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- 1 II. Development of the Central Nervous System
- 1.1 Development of Central Nervous System during First Month
- 1.2 Table showing Subdivisions of Neural Tube and their Derivatives
- 1.3 The Central Nervous System at the End of the First Month
- 1.4 The Spinal Cord from the End of the First Month to Maturity
- 1.5 Development of the Hindbrain from the End of the First Month on
- 1.6 The Cerebellum
- 1.7 Development of the Midbrain
- 1.8 Development of the Diencephalon
- 1.9 Development of the Telencephalon
- 1.10 Development of the Wall of the Hemisphere
- 1.11 Formation of Sulci and Convolutions
- 1.12 Development of the Myelin Sheaths
- 1.13 Literature
II. Development of the Central Nervous System
By George L Streeter, Ann Arbor, Mich.
The nervous systems of all vertebrates develop from the same ectodermal germ layer and within certain limits they always pass through the same series of developmental stages. The difference between the higher and lower forms consists only of a variation in size and degree of development of certain of the component structures, owing to the variation in the demand made upon those particular structures by the special life habits, size, and requirements of the respective animals. The nervous system is delicately responsive to the requirements of each individual animal and all of its parts are subject to a greater or lesser development in accordance with their functional necessity.
In this variability in the development of its different parts the nervous system does not adhere to a phylogenetic order. Hence it is impossible to definitely determine the relative position of two animals by the character of their nervous systems. With the exception of one portion the nervous system of the lower vertebrates possesses all the essential features and the same general grouping found in the highest vertebrates. In fact in certain instances they possess structures that are more complicated and presumably more efficient than the analogous structures in higher forms. Even the same structure may exhibit in closely related families a marked difference in the degree of its development, particularly in case of the higher co-ordinating apparatuses such as is represented by the cerebellum. One portion (pallium), however, contrary to the rest of the nervous system, varies in its development directly according to each animal's phylogenetic position. It follows a definite phylogenetic curve. It is present as a small rudiment in fish and amphibians and gradually increases in relative size and complexity as we ascend the vertebrate scale until it finally forms the prominent cerebral hemisphere of man.
In all vertebrates the central nervous system consists of a dorsally placed hollow tube, the walls of which are connected by the peripheral nerves with the different parts of the body. "Where many nerves enter or arise the central apparatus is larger, as in the enlargements of the cord, the medulla oblongata, midbrain roof and thalamus. Further enlargement is produced by the establishment of fibres connecting different levels. A third group of enlargements is produced by the establishment of nuclear masses which serve as higher receptive and co-ordinating centres. In general, it may be said that the nervous system consists of afferent and efferent tracts, or peripheral system, and a central mass that serves to connect and co-ordinate them, or central system. Of the former, the afferent tracts are made up of receptor neurones and the efferent tracts of effector neurones. The latter, or central nervous system, in addition to the central extension of peripheral neurones, consists of intersegmental neurones, uniting different levels, and suprasegmental neurones, that form the receptive and co-ordinating centres for control over the lower neurones. The location of the elaborated sense organs at the forward end of all vertebrates, to facilitate the gathering of food and the detection of enemies and mates, results in the highest development of the nervous system in the head region. We thus speak of cephalization of the central nervous system and distinguish the enlarged anterior end, with which the special sense organs are connected, as brain, and the remainder as spinal cord.
At the time of the closure of the neural tube that portion corresponding to the brain undergoes a threefold constriction, forming three primary brain vesicles which are constant in all vertebrates and form a definite morphological basis for the subdivision of the brain into three primary portions. These are known as the prosencephalon (the most oral one), the mesencephalon, and the rhombencephalon (the most caudal one). Subsequently the first of these (prosencephalon) becomes further subdivided into an end portion or telencephalon and an intermediate portion or diencephalon. The last, or rhombencephalon, is also often subdivided for descriptive purposes into the metencephalon, from which the pons and cerebellum are developed, and the myelencephalon, from which the medulla oblongata is developed. Owing to the tendency to metamerism of the mesencephalon and the rhombencephalon and their conformity with the type seen in the spinal cord, it has been suggested (Strong) that we recognize an epichordal system including all that portion of the central nervous system from which the true cerebrospinal nerves arise, and which lies dorsal to the chorda. The remainder is designated as prechordal, the boundary between the two being the primary ventral infolding of the brain wall (plica encephali ventralis). These terms of subdivision will be constantly made use of in the following pages.
