and significance of the rhombic lip. Herrick (14) figures it as of extensive development in the guinea-pig, and dilates upon its high position as an agent in the formation of the cerebellum.

Dexter (15), on the other hand, avers that in the rabbit there is no trace ofit. Kuithan (16) also, after following the development of the cerebellum in the sheep, expresses himself as doubtful of the occurrence of a lip.

Blake (12), in 1900, claimed that it is present in several mamimals (pig, sheep, cat, and rat), and gave an illustration of a transverse section through the hind-brain of an embryo rat (3 mm. long) which certainly closely resembled some of the figures given by His. Blake stated that “hitherto it has not been demonstrated in the lower mammalia,” and suggested that this omission may be due to the fact that “it is probably extremely transi tory in an unfused condition.”

Yrônberg (6), writing still more recently, and basing his statement on the examination of Erinaceus embryos, speaks in no uncertain voice against the occurrence of a rhombic lip. Not only does he deny its

1 Figs. 1 to 44 accompany Part I. of this paper, which was published in the last

number of the Journal (Oct. 1905). VOL. XL. (THIRD SER. VOL, I.)—JAN. 1906. 12 134 Professor O. Charnock Bradley

presence in hedgehog embryos, but he even seriously questions its formation in Man.

So far as Man is concerned, the occurrence of à rhombic lip may be assumed to be proved. In regard to its presence in the embryonic brain of the lower mammals, there is not vet sufficient evidence to prove that it is universal or even common. For this reason considerable attention has been paid to the condition of the dorsal border of the alar lamina in the hind-brain of the various pig embryos employed in this research.

In the youngest embryo the edge of the alar lamina passes in a simple manner into the membranous roof of the ventricle. No indication of an outward folding is to be observed in any part of the rhombencephalon of the 19 and 22 days embryos. In the next older embryo (15 mm.) there is a considerable difference. In the most posterior part of the medulla the upper border of the alar lamina is no longer thin, but has become thick and rounded, forming an apparent equivalent to His “ Flügelwulst,” along the lateral border of which the membranous rouf of the ventricle is attached (fig. 12). When sections are followed forwards it is found that not only is the border of the lamina rounded, but there is also the appearance of an outward bending ; that is to say, there is distinct evidence of the formation of a rhombic lip with a well-marked outer and à shallow inner “ Lippenfurche” This is well seen opposite the otic vesicle. Towards the anterior limit of the vesicle the folding-over almost entirely disappears, to be again well developed as soon as the vesicle is completely passed. On a level with the origin of the root-complex of the N. acusticofacialis there is a slight diminution in the size of the lip—a diminution doubtless associated with the exit and entrance of nerve-fibres at this point (fig. 13). Immediately in front of this root the lip assumes its maximum development, both its outer and inner “ Lippenfurchen”” being deep (fig. 14). The root of the N. trigeminus is connected with another diminution in the size of the lip, which is once more clearly marked externally in the region of the lateral recess; the outer “Lippenfurche”” being continued slightly beyond the anterior limit of the recess (fig. 5).

The various neuromeral grooves cross the “ Flügelwulst,” so causing the production of a number of rounded eminences.

With certain reservations it may be said that, so far as concerns the rhombic lip, sections through the hind-brain of this embryo bear à marked resemblance to the figures given by His of a five-weeks’ human embryo. There is, however, none of that flattening of the medulla at the widest part of the ventricle, so conspicuously present in Man. There is, further, as has been previously stated, no clear distinction of alar and basal laminæ in the widest part of the medulla. Development of the Hind-Brain of the Pig 135

It is not possible to follow the rhombic lip for even the shortest distance on to the cerebellum at this stage.

À considerable advance has been made in the growth of the lip between the 15 mm. and the 23 mm. stages. In à 23-mm. embryo it is again poorly developed in the posterior part of the medulla, and fusion is apparently taking place between it and the wall of the brain-tube (fig. 16). Opposite the anterior part of the otic vesiele it would be difficult to say that a rhombic lip had ever existed were it not for the evidence afforded by the younger embryo. In connection with the lateral recess, on the contrary, the lip has grown considerably and now forms a substantial floor to the recess (fig. 18). This region obviously corresponds to the district in which the lip was greatest in the 15-mm. embryo.

At this stage there are unmistakable traces of a folding of the edge of the cerebellar lamina ; but in no part is it so well marked as was formerly the case in the medulla (fig. 19). A cerebellar rhombic lip can be detected in both transverse and sagittal sections; the latter showing it best in the region of the lateral recess. As sagittal sections are followed towards the middle line the lip becomes gradually less and less, but does not entirely disappear until the median plane is closely approached.

In the posterior part of the medulla of à 25-mm. embryo there is a thickened hem appended to the border of the former alar lamina, and to it the membranous roof of the ventricle is attached. The hem is sharply warked off from the rest of the wall of the ventriele by an internal furrow, above which is a rounded ridge-like prominence (figs. 21 and 22). The furrow began to appear in the 23-mm. embryo (ef. fig. 16), and it does not seem altogether unreasonable to compare it with a groove figured by His (fig. 13 (13)) as being present in à five-weeks human embryo internal to the “ Flügelwulste” If such a comparison be allowed, then the rounded ridge above the furrow must be the remains of the “ Flügelwulste.” However this may be, the hem itself may be considered the representative of the rhombic lip, Blake having shown that in the lower mammals it has such an appearance.

In connection with the lateral recess the rhombic lip continues to grow both in thickness and also in an outward direction (fig. 23). Attention has already been called by Blake to the important rôle played by the lip in the formation of the recess, and the material at present described lends support to his statement. It should be added that the N. acustico-facialis has established à close connection with the ventral wall of the recess so formed.

There is still à slight trace of a rhombie lip in connection with the cerebellum in the 25-mm. embryo, but this is the latest stage in which ït can be detected, 136. Professor O. Charnock Bradley

As has been previously stated, the most posterior part of the medulla has become “closed ” in the 32-mm. embryo; the “closed” portion being provided with a dorsal median furrow. Just before the central canal enters into the ventricle à ridge makes its appearance in this furrow (fig. 24). If it be followed forwards it is found that the ridge is continuous with rhombic lips such as were described as occurring in the 25-mm. embryo (figs. 25 et seqg.); that is to say, the closure of the medulla has been caused by the fusion of the lips of the two sides. From this point the rhombic lip can be easily followed forwards—being found to present an appearance not unlike that of the next younger specimen, and gradually increasing in size as the entrance to the lateral recess is approached (figs. 28 and 29).

A slight exagveration in the thickness of the lip is shown in fig. 29. This follows upon a narrowing of the roof of the ventricle just behind the opening into the lateral recess, which causes the lip to incline inwards and forwards. Sections of it, therefore, are eut somewhat obliquely. The obliquity of section, however, does not account for more than a comparatively small part of the width of the lip as illustrated.

That part of the rhombic lip which is associated with the lateral recess has increased in thickness as well as in lateral dimensions. Consequent upon the addition to its width, the lip is now folded farther over the side of the medulla; but there is still no very remarkable degree of fusion between the medulla and the lip. The independence of the two structures is well shown in fig. 29. Fig. 29 also demonstrates that the lateral recess is growing backwards beyond the level of the aperture of communication with the body of the ventricle, and that the N. acustico-facialis is now closely associated with the rhombic lip.

The “elosed ” part of the medulla has increased in length in the 52-mm. embryo. As in the yvounger spechmen, it possesses à dorsal median fissure. And, again, before the central canal opens out into the fourth ventricle a low rounded ridge appears in the fissure, thus materially reducing its depth (fig. 32).

In transverse sections there is an area of tissue, differing structurally from that adjacent to it, stretching from the surface of the medulla down to the central canal, and corresponding in lateral extent to the width of the ridge in the bottom of the dorsal fissure (fig. 32}. It has evidently been produced by the fusion of the two rhombie lips, for the examination of serial sections shows à continuation of the area with lips such as were present in the 32-mm. embryo (figs. 32 and 33).

The disposition of the epithelium over the rhombic lip in the neïghbourhood of the posterior end of the ventricle is noteworthv. Immediately upon the opening up of the central canal to form the ventricle, 4.6. as soon Development of the Hind-Brain of the Pig _- -137

as the area of union of the two rhombic lips is passed, the epithelium, though of the same thickness over the greater part of the wall of the ventricle as in the central canal, becomes remarkably thin over the lips themselves (figs. 33, 34, and 35). This peculiarity is retained for some distance forwards:; but more anteriorly the lip carries as thick an epithelium as the rest of the interior of the ventricle.

Just as the opening into the lateral recess is being reached, there is, as previously, à conspicuous increase in the size of the rhombic lip (fig. 41) —-a condition, however, not demonstrable in older embryos. That part of the lip which assists in bounding the recess is beginning to lose its hitherto remarkable independence.

The appearance presented by the central canal in an 80-mm. embryo is possibly of interest. About the junction of the spinal cord and the medulla the canal is of fair width, and, judging from the arrangement of its epithelium, is undergoing constriction by fusion of its walls both dorsally and ventrally. If the canal be followed forwards, it is first observed to narrow ; and then its lateral walls «ppeur to fuse about their middle, thus producing the appearance of two canals—a dorsal and a ventral. Into the dorsal canal projects a slight dorsal ridge of epithelium. Still farther forwards the dorsal canal enlarges—the ridge of epithelium being still present—and finally appears to form the single central canal which opens into the ventricle Though this is the appearance presented by sections, it is very doubtful if there is even an attempt at fusion of the lateral walls of the canal. Some sections which had doubtless been rather more roughly handled in preparation show the walls separated from each other by à very narrow chink.

This condition of the central canal of the medulla would not have been so fully described were it not that Balfour (17) was originallv of opinion that diminution in the size of the central canal of the spinal cord was produced by a median coalescence of its walls. It was thought that here might possibly be an appearance shmilar to that which led Balfour to his conclusions.

À dorsal median fissure in the “closed” part of the medulla is not present in the 80-mim. embryo. Its place is taken by à triangular area of tissue, scantily provided with nuclei, which represents the opposed and fused rhombic lips (fig. 46). At the apex of the ventricle the lips no longer project from the edge of the medulla: but their extent is determinable as a sparsely nucleated area continuous with the structurally similar field in the “closed”? portion of the medulla (fig. 47).

In view of the condition exhibited in the older material, it is well here to call attention to the fact that there is à manifest thickening of the 138 Professor O. Charnock Bradley

epithelium about the lower limit of the fused rhombic lips (figs. 47 and 48). Over the major part of the lip the epithelium is almost as thin as was found to be the case in the next younger embryo.

On passing forwards the pale area representing the rhombic lip disappears and the lip forms à projection such as has been seen previously (figs. 49 and 50).

Fusion between the floor of the lateral recess and the medulla still goes on, but there is no difficulty in seeing the line along which it has taken place (fig. 51).

In the embryo 100 mm. in length there is again a trace of a dorsal median fissure in the most posterior part of the medulla (fig. 52) As stated above, this was not to be found in the 80-mm. embryo; it appears possible, therefore, that it is a new formation produced by inequalities in the rate of growth of different parts of the medulla. As the groove runs forwards it becomes obliterated by the presence of à pale triangular area like that previously seen (fig. 53). Careful measurements show that the area increases in both its lateral and vertical dimensions as it is followed forwards. Its continuity with the rhombic lips is as evident as it was in the younger embryo (figs. 53, 54, and 55). Contrary to the condition present in the earlier stages, the bulk of the rhombic lip diminishes as the opening into the lateral recess is approached (figs. 55 and 56).