We will first consider the anlage of the nervous system as it is found in the earliest stages, and will then follow its conversion into the medullary tube, and trace the development of the latter during the first four weeks. This will be followed by a description of the central nervous system as it is found at the end of the first month. Up to that time it is necessary to consider the different portions more or less in conjunction with each other. After the first month, however, the further development of the individual subdivisions will be described separately.
Development of Central Nervous System during First Month
The first evidence of the nervous system is the neural groove that forms as an axial furrow in the median line of the germin.-i! plate, as can be seen in Fig. 22. The thickened ectoderm on each side of this groove forms the neural plate. In the Von Spee embryo Grle the borders of the neural plate are beginning to be indicated, and just a little later, in embryos about two weeks old, the elevated edges of the neural plate are clearly marked off from the rest of the ectoderm, as shown in Fig. 23, A.
Fig. 22. Dorsal view of human embryo in the neural-plate stage. The amnion is opened, exposing the germinal plate lying directly on the yolk-sac. (Graf Spee, from Kollmann.) The further elevation of the edges and their approximation and fusion across the median line to form the neural tube is shown in four stages in Fig. 23. The comparison of these figures shows that the formation of the neural tube is most advanced in the middle of the germ plate corresponding to the junction of brain and spinal cord. From this region the differentiation and closure of the tube extends caudally and orally, the last portions to close being called the anterior and posterior neuropores (see Figs. 24 and 26). The process of closure, though it always begins in about the same region, shows some variation in the time of its occurrence. In Fig. 23, C, it is further advanced than in Fig. 23, D, which, judging from the number of somites, is the older embryo of the two.
The anterior neuropore is found closed in embryos of about 23 somites and the posterior neuropore a little later in embryos of about 30 somites, the end of the third week. The neuropores do not exactly represent the anterior and posterior ends of the neural tube. The anterior and posterior margins of the neural plate are rounded off laterally so that the extreme anterior and posterior ends of the neural plate are found in the median line. In the closure of the tube it is the lateral portions of the anterior and posterior margins that unite last, and so the neuropores are found dorsal to what was originally the extreme ends of the neural tube. This is particularly marked in case of the posterior neuropore (Fig. 24). The region in the adult brain corresponding to the anterior end of the neural plate was placed by His at the infundibulum. Johnston (1909) from comparative embryological studies places it at the optic chiasma. The anterior neuropore forms dorsal to this, and by its closure completes the lamina terminalis.
Fig. 23. Four stages in the closure of the neural tube in human embryos possessing from 5 to 14 somites. A, embryo Klb, 5-6 somites, from Keibel u. Elze (Normentafeln); B, embryo No. 391, 7 somites, Mall collection, after Dandy; C, Eternod's embryo, 2.11 mm. long, 8 somites, after Kollmann; D, embryo 2.4 mm. long, 14 somites- estimated age 14 to 16 days. (C and D after Kollmann.)
Fig. 24. Profile reconstruction of human embryo 3.2 mm. long, showing neural tube closed except for anterior and posterior neuropores. The chorda lies closely against its ventral surface. The optic evagination is shown by'a dotted line and is connected with the neural tube by a wide slit. The ear vesicle is indicated lateral to the hindbrain. In the area reuniens the neural tube, chorda, and foregut are still undifferentiated from one another. (After His, 1904.) Ab., truncus arteriosus; All., allantoic duct; Bs., abdominal stalk; CL, cloake; Lb., liver anlage; Lg., lung anlage; Nh., stalk of the umbilical vesicle; Vh., atrium; Vt., ventricle.
While still in the neural plate stage before its closure the central nervous system is differentiated into an anterior portion that is to form the brain and a posterior portion that is to form the spinal cord, as shown in Fig. 23, A. The brain portion is wider, more irregular, and projects beyond the yolk sac, bending forward nearly at a right angle. It forms about one-half of the neural plate. We cannot yet with any clearness recognize the subdivisions of the brain. The spinal cord portion is narrower and uniform in width. It extends caudally to the neurenteric canal, extending on each side a little beyond it. Most of the spinal portion of the neural tube that is differentiated at this time is that which is to form the cervical cord. The lower cord is formed by the caudalward expansion of the neural plate. In embryos of seven somites, Fig. 23, B, where the neural tube is just beginning its closure, there appear two distinct constrictions in the brain wall, subdividing it into a prosencephalon, mesencephalon, and rhombencephalon. These are best seen in Fig. 25, which is from the same embryo, but the ectoderm is partially removed, showing the cut edge of the right half of the neural plate. With the closure of the tube they become still more marked, as shown in Fig. 23, D. In these young stages the neural tube follows the flattened curve of the yolk sac, the only bending in the axial line being anteriorly and posteriorly where it projects free beyond the surface. It is now supposed that the sharp ventral convexity sometimes found in the spinal region in these young specimens is artificially produced by the preserving medium.