The character of the central canal, and its modification as it opens into the ventricle in the 100-mm. embryo, seem worthy of note. Some little distance (less than 300u) before the canal reaches the ventricle it has the form of a moderately wide vertical slit with à median constriction, but none of that approximation of its lateral walls seen in the 80-mm. embryo (fig. 52). (The constriction is greater in a section 140w farther forwards than the one from which this figure was made.) The constriction produces the appearance of two dilatations in the canal. A little farther forwards the slit is elongated by the occurrence of à third dilatation dorsal in position (fig. 53). Still more anteriorly a cleft sunders the pale area which represents the combined rhombic lips. At the upper edge of the third dilatation and about the lower limit of the rhombic-lip area is a thickened patch of epithelium such as was seen at an earlier stage (fig. 54).

The manner in which the central canal of à 150-nnn. embryo comes to an end differs somewhat from the foregoing description. Here the pale triangular area is present on a level at which the canal is still small ; that is, the third dilatation mentioned in the preceding paragraph has evidently been obliterated by the coalescence of the dorsal part of the walls of the canal. The area itself is even more obvious than before on account of Development of the Hind-Brain of the Pig 139

its marked vascularity. (Blake has directed attention to the fact that the extent of the fused rhombic lips can be determined by the greater vascularity of the area of tissue so produced.) In addition, the area forms a dorsal projection in transverse sections (figs. 59 and 60). In this specimen the antero-posterior diameter of the area is absolutely less than it was in the 100-mm. embryo. In the latter it measured 252u from its most posterior recognisable limit to the point of separation of the two rhombie Lips; in the 150-mm. embryo it only measures 204u between similar points. This circumstance indicates à gradual loss by the area of its distinctive histological characters, the structural change occurring first posteriorly and advancing towards the apex of the ventricle. The area clearly forms the obex of the adult brain.

As the central canal is entering the ventricle it shows the constriction noted in the 100-mm. embryo; but the third—most dorsal—dilatation is replaced by a rounded ridge on each side of the canal. This is the funiculus separans of Retzius (fig. 8). The two funiculi blend posteriorly in such à manner that there is a slight backward prolongation of the cavity of the ventricle above them (figs. 8 and 60). The more dorsal of the two dilatations of the central canal is continued into the ventricle as the ala cinerea (fig. 8). The rhombic lip, passing forwards from the obex, forms the area postrema, which gradually becomes smaller and more and more separated from the bulk of the medulla A little distance behind the opening into the recess it is very small and forms a thin projection : just as the opening is reached it can hardly be said to be present at all.

That the rhombic lip is an important factor in the formation of the tuberculum acusticum has been claimed by Blake. The present research lends support to the claïm (figs. 63 and 64).

From what has been saïd above, it follows that the rhombic lip of the pig differs somewhat from the like structure in Man. From the time of its earliest appearance it is much more perfectly formed in the region of the lateral recess. In the posterior part of the medulla the lip is small in the younger material, but attains a good development later. In the middle district of the medulla there is an imperfect development of the lip during the whole of embryonic life. Immediately behind the opening into the lateral recess it is large enough to be remarkable during the earlier stages covered by the material at present considered: but later this comparative prominence is lost (cf. figs. 41 and 56). At no period is the folding over of the lip so great as has been described by His as occurring in the human embryo; there is never even an approach to the condition as depicted in His’ fig. 16 (18). It is difficult to imagine that the rhombic lip of the pig forms the olivary body, etc.—at any rate in the manner as related by His; 140 Professor O. Charnock Bradley

it seems more probable that the fasciculus solitarius becomes buried as the consequence of migration of neuroblasts independent of the formation of the lip. This would harmonise with the inability of Grônberg and Dexter to find the lip in the hedgehog and rabbit. Further, it cannot be claimed that it plays more than a very small part in the formation of the cerebellum of the pig. The cerebellar rhombic lip appears later than the medullary lip ; it is much smaller, does not reach the middle line, and all traces of it are soon lost.

It must be concluded therefore from these observations on the pig, and from the published results of other investigations, that a rhombic lip is not invariably present in mammals, and, when present, is not so important a factor in the development of the medulla as it is in Man. In connection with the cerebellum its morphologie value is small.

THE CEREBELLUM.

Since the earliest observers were of opinion that the hind-brain presented à yawning cleft in its roof during the first stages of its development, it was natural that they should conceive the cerebellum as arising from a pair of lateral Anlagen which, gradually growing towards each other, ultimately fused in the middle line. This view originated, according to Mihalkovies, with Fracassati (19), and was acquiesced in by all subsequent writers up to the time of the appearance of the first edition of Külliker’s Embryology (9). Tiedemann (20), Serres (21), v. Baer (22), Valentin (23), Schmidt (24), and Kollmann (25) were of this opinion.

Kôlliker gave pause to the prevailing theory when he described the cerebellum as developing as a thickening of the roof of the most anterior part of the hind-brain—the thickening soon attaining the form of a transverse plate. Mihalkovics (26) followed Külliker in considering the cerebellum to grow out of a transverse curved “Kleinhirnlamella”? Lahousse (1888 (27)) and Hertwig (1893 (28)) are examples of moderns who hold with an unpaired cerebellar Anlage.

Most recent writers, however, describe a pair of lateral Anlagen. Goronowitsch (29) so represents the development in Acipenser, and Schaper (8) believes that the cerebellum of Teleosts Springs from a bilaterally symmetrical Anlage.

Stroud (30) doubts w hether the cerebellum as a whole grows out of a thickening occurring in the roof of the hind-brain at the constriction of the isthmus. If this transverse plate is the cerebellum, he asks, “ Where is the valvula ?” He appears to incline to the view that the cerebellum proper develops from a pair of Anlagen which appear posterior to the Development of the Hind-Brain of the Pig 141

thickening, and sums up by saying, “The mammalian cerebellum is developed from the caudal part of the epicælian roof.” '

Kuithan (16), from his observations on the sheep, is of the opinion that the embryonice cerebellum has at first an unpaired Anlage, but later it passes through à stage in which paired Anlagen can be detected. Prenant (31) joins the ranks of those who adhere to the opinion that there are originally two lateral structures from which the cerebellum arises; and Grünberg (6) is led to the same conclusion by his examination of hedgehog embryos.