Fig. 25. — Dorsal view of model of human embryo possessing 7 somites, being the same embryo shown in Fig. 23, B. Portion of ectoderm of right neural plate is removed, showing thickness of wall and its relation to deeper structures. The three primary cerebral vesicles are indicated. (After Dandy.) All., allantois; Ch., chorda; Coe., ccelom; Fg., foregut; Hg., hindgut; Ht., heart; Mes., mesoderm; P. c, pericardial ccelom; U., umbilical arterial sinus; V., umbilical vein.
The character of the neural tube at the beginning of the third week is shown in Figs. 24, 26, and 27. The age of embryo from which these reconstructions were made was estimated by His at two weeks, but on comparing it with other embryos we are probably safer in considering it as being in the third week. The closure of the tube is now complete except for the small anterior neuropore and a small portion at the caudal end. The cranial portion of the tube is distinctly subdivided into the three primary vesicles. The most caudal one, or rhombencephalon, is much the largest. Its roof is not yet thinned out, the wall of the neural tube being everywhere of about the same thickness.
Fig. 26. — Median view of a model of the brain of a human embryo 3.2 mm. long, being the same specimen shown in Fig. 24. (After His.)
The first flexure to form in the neural tube is the cephalic flexure. It is well marked at this time, being a sharp bend in the neural tube in the region of the midbrain so that the axis of the forebrain forms approximately a right angle with that of the hindbrain, the notch formed on the ventral surface being known as the ventral cephalic fold. The location of the future pontine flexure is marked by a ventral bulging of the floor of the tube. The anterior primary vesicle or forebrain at the completion of its closure is already marked off into its main subdivisions. The optic evagination exists as a depression in the lateral wall before the closure is complete, but at the time under consideration it forms a distinct pocket projecting later alward and caudalward. Extending from its dorsal border is a fold (margo thalamicus) which marks the boundary between the telencephalon and diencephalon and separates the anlage of the thalamus from that of the pallium. The wall adjacent to and forming the anterior border of the evagination forms the anlage of the corpus striatum. The wall posterior to the evagination forms the ventral half of the diencephalon or hypothalamus.
Fig. 27. — Lateral view of same model shown in Fig. 26.
The changes occurring in the central nervous system between the third and fourth weeks may be seen by comparing Figs. 28 and 29 with Figs. 26 and 27. The tube is now completely closed and the neuropores have disappeared. The walls due to their differentiation begin to show a variation in thickness. This is particularly marked in the thinning of the roof of the rhombencephalon. The flexures of the tube are more marked. The cephalic flexure has increased from a right angle to an acute one, so that the axis of the forebrain is about parallel with that of the hindbrain. A distinct pontine flexure is now present in the rhombencephalon.
Fig. 28. — Median view of a model of the brain of a human embryo 6.9 mm. long. This figure. should be compared with Fig. 26. (After His.)
Fig. 29. — Lateral view of same model shown in Fig. 28. Compare with Fig. 27.
The formation of the flexures of the neural tube is shown in Fig. 30. It will be seen that there are three distinct flexures, cephalic, pontine and cervical. Two of them have already been mentioned. The third, or cervical flexure, marks the junction of brain and spinal cord and is formed about the same time as the pontine flexure. They are formed, in part at least, in consequence of unequal growth of different parts of the neural tube. They probably influence and also are influenced by the growth of the surrounding structures. The cephalic and cervical flexures involve the surrounding structures to a considerable extent so that there is a corresponding bend of the axis of the whole head, and thus the presence of them can be recognized on the exterior of the embryo. The pontine flexure, however, is limited to the nervous system. The cephalic flexure persists into adult life. The pontine flexure finally disappears and the cervical flexure nearly does.
Fig. 30. Profile views of the brains of human embryos as seen during the third (A), fourth (B), and eighth (C) weeks, showing the conversion of the three primary cerebral vesicles into their chief subdivisions and the formation of the flexures of the neural tube. A, optic vesicle; Br, pontine region; Gb, auditory vesicle; H, telencephalon; Hb, metencephalon; J, isthmus; M, mesencephalon; N, myelencephalon; NK, neck bend; Pm, mammillary recess; Rf, posterior medullary velum; Tr, infundibular recess; Z, diencephalon. (After Wilhelm His (1831-1904))
The formation of the pontine flexure marks a line dividing the rhombencephalon into an oral portion (metencephalon), from which the cerebellum and pons are developed, and a caudal portion (myelencephalon) which forms the medulla oblongata. The constricted portion separating the rhombencephalon from the mesencephalon (Fig. 28) is known as the isthmus. It differs from the adjoining portions of the neural tube in never undergoing any special development. It eventually forms the velum medullare anterius and through its lateral and ventral walls pass fibre tracts connecting other, parts of the neural tube.
The mesencephalon and diencephalon do not differ materially from the preceding (three weeks) stage, though in the hypothalamic region one can recognize two shallow pockets in the midline in the floor, the more oral one being the anlage of the infundibulum and the more caudal one being the mammillary recess. The optic evagination has undergone considerable modification, the inversion of its lateral wall changing it from a simple vesicle to an eye cup which remains connected with the brain wall by a narrow hollow stalk. The former constitutes the eyeball and the latter the optic nerve. The subdivisions of the telencephalon are more clearly marked in Fig. 28 than in Fig. 26. It is easy to recognize the protruding pallium separated from the optic evagination by the corpus striatum and from the thalamus by the margo thalamicus. The wall in front of the corpus striatum and adjacent to the median line (lamina terminalis) constitutes the anlage of the rhinencephalon. The subdivisions of the neural tube that can be recognized toward the end of the fourth week, in embryos about 7 mm. long, may be summarized as in the accompanying table (p. 39).
Table showing Subdivisions of Neural Tube and their Derivatives
Prosencephalon (Anterior vesicle)
Telencephalon Rhinencephalon Corpora striata
Cerebral hemisphere Oral end of third
Optic thalamus Optic tract Hypothalamus
Colliculi Mesencephalon Mesencephalon Tegmentum (Middle vesicle) Crura cerebri
ventricle Lateral ventricle
Aqueduct of Sylvius
Rhombenceph- Metencephalon alon (Poste
rior vesicle) Myelencephalon Medulla oblongata
The Central Nervous System at the End of the First Month
By the end of the first month there is completed what we may call the primary stage in the growth of the nervous system. The primary neurons forming the peripheral nerves are by that time well laid down; all their chief peripheral branches and plexuses are indicated, and centrally the nerve roots can be traced into the substance of the walls of the neural tube, where the nuclei from which the motor roots arise can be definitely outlined, and the sensory roots can be recognized as forming definite longitudinal fibre bundles, extending upward and downward in the outermost layer. The higher neuron systems, however, are still in a rudimentary state, and in sections through the brain and cord at this time we see only the primary apparatus differentiated. Such co-ordinating centres as the pons, olive and cerebellum are still undeveloped, and the forebrain, further than presenting the beginning threefold division into ependymal, mantle, and marginal zones, shows little evidence of differentiation and still remains a relatively simple thin-walled tube. This period in development thus corresponds to a rudimentary nervous system in which there is found only the apparatus necessary for the simple cerebrospinal reflexes, the system of primary neurons.
The outer form of the brain and spinal cord and their relation to the body outline are shown in Fig. 86. A series of transverse sections through the same specimen is shown in Fig. 31. It is at once seen that the greatest bulk of the central nervous system is formed by the rhombencephalon and the spinal cord. Of these two the rhombencephalon is relatively the larger; it is approximately two-thirds as large as the whole spinal cord and is as large as the midbrain and forebrain taken together.