There appears to be sufficient justitication for the assertion that the cerebellum of the pig develops from à pair of lateral rudiments. The median connection present in the youngest embryo examined (19 days) is so thin that there appears to be no reason for considering it of more importance than the Deckplatte of the spinal cord. It is merely à connecting-link between the alar laminæ of opposite side of the rhombencephalon. Further, the connection so established is of short sagittal extent only.

The rudiments of the cerebellum which are present in the 19-days embryo are not marked off from the medulla by anything more than the occurrence Of à maximum width of the brain tube. The main connection of the two halves of the organ is the thin membranous roof of the ventricle, each half having a border which slopes gradually inwards as it passes forwards. Speaking generally, there is an interval between the two halves of the cerebellum in the form of a moderately elongated isosceles triangle whose base is formed by a line drawn transverse to the long axis of the rhombencephalon on à level with its widest part, and whose apex points forwards.

As development procceds the superficial area of the two moieties of the cerebellum increases, and their median connection is extended anteroposteriorly from an expansion of their line of contact. The median connection, though gradually becoming thicker, does not do so in proportion to the increase in its sagittal extent: the consequence being that, for a long time, the two halves of the cerebellum are joined to each other by a remarkably thin bridge, internal to which is à longitudinal fissure whose relative depth increases, rather than diminishes, up to à certain stage of development. How this fissure develops into the cerebellar ventricle, and how it is not entirely obliterated even in à 100-mm. embryo, have been related.

Concerning the manner in which the originally thin median portion of the cerebellum increases in thickness, with a concomitant diminution in the depth of the internal longitudinal fissure, there has been some divergence of 142 Professor O. Charnock Bradley

opinion. Kuithan inclines to the view that there is an approximation of, and, finally, fusion between the two walls of the fissure. Grünberg, on the other hand, holds that Erinaceus embryos do not exhibit any fusion of the ependyma. Schaper, as the result of his investigations into the development of the cerebellum in teleostean fishes, concludes that the connecting lamina between the two lateral halves does not develop into typical cerebellar tissue.

The question is evidently not one to which a satisfactory answer can be readily found. In the embryo of the pig there is certainly some thickening produced by proliferation of cells within the median part of the cerebellum itself. But there is the possibility that these cells have migrated thither from more lateral areas. It is not without interest to note that a ridge is present, in certain embryos, at the bottom of the internal median fissure of the cerebellum (figs. 30 and 43), not altogether unlike that which appears in the depths of the sulcus centralis of the floor of the ventricle.

The extraordinary uniformity in the architecture of the whole of the hind-brain in the youngest embryo recalls the question as to whether à division of the rhombencephalon into two distinct segments, as originally suggested by v. Baer, is based upon altogether good morphological grounds.

Edinger’s assertion that the cerebellum is in the highest probability one of the oldest segments of the brain (32) does not remove the impression, gained from an examination of the literature, that it is fundamentally merely a continuation of the posterior part of the rhombencephalon; or, as Spitzka has expressed it, a dorsal hypertrophy of the hind-brain.

That the cerebellum of the lower animals is mainly, if not entirely commissural has been shown by the researches of Burckhardt (on Protopterus (33) ), Osborn (on Cryptobranchus and Amphiuma (34)), Fish (on Desmognathus (35) ), Kingsbury (on Necturus (36)), and others. This leads to the deduction that, in its original form, the cerebellum was not an important nerve-centre ; its subsequent attainment to a high morphological position being due to an augmentation in volume and an elaboration of structure rendered necessary by physiological specialisation.

The structural continuity of medulla and cerebellum lends support to the hypothesis that they are merely different parts of one and the same brain segment. In 1888, Goronowitsch (29) made the statement that, in Acipenser, the molecular layer of the cerebellum (with cells of Purkinje) is continued over the tuberculum acusticum as à crest, to which he gave the name of “ Cerebellarleiste.” A like condition has been found to obtain in Amia (Kingsbury (37)), Acipenser rubicundus (Johnston (38)), Mustelus (Houser (39)), and Petromyzon (Johnston (40)). Johnston in particular is very earnest in his insistence upon “the morphological unity of the dorsal Development of the Hind-Brain of the Pig 143

horn, acusticum, and cerebellum ” : a unity rendering à dividing line between the cerebellum and tubereulum acusticum an impossibility.

The relationship between the acusticum and cerebellum is further shown by the fact that the N. acusticus has an end-station in both. This has been demonstrated by à multiplicity of observations on all classes of vertebrates. Of those to whom we owe knowledge of this fact may be mentioned Mayser (41), Goronowitsch (29), Johnston (38 and 40), Kôppen (42), Edinger (43), Sala (44), Brandis (45), and Wallenberg (46). Even in Man himself, in whom the cerebellum has become most highly specialised, the vestibular nerve sends fibres into the cerebellum.

In view of the facts which have been accumulated, and which are still rapidly accumulating, there seems good reason for considering the cerebellum and medulla as part of one segment of the brain, even if we do not go so far as Haller (47) and say that beyond doubt the “ Cerebellarleiste ” and its associated cerebellum have developed from the outer sensory region of the medulla oblongata—thus reducing the cerebellum to the level of a were appendage to the medulla. That even the latter and more extreme conclusion is justitied by some-—not to say many—facts may, however, be readily contended.

The problem being one of much complexity, and further evidence being still needed for its solution, it may be well to suspend judgment and await further developments ; concluding with Wilder (48) that there is no reason why we should not go on “entertaining and employing, «s « convenient “working kypothesis, the interpretation made by v. Baer and accepted by the majority of later authorities upon the subject,” at the same time remaining alive to the possibility that the division of the rhombencephalon into two segments, though convenient, may not be strictly scientific.