The spinal cord is largest in the cervical region and from there gradually tapers down to the coccyx, except in the lumbosacral region, where it is somewhat larger again. The tendency toward cervical and lumbar enlargements is plainly indicated. The cord in cross section (Fig. 31, A) presents a rounded quadrilateral outline. It consists principally of two thick lateral walls. These are united ventrally and dorsally in the median line by what we have previously recognized as the floor plate and roof plate, which are here reduced to narrow seams. The thick lateral walls are subdivided by a longitudinal furrow, the sulcus limitans, into ventral and dorsal portions, known respectively as the basal and alar plates. The ventral or basal plate is the thicker of the two. Its thickness is largely due to the proliferating cells of the mantle layer, the anlage of the future anterior horn. Among these are grouped clusters of neuroblasts whose growing processes extend out through the marginal zone and are assembled to form the anterior nerve roots. The dorsal nerve roots enter the cord opposite the sulcus limitans and form in the marginal zone a longitudinal strand which is the forerunner of the posterior funiculi of the cord. In the marginal zone, in addition to the prominent bundle of axons derived from the posterior roots, there can be seen scattered axons running both longitudinally and transversely which belong to the co-ordinating neurons of the mantle zone. It is these that later form in large part the anterolateral tracts of the cord.
Fig. 31. — Series of transverse sections through the central nervous system of human embryo one month old, made from tracings taken from the model shown in Fig. 86. These are all on the same scale of enlargement and thus graphically represent the relative size and thickness of the neural tube in the different regions. S.I., sulcus limitans. Enlarged 25 : 1.
In the transition from the spinal cord to the rhombencephalon the most striking difference consists in the widening out of the thin roof plate and the accompanying flaring apart of the alar and basal plates. As a result of this the lumen of the neural tube widens out from the narrow lanceolate cleft characteristic of the spinal region to the capacious fourth ventricle. Opposite the entrance of the trigeminal nerve the lumen is larger at this time than in any other part of the neural tube.
The lateral walls of the rhombencephalon have a larger area in cross section than the lateral walls in the spinal region (Fig. 31, B, C). Their form and degree of differentiation, however, are essentially the same. There is the same sulcus limitans separating them longitudinally into basal and alar plates ; and, as in the spinal cord, there is the marginal zone containing the longitudinal fibre tracts, and the mantle zone consisting of clusters of proliferating neuroblasts which in part form the nuclei of the motor nerve roots. The ependymal zone is made up of closely packed and deeply staining primitive cells. The layer is several cells thick and the uneven line separating it from the mantle zone indicates that it is still active and giving off cells to the latter.
Fig. 32. Reconstruction showing the cranial nerves in a 10 mm human embryo (Huber col. No. 3). The brain wall is removed so as to show the primary sensory paths and motor nuclei of the different nerves.
The arrangement of the nuclei of origin of the nerves connected with the rhombencephalon and the entering fibres of their sensory rootlets is on the same general plan as in the cord. The motor nuclei are grouped in a longitudinal column in the mantle zone of the basal plate. The fibres supplying somatic muscles pass directly ventralward through the marginal zone and emerge as the rootlets of the hypoglossal and abducens nerves, as shown in Figs. 31, B, and 32. In the lateral part of the basal plate is the nuclear series supplying motor fibres to visceral musculature. These fibres pass lateralward and unite with the entering sensory fibres of the corresponding nerves. It is these fibres that constitute the motor elements in the trigeminal, facial, glossopharyngeal, vagus and spinal accessory nerves. This series of lateral motor nuclei may be subdivided on the one hand into a part that lies directly lateral to the somatic motor group, constituting eventually the nucleus ambiguus and the nucleus of the facial nerve, and on the other hand into nuclei massed nearer the entrance of the sensory fibres. The latter is well represented in case of the trigeminal nerve and in lesser degree in the dorsal motor nuclei of the ninth and tenth nerves. (Compare Figs. 31, B and C, and 32.) The sensory fibres enter the marginal zone near the junction of the basal and alar plates, and immediately form longitudinal tracts analogous to the posterior funiculi of the spinal cord. The entering fibres of the seventh, ninth and tenth nerves in this manner unite to form the tr actus solitarius, as shown in Figs. 32 and 96. The entering fibres of the trigeminal nerve form a similar but separate bundle. In the latter case we can recognize a cephalic limb extending to the anlage of the cerebellum and midbrain and a caudal limb extending toward the spinal region. A similar but smaller tract is formed by the entering fibres of the acoustic nerve, which at this time consists mostly of vestibular fibres. In addition to the tracts mentioned there are present in the marginal zone a few early representatives of the correlating fibres which later form the formatio reticularis and system of arcuate fibres and their longitudinal extensions. Near the median line the marginal zone is somewhat thicker from the presence of such fibres.
That portion of the alar plate in front of the trigeminal nerve constitutes the anlage of the cerebellum, but as yet it shows no apparent difference from the alar plate of the caudal half of the rhombencephalon.
The so-called rhombic grooves or transverse furrows, shown in Figs. 33, 34, and 95, are sharply marked at this time in the floor of the fourth ventricle. These grooves evidently form an important feature in the early growth of the rhombencephalon. They have been reported in a variety of different mammals (pig, sheep, dog, cat, rabbit, and rat) beside man and seem to be fairly constant in form and number. In man they are best seen during the third and fourth weeks. At first they are described as involving the whole thickness of the wall so that they can be seen both on the inner and outer surfaces of the brain wall (Gage, 1905). At the fourth week the outer surface of the wall is smooth and the grooves involve only the ependymal layer. After the fourth week the grooves rapidly disappear, leaving no marking that can be seen in the adult.
There are six rhombic grooves. The most cephalic one is in the region of the pontine bend, and they extend from there caudally as shown in Fig. 34. They bear a constant relation to the cranial nerves, which is indicated in Figs. 33 and 95. If the grooves are labelled a,b, c, d, e, and /, then it can be seen that we have the following relations : the trigeminal nerve arises conjointly from a and b; the facial nerve (motor root) runs transversely beneath the floor of groove c, which usually is the deepest and most sharply cut of all six grooves; the acoustic nerve has its attachment to the alar plate adjoining grooves c and d; the abducens nerve arises from d, a shallow and somewhat quadrilateral groove ; the glossopharyngeal nerve (motor portion) runs under the floor of the narrow groove e, and the motor roots of the vagus arise from /, which groove merges caudally into the general floor of the ventricle.
Fig. 33. — Diagram showing relation of the cranial nerves to the floor of the fourth ventricle and the rhombic grooves, being the same specimen as shown in Fig. 34.
Fig. 34. — Dorsal view of model showing rhombencephalon of human embryo one month old, being the same model shown in Fig. 86. The thin tela chorioidea is removed, exposing the floor of the fourth ventricle and rhombic grooves. The anlage of the cerebellum is formed by the alar plates cephalad to the pontine flexure. Compare with Fig. 33.
This nerve distribution is constant in the different mammals, and it is very likely that in this we have an explanation of the significance of these grooves. The predominant view regarding them heretofore has been that they are neuromeric and in a series with the spinal segments and the coarser transverse divisions of the mid- and forebrain. Instead of this, if emphasis is laid on the fact that they stand in constant relation to the lateral group of cranial nerves (fifth, seventh, ninth and tenth), then they may be fitted in with and form part of the branchiomeric system. This view has in its favor the fact that they are not only united by nerve trunks, but also numerically correspond to and are embryologically contemporary with the branchial and facial arches in the manner shown in the following table : Maxillary process \ N tri eminus f Groove a Mandibular arch J ° \ Groove b Hyoid arch N. facialis Groove c — N. abducens Groove d Third branchial arch N. glossopharyngeus Groove e Fourth branchial arch N. vagus Groove / The one discordant feature is groove d, which has no corresponding branchial arch. As yet we have no satisfactory explanation for either the aberrant course of the abducens nerve or its connection with this particular groove.
In the region of the midbrain the basal plate is much like that of the rhombencephalon and is in about the same stage of differentiation. In its mantle zone are the clusters of neuroblasts constituting the nuclei of the third and fourth cranial nerves. The fibres from the former pass through the marginal zone directly ventralward, as shown in Figs. 31, D, 32, and 86, and emerge from the hollow of the mesencephalic bend. The fibres of the fourth nerve on the other hand pass dorsalward just beneath the ependymal layer and decussate in the roof at the junction of the mid- and hindbrains and emerge directly after their decussation. No satisfactory explanation has as yet been given for this dorsal decussation of the fourth nerve.
The alar plates of the midbrain are thinned out and extend around dorsally to meet in the median line, the roof plate thus being reduced to a narrow seam. The only evidence suggesting the later development is found in the ependymal layer which forms an extensive germinal bed from whose cells are to be derived the neuroblasts composing the future corpora quadrigemina. The ependymal and mantle zones still exist as one layer. It is the outer portion that gradually becomes differentiated as the mantle zone and that gives origin to the quadrigeminal neuroblasts.