THE FORAMEN OF MAJENDIE.

À figure given by His (fig. 33 (49)) shows the roof of the embryonic fourth ventricle to be of the same thickness throughout. In the process of development a relative thinning takes place, and it seems probable that, in some mamimals at least, this continues until an actual break occurs at certain points of the roof, whereby the cavity of the ventricle is placed in communication with the sub-arachnoid space. That such à communication is established in Man and the higher apes, at least, appears to have been proved beyond doubt by careful work recently undertaken. Whether all the apertures found in Man occur with the same regularity in all mammals has not been so clearly demonstrated. The older methods of research were

1 The italics are not in the original. 144 Professor O. Charnock Bradley

not such as lent themselves to proving or disproving the existence of small apertures in so delicate à membrane as that which closes in the fourth ventricle. So long as the only method employed was that of ordinary dissection it was only natural that different observers should arrive at different conclusions, the amount of tension requisite for the production of an artificial opening being so very small. Even when the process of embedding and cutting sections in paraffin or celloïdin is used the results may be untrustworthy if there has been any roughness indulged in during the extraction of the brain from the cranium.

The only way in which all danger of producing artifacts can be obviated is by embedding and cutting the whole head-—a matter of obvious difficulty in the case of the larger animals. Embryos lend themselves much more readily to this method than do adult animals. But in the case of the use of embryonic material, negative evidence is of greatly less value than positive. If there be no opening in the embryo, it does not follow that there should also be none in the adult: it is easily conceivable that an intercommunication between the ventricle and the sub-arachnoïid space may be formed after birth. If, however, an opening is found to be present in the embryo there is a strong probability of its being present in the adult also.

In the early part of last century Burdach (50) described the hinder end of the roof of the fourth ventricle as being perfectly closed. But, in 1842, Majendie (51) pointed out that there is normally and constantly an opening in the roof of the human ventricle; this foramen being bounded by the choroid plexus and the posterior medullary velum, and its size differing very much in different individuals.

Since 1842 conflicting opinions have been expressed as to whether the foramen of Majendie is an entity or a chimera Virchow (52) denied the existence of any connection between the ventricle and the sub-arachnoïd space. Luschka (53) succeeded in finding an opening in the tela choroïdea inferior of Man, but added that in many animals the ventricle is closed. In 1861, Reichert (54) averred that the foramen is only produced during the process of removal and manipulation of the brain: whereas, in the same year, Kollmann (25) not only described the opening as being natural, but also stated in what manner it is bounded.

Quincke (55) saw in the foramen à very variable and not always demonstrable opening in the connective tissue of the roof of the ventricle, Key and Retzius (56) examined 100 human brains and found a foramen of Majendie in 98 of them. Sée (57) declared himself on the side of those who denied the existence of the foramen, and stated reasons for his attitude. It is exceedingly easv, he said, to tear the fine membranous roof of the ventricle during the removal of the brain; in several annnals, e.y. horse, Development of the Hind-Brain of the Pig 145

goat, etc., it has been shown that the ventricle is closed, and the overfilling and distension of the ventricle, as the consequence of pathological processes, is not reconcilable with the acceptance of the presence of an opening. Kôülliker (9) held that there is complete closure of the ventricle in the embryo, and that this is the rule in the adult also The foramen of Majendie, when present, he said, is no regular structure.

In 1885 the problem was attacked by Hess (58). He examined the brain of thirty adult human beings, ten new-born children, and seven embryos of different ages. In only one instance did he fail to find an opening. He came to the conclusion, therefore, that the foramen is constant in man. He thought that it is possible that there is always an opening in the roof of the embryonic ventricle, since at five months the aperture is wide. He also found à foramen in the embryo of the cat.

.. Later observations by Wilder (59), Morton (60), Jacobi (61), Kohlmann (62), and others appear to indicate that the foramen as described by Majendie is à natural opening in Man at least. Cannieu (63) is not so sure of the presence of à natural and normal opening in the lower animals.

The subject has received very careful attention at the hands of Blake (12), whose results were published in 1900. He describes à protrusion of the roof of the ventricle in the form of à glove-finger-like projection, which remains closed in the majority of mamimals but becomes an opening in Man and the anthropoid apes.

In the pig there is little that is remarkable in the changes which occur in the roof of the ventricle before the embryo has attained a length of 50 num. The only point which needs mention is the relative thickness of the roof in different regions. In all the younger embryos (except that Of 19 days) an oval patch of the membranous roof differs from the rest in being noticeably much thinner. This occurs about the centre of the “ Rautenfeld,” and can be distinguished as early as the twenty-second day. It is not due to à reduction in the number of the layers of cells forming the membrane but rather to à flattening of the individual cells: for the zone immediately surrounding the patch is provided with no more than one layer of cells, thus agreeing in constitution with the patch itself.

Transverse sections through the “closed” part of the medulla of an SO-mn. embryo show a backward extension of the cavity of the ventricle into a membranous cul-de-sac which lies on the dorsal surface of the medulla. At this stage the cul-de-sac is closely applied to the medulla, to which it is adherent; its extent, in a sagittal direction partly and in à lateral direction entirely, corresponds to a triangular area formed by the coalesced rhombic lips (fig. 46). À younger embryo (52 mm.) shows the commencement of the condition. It is evident that, as the rhombic 146 Professor O. Charnock Bradley

lips fuse together, there is not a corresponding diminution in the anteroposterior diameter of the roof of the ventricle; the “closed” medulla rather, in à sense, burrowing under the roof and so causing a cul-de-sac.

The backward continuation of the cavity of the ventricle is very definite in a 100-mm. embryo. Its form may be well likened to that of a finger of a glove. It extends farther back than the caudal limit of the area produced by the fusion of the rhombic lips, and it is now free, its caudal extremity being some distance removed from the surface of the medulla (fig. 52).