The outlines between the mesencephalon, thalamencephalon, and prosencephalon can be distinctly made out both externally and internally. The prosencephalon is characterized by a prominent lateral evagination whose lumen is to form the lateral ventricle and is connected with the main lumen of the neural tube by the large foramen of Monro. It is the wall of this pouch that is to form the future cerebral hemisphere, as will be described later. Two other evaginations are developed from the floor of the prosencephalon to form the special sense organs of smell and sight. The former at the end of the first month is just making its appearance in the form of a slight depression in the lumen of the anterior brain wall just lateral to the lamina terminalis and does not yet form a distinct pouch. The visual apparatus is much further advanced. As seen in Fig. 31, E, we have a well-formed optic cup connected by a hollow optic stalk with the floor of the prosencephalon at its junction with the thalamencephalon.
The thalamencephalon as yet shows little sign of differentiation, though it is possible to divide it into a ventral portion that is to form the hypothalamus and infundibulum, and a dorsal portion that is to form the thalamus. The latter is continuous with and resembles the alar plate of the midbrain.
The Spinal Cord from the End of the First Month to Maturity
A general sketch of the formation of the neural tube and the differentiation of its walls and its change in form up to the completion of the first month has been given. The further changes by which it becomes converted into the adult spinal cord now remain to be considered.
In considering the different elements taking part in its further development it is important to follow the subdivision of the wall of the cord into its three constituent layers or zones (ependymal, mantle, and marginal), tracing the fate of each up to the adult condition. At the same time one should keep in mind the foursided form of the cord, consisting of two lateral walls united ventrally by a floor plate and dorsally by a roof plate. The roof and floor plates retain their primitive characteristics throughout and are only modified secondarily, due to the changes in the adjoining portions of the lateral walls. The lateral walls on the other hand undergo enormous growth, and it is the character of their thickening that determines the shape of the cord.
The lateral walls are subdivided into a ventral or basal plate and a dorsal or alar plate, the junction between the two corresponding to the sulcus limitans. These are also known as the anterior "Markcylinder" and posterior "Markprisma" of His. From the first of these are developed the anterior gray columns or horns, the motor nerve roots, and the surrounding funiculi of longitudinal fibres (anterolateral ground bundles). From the dorsal or alar plates are developed the posterior gray columns, the substantia gelatinosa and the dorsal funiculi into which the posterior nerve roots enter. The basal plate is primarily a motor apparatus and the alar plate is primarily a sensory one.
The basal and alar plates are united by an isthmus-like intermediate portion known as the "Schaltstiick" of His. This area, owing to the shrinking of the tissues, particularly the radial framework fibres, in prepared specimens is usually sharply demarcated on the surface of the cord by two longitudinal furrows, the marginal groove directly in front of the entering posterior roots and the cylinder groove at a point about midway between there and the emerging anterior roots. From the gray substance of this area are developed many of the internal arcuate fibres, and the adjoining marginal zone becomes converted into the formatio reticularis and supplies a pathway for the spinocerebellar and cerebrospinal tracts.
In Figs. 36, 37, 38, and 39 are shown the typical stages in the conversion of the neural tube with its three primitive zones into the more complicated solid cord as found in the adult. Starting with the ependymal zone and tracing it through these successive stages we meet with the appearances that are schematically shown in Fig. 35. To facilitate comparison these are all drawn on the same scale of enlargement.
Fig. 35. — Diagram showing the fate of the ependymal layer and the formation of the posterior median septum and the central canal of the spinal cord. The approximate length (crown-rump) of the embryo is indicated in mm. below each stage, s. g., dorsal gray column and substantia gelatinosa.
It can be seen that at the beginning of the second month (15 mm.) the lumen of the cord is still relatively large, and that from that time on up to embryos of 80 mm. it decreases in actual size and still more so in size relative to the size of the cord. The shape of the lumen passes through characteristic changes. As seen in transverse section it is at first (15 mm.) an elongated oval slit, and is wider in the dorsal half. At 30 mm. the condition is reversed and the lumen is" wider in the ventral portion, while the dorsal portion is reduced to a narrow slit. Eventually the dorsal portion becomes obliterated and there onlv remains the rounded ventral portion, and it is this that forms the permanent central canal. The longitudinal furrows that have been described as indenting the sides of the lumen are probably to be classed as shrinkage phenomena, since they are not present in razor sections of unembedded pig embryos. The most constant of these furrows is the sulcus limitans at the junction of the basal and alar plates.