À 150-mm. embryo shows the same kind of protrusion, but much better developed. It now extends backwards almost to a level with the most caudal part of the cerebellum, and is, posteriorly, in even closer relation with the cerebellum than with the medulla. Although the walls of this caudal protrusion are thin, there is no indication of a foramen of Majendie.

The embryo of the pig, therefore, corroborates the statement made by Blake. And, it may be added, à careful examination of the adult brain leads one to assert that the protrusion never becomes an opening.

OPENINGS IN THE LATERAL RECESSES.

Although Bockdalek (64), in 1849, stated that the choroïd plexus lies free under the arachnoïd mater in the region of the “ Fullhorn,” the description he gave was not such as to cause modern morphologists to associate his name with the opening in the lateral recess of the fourth ventricle.

Luschka (53), some years after the publication of Bockdalek’s paper, described the outer angle of the ventricle as standing in connection with the sub-arachnoïd space, and the lateral part of the choroïd plexus as lying free under the arachnoïd. This, however, was not supported by Reichert (54), who, after à minute description of the choroïd plexus, concluded with the declaration that there is a membranous closure of the lateral recess of the ventricle. °

There seems little doubt that to Key and Retzius (56) should be viven the credit of having provided the first clear and detailed description of the connection of the cavity of the ventricle with the sub-arachnoïd space through the intermediation of an aperture in the lateral angle of the ventricle. Out of 100 human brains examined by them the communication was found in ail but three.

Kôülliker (9) expressed himself as convinced that the openings are even less of regular structures than the foramen of Majendie, which, as previously mentioned, he held to be usually absent. Hess (58) concluded that the apertures are constant in man. Bland Sutton (65) attached great imDevelopment of the Hind-Brain of the Pig 147

portance to the openings, and stated it as his opinion that their complete absence, or their closure before or after birth, leads to pathological results.

Morton (60) and Jacobi (61) have averred that the openings are normal and always present, whereas Cannieu (63) casts doubt on their natural occurrence in the lower animals.

Blake (12) included the considerations of these openings in the paper to which reference has already been made. The results of his investigations are of great interest, since they indicate that the openings are always present in mamimals, and are even larger in the lower animals than in Man. It would appear that there is a kind of compensatory development. When the foramen of Majendie is absent the openings in the lateral recesses are larger than when the foramen is present.

The first rudiments of lateral recesses occur in the 15-mm. embryo of the pig, 4e. in the same specimen in which a rhombic lip is first observed. From this stage onwards the recess is bounded ventrally by the rhombic lip. Its caudal boundary is very indefinite in the 15-mm. embryo, but in the next older specimen (23 mm.) this limit is clearly formed, for now the recess has à greater antero-posterior diameter than has the opening from it into the body of the ventricle. It extends farther back, as well as farther forward, than the level of the bounds of the opening into it; there has been, therefore, a bulging backwards of the caudal wall of the recess. The disparity between the antero-posterior measurements of the recess and of its opening into the ventricle becomes exaggerated as development proceeds.

As early as the 23-mim. stage the choroïd plexus has invaded the recess (fig. 18). In the 25-nun. embryo, that part of the plexus which invaginates the outer wall of the recess is more anterior in position than the portion of it which belongs to the ventricle itself. Later, the median part of the plexus grows at à greater rate than the lateral portion.

À very important process begins in the 80-mm. embryo. The most posterior part of the recess in this specimen has very attenuated walls, consisting solely of very thin epithelium, which, over blood-vessels especially, can scarcely be said to be perfectly continuous (fig. 50). There is, however, as yet no definite discontinuity of the epithelium. The rest of the wall of the recess is composed of thick nervous tissue except along the line of invagination produced by the choroïd plexus (fig. 51).

In the 100-mim. embryo there is a wide area in the most posterior part of the posterior end of the recess from which the epithelium has entirely disappeared. In fig. 56 the termination of the epithelium is shown to occur abruptly, the contour of the recess remaining imperfectly preserved by loose and delicate connective tissue. In some sections from the same 148 Professor O. Charnock Bradley

embryo this tissue is more scanty and interrupted than in the one from which the figure was made.

The break in the wall of the recess is complete in the 150-mm. embryo (fig. 63), and the communication between the cavity of the ventricle and the sub-arachnoid space is fully established. Sections taken farther back than the one illustrated in the figure show the choroïid plexus lying free in the sub-arachnoïd space at some distance posterior to the caudal end of the recess. It seems worthy of note that the break in the wall does not occur along the line of invagination of the choroïd plexus. Both fig. 56 (100-mm. embryo) and fig. 63 (150-mm. embryo) show that the opening has been produced by à thinning: of the lower part of the outer wall of the recess.

The embryo of the pig, then, lends confirmation to the statement as made by Blake that, while the foramen of Majendie is wanting in the lower animals, openings of large size exist in the lateral recesses.

REFERENCES.

(1) Kerr, F., Normentafel zur Entwicklungsgeschichte des Schweines, Jena, 1897.

(2) Brancey, O. CHarnock, “ Neuromeres of the Rhombencephalon of the Pig,” Rev. Neurol. and Psych., vol. ii., 1904.

(3) Orr, H. B., “Contribution to the Embryology of the Lizard,” Journ. Morph., vol. i., 1887.

(4) Hire, C., “ Developmental History of the Primary Segments of the Vertebrate Head,” Zocl. Juhrb. Abth. f. Anat. u. Ontogenie, Bd. xiii., 1900.

(5) v. Kuprrer, C., “Die Morphogenie des Centralnervensystems,” Handburh der vergleichenden und experimentellen Entwicklungslehre der Wirbeltiere, Herausgegeben von Dr O. Hertwig, Jena, 1903, Lief. 14-15 and 16.

(6) GRônBerG, G., “Die Ontogenese eines niederen Säugerhirns,” Zoo!. Jahrb. Abth. f. Anat. u. Ontogenie, Bd. xv., 1902.

(7) PRENANT, A., ‘Note sur l’existence des replis médullaires chez l'embryon du porc,” Bull. de la Soc. d. Se. de Nancy, sér. 2, t. ix., 1889.

(8) ScHaper, A. “Die morphologische und histologische Entwicklung des Kleinhirns der Teleostier,” Morph. Jahrb., Bd. xxi., 1894.

(9) KôzuiKER, A., Entwicklungsgeschichte des Menschen und der hôheren Thiere, Leipzig, 1861 ; 2te. Aufl., Leipzig, 1879.

(10) Borx, L., “ Hauptzüge der vergleichenden Anatomie des Cerebellum der Säugetiere mit besonderer Berücksichtigung des menschlichen Kleinhirnes,” Monatsch. f. Psych. u. Neurol., Bd. xi., 1902.

(11) Brapzey, O. CHarnock, “On the Development and Homology of the Mammalian Cerebellar Fissures,” Journ. Anat. and Phys., vol xxxvii., 1903.

(12) Braxe, J. A., “The Roof and Lateral Recesses of the Fourth Ventricle,” Journ. Comp. Neurol., vol. x., 1900.

(13) His, W., “Zur Geschichte des Gehirns,” Abhandl. 4. math.-phys. Classe d. k. sächs., Gesell. d. Wissen., Bd. xiv., 1888. Development of the Hind-Brain of the Pig 149

(14) Herrice, C. L., “Illustrations of the Archetectonic of the Cerebellum,” Journ. Comp. Neurol., vol. i., 1890.

(15) Dexrer, F., “ Ein Beitrag zur Morphologie der verlängerten Markes beim Kaninchen,” Arch, f. Anat. u. Phys. 1895.

(16) KUITHAN, W., “Die Entwickelung des Kleinhirns bei Säugetieren,” Miünchener medic. AbhandL., vii. Reihe, 6 Heît, 1895.

(17) Bazrour, F. M. Comparative Embryology, vol. ii., 1881.

(18) His, W., “ Die Entwickelung des menschlichen Rautenhirns vom Ende des ersten bis Beginn des dritten Monate.” Abhandl. d. math.-phys. Classe d. k. säche. Gesell. d. Wissen, Bd. xvii., 1891.

(19) FRACASSATI, “ÆEpistola de cerebro ad M. Malpighium,” Opera omnia Malpighi, T. xi. (Quoted by Mihalkovics.)

(20) TreDEMANN, FR, Anafomie und Bildungsgeschichte des Gehirns im Foetus des Menschen, N ürnberg, 1816.

(21) SERRES, E. R. A., Merckels Archiv, Bd. i., 1815.

(22) v. Baer, K. E,, Ueber Entiwicklungsgeschichte der Thiere, Beobachtung und Reflexion, Künigsburg, 1828. (23) VALENTIN, G., Handbuch der Entwicklungsgeschichte des Menschen, Berlin, 1845.

(24) Scamior, F., “ Beiträge zur Entwickelungsgeschichte des Gehirns,” Zeitschr. J. Wissen. Zool., Bd. xi., 1862.

(25) KoLLMANN, Entwicklung der menschlichen Adergeflechte, Leipzig, 1861.

(26) v. Mixazxovics, V., Entwicklungsgeschichte des Gehirns, Leipzig, 1877.

(27) Lanousse, E., “Recherches sur l’ontogenèse du cervelet,” Arch. de Biol. t. vil, 1888.

(28) HerrwiG, O., Lehrbuch der Entwicklungsgeschichte des Menschen und der Wiüirbelthiere, 3 Auf. Jena, 1893.

(29) GoronowiTscH, N., ‘Das Gehirn und die Cranialnerven von Acipenser ruthenus,” Morph. Jahrb., Bd. xiïi., 1888.

(30) Srroup, B. B., ‘The Mammalian Cerebellum. Part 1: The Development of the Cerebellum in Man and the Cat,” Journ. Comp. Neurol., vol. v., 1895.

(31) PRENANT, À., Éléments d'Embr yologie, Paris, 1896.

(32) Enincer, L., ? Bau der nervüsen Zentralorgane, Leipzig, 1904.

(33) BURCKHARDT, R., Das Centralnervensystem von Protoplerus annectens, Berlin, 1892. |

(34) Ossorn, H. F, ‘A Contribution to the Internal Structure of the Amphibian Brain,” Journ. Morph., vol. ïi., 1888. “ Preliminary Observations upon the Brain of Amphiuma,” Proc. Philadelphian Acad. Nat. Sci., 1893.

(35) Fisx, P. A., “The Central Nervous System of Desmognathus fusca,” Journ. Morph., vol. x., 1895.

(36) KinesBury, B. F., ‘On the Brain of Necturus maculatus,” Journ. Comp. Neurol., vol. v., 1895.

(37) KixesBury, B. F., “The Structure and Morphology of the Oblongata in Fishes,” Journ. Comp. Neurol., vol. vii., 1897.

(38) Jonnsron, J. B., “ Hind-Brain and Cranial Nerves of Acipenser,” Anat. Anz., Bd. xiv., 1898. “The Brain of Acipenser,” Zoo!. Jahrb. Abth. f. Anat. u. Ontogenie, Bd. xv., 1902.

(39) Houser, G. L., “The Neurones and Supporting Elements of a Selachian Brain,” Journ. Comp. Neurol., vol. xi., 1901.

(40) JonnsTon,J.B.,‘“* The Brain of Petromyzon,” Journ, Comp.Neur., vol. xii., 1902,

VOL. XL. (THIRD SER. VOL. L)—JAN. 1906. 13 150 Professor O. Charnock Bradley

(41) Mayser, P., ‘ Vergleichendanatomische Studien über das Gehirn der Knockenfische mit besonderer Berücksichtigung der Cyprinoiden,” Zeitschr. f. Wiss. Zool., Bd. xxxvi., 1881.

(42) KôPPen, M., ‘Zur Anatomie des Froschgehirns,” Arch. f. Anat. u. Phys. Anat. Abth., 1888.

(43) Enincer, L., ‘“ Ueber Ursprungsverhältnisse des Acusticus und die directe Kleinhirnbahn,” Neurol. Centralbl, 1886. ‘ Das Cerebellum von Scyllium canicula,” Arch. f. mikrosk. Anat., Bd. lvüi., 1901.

(44) Saza, L., ‘Ueber den Ursprung des Nervus acusticus,” Arch. f. mikrosk. Anat., Bd. xlii., 1893.

(45) BranDis, F., ‘ Untersuchungen uber das Gehirn der Vogel, ii. Th, Ursprung der Nerven der Medulla oblongata,” Arch. f. mikrosk. Anat., Bd. xli. u. xliïi., 1893-1894.

(46) WaLLenBERG, A., ‘‘ Die secundäre Acusticusbahn der Taube,” Anat. Anz., Bd. xiv., 1898.

(47) HaLer, B., “Vom Bau der Wirbeltiergehirns,” i. Th., Morph. Jahrb., Bd. xxvi., 1898.

(48) Wizper, B. G., “Do the Cerebellum and the Oblongata represent Two Segments or only One?” Proc. Amer. Ass. Adv. Science, vol. xxxiii., 1884.

(49) His, W., Die Entwickelung des menschlichen Gehirns während der ersten Monate, Leipzig, 1904.

(50) Burpacx, Bau und Leben des Gehirns, Leipzig, Bd. ü., 1822; Bd. ii, 1826. ‘

(51) MaJENDIE, Recherches anatomiques et physiologiques sur le liquide céphalorachidien, 1842. ‘

(52) VircHow, Handbuch der speciellen Pathologie und Therapie, 1854.

(53) LuscaxaA, H., Die Adergeñflechte des menschlichen Hirns, 1855.

(54) ReicmerT, C. B., Der Bau des menschlichen Gehirns, Leipzig, 1861.

(55) QuinoKe, “Zur Physiologie der Cerebrospinalfiüssigkeit,” Arch. v. Reichert u. du Bois-Reymond, 1872.

(56) Key u. Rerzius, Séudien in der Anatomie des Nervensystems, Stockholm, 1875.

(57) SÉE, M., “Sur la communication des cavités ventriculaires de l’encéphale avec les espaces sous-arachnoïdiens,” Revue Mensuelle, ii. (1878), üïi. (1879). |

(58) Hess, C., “Das Foramen Magendie und die Offnungen an den Recessus lateralis des iv. Ventrikels,” Morph. Jahrb., Bd. x., 1885.

(59) Wien, B. G., “The Foramen of Magendie in Man and the Cat,” W. F. Med. Journ., vol. xxxix., 1884. “Note on the Foramen of Magendie in Man and the Cat,” Journ. Nerv. and Ment. Diseases, vol. xüi., 1886. “The Metapore (Foramen of Magendie) in Man and an Orang, Medical News, 1893.

(60) Morron, C. A., “The Pathology of Tuberculous Meningitis with reference to its treatment by tapping the Subarachnoiïid, Brit. Med. Journ., ü., 1891. “The Opening between the Fourth Ventricle and the Subarachnoid Space,” Brit. Med. Journ., i., 1893. °

(61) JacoBi, G. W., ‘ Lumbar Puncture of the Subarachnoid Space,” N. 7. Met. Journ., 1895.

(62) KoHLMANN, J., Lehrbuch des Entwicklungsgeschichte des Menschen, Jena, 1898.

(63) Canxiue, A. ‘ Note sur le trou de Luschka,” Journ. de Méd. de Bordeaux, 1897. ‘Contribution à l’étude la voute du quatrième ventricule chez les mammifères,” Development of the Hind-Brain of the Pig 151

ibid. “ Recherches sur la voute du quatrième ventricule des vertébrés. Les trous de Magendie et de Luschka,” Bibliogr. Anat., t. vi., 1898.

(64) BockDaLek, ‘‘ Neue Beobachtungenim Gebiet der physiologischen Anatomie,” Präger Vierteljahrschr, 1849.

(65) Surron, J. BLanD, “The Lateral Recesses of the Fourth Ventricle,” Brain, vol. ix., 1887.

e. EXPLANATION OF FIGURES.

The outlines of all the figures representing sections were made by means of a Leitz camera lucida.

The figures illustrating sections are arranged so that the first figure belonging to one particular embryo represents the most pasterior section ; the last figure of the series representing the most anterior. |

The following reference lettering is common to all the figures :—

a.c. ala cinerea. fu. Flügelwulst. a.l. alar lamina. h.b. hind-brain. a.m.v. anterior medullary velum. L.r. lateral recess. a.p. area postrema. m.b. mid-brain. b. backward projection of the | n X. etc. nucleus of X etc. cranial roof of the fourth ventricle. nerve. b.1. basal lamina. ob. obex. bl.vs. blood-vessels. o.v. otic vesicle. cb. cerebellum. pf. paraflocculus. c.e. central canal. p.m.v. posterior medullary velum. c.v. cerebellar ventricle. rl rhombic lip. ch.pl. choroid plexus. s-a.s. subarachnoiïd space. d.m. dura mater. 1,2, 3, etc st, 2nd, 3rd, etc., neuroJloc. flocculus. meral grooves. f.s. fasciculus solitarius. V. etc. V. etc. cranial nerves.

J.sp. funiculus separans.

Figs. 47-51. 80 mm. embryo. ‘lransverse sections through the hind-brain. Fig. 50 passes through the posterior part of the lateral recess.

Figs. 52-58. 100 mm. embryo. Transverse sections through the hind-brain. Figs. 53-55 illustrate the rhombic lip. Figs 56 and 57 pass through the lateral recess. Fig. 58 shows the cerebellar ventricle.

Figs. 59-64. 150 mm. embryo. Transverse sections through the hind-brain. Figs. 59-62 illustrate the rhombic lip. Figs. 63 and 64 pass through the lateral recess.

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