The ependymal cells that form the ventral portion of the lumen differ already in the 15 mm. stage in character and arrangement from those forming the dorsal portion. They are more compactly arranged and form a narrow band that is more sharply separated from the adjacent mantle zone than is the case in the dorsal portion of the cord. If we may regard the ependymal zone as a germinal bed delivering proliferating cells to the mantle zone then it is apparent that this phenomenon is practically completed in the ventral portion and the remaining cells are entering the resting stage, while the process is still in active operation in the dorsal portion. The ventral portion of the ependymal zone, like the ventral portion of the cord in general, may be regarded as further advanced in its development than the corresponding dorsal portions.
Fiq. 36. — Cervical spinal cord of a human embryo 15.5 mm. long. Enlarged 60 : 1. Dp., roof plate; Bp., floor plate, in which the anterior commissure is developing. (After Bryce.)
In embryos from 15 mm. on, coincident with the formation of the dorsal columns of gray matter, there is a gradual subsidence of the proliferation of ependymal cells around the dorsal portion, and the whole ependymal border comes to a resting stage and forms a narrow, sharply demarcated border for the central canal. In doing this the size of the canal is decreased through the approximation and fusion of the walls of its dorsal portion. In Fig. 37 this process of fusion is in active operation. As the walls come together the cells lose their radial direction and form a unilateral compact strand which is soon replaced by a sparsely nucleated seam of supporting tissue like that forming the framework of the mantle zone. It is the extension of this seam of closure that eventually forms the posterior median septum. The ventral end of the septum is a fixed point and its further growth and elongation, coincident with the development of the dorsal funiculi, must be considered as taking place principally at the dorsal end.
Fig. 37. — Cervical spinal cord of a human embryo 30 mm. long (Huber collection, No. 15). Enlarged 60 : 1. S.m., junction of lateral and posterior funiculi, which point in shrunken specimens is marked by a deep groove.
The development of the mantle zone is closely associated in the earlier stages with that of the ependymal zone and the line of demarcation between them is ill-defined. As has been described in the section on histogenesis of nervous tissues the mantle and ependymal zones were originally one common layer, and the mantle zone may be regarded as a proliferation and differentiation of the outer ependymal cells. Later, as the anterior and posterior columns of gray substance begin to take form (15 mm.), the ependyma gradually enters upon its resting stage and from then on becomes sharply marked off from and takes no further part in the development of the mantle zone.
On comparing Fig. 36 to 39 it is seen that in 15 mm. embryos we can already speak of an anterior gray column (horn) which is composed of a supporting framework and clusters of developing neuroblasts. The processes from the neuroblasts are assembled into rootlets which emerge on the ventrolateral border of the cord as the anterior nerve roots. The anterior columns in the later stages enlarge and their contour becomes irregular and eventually we can recognize a lateral division, the so-called lateral horn. In the 80 mm. embryo (Fig. 39) there is presented practically the adult form. The enlargement from 30 mm. on consists partly in the elaboration of the supporting framework and partly in the increase in size of the contained neuroblasts. The growth of the latter involves also their processes, so each ventral column would become larger through the growth of its own processes as well as the invading processes from other portions of the mantle zone. The elaboration of the supporting framework and development of the processes of the neuroblasts results in a greater separation of the neuroblasts from each other and gives the mantle zone the appearance of being more sparsely nucleated. There are also certain supplementary factors in the growth of this tissue due to the process of vascularization and later due to the acquisition of myelin sheaths.
Fig. 38. — Cervical spinal cord of a human fetus 45 mm. long (Huber collection, No. 18). Enlarged 45 : 1. This figure should be compared with Figs. 36, 37, and 39, all of which represent the same region in its different stages of development.
The formation of the dorsal gray columns (posterior horns) occurs somewhat later than the ventral ones. In the 15 mm. embryo (Fig. 36) it is possible to outline that portion of the mantle zone that is to form them. They possess, however, very little at that time either in structure or form that is characteristic; the cells of the ependymal zone of that region are still actively crowding outward to become incorporated in the mantle zone. In embryos of 30 mm. the outline of the dorsal columns commences to take form and masses of neuroblasts group themselves so as to form a cap at the dorsal border, which eventually becomes the ganglionic mass known as the substantia gelatinosa. The further elongation of the mantle zone into typical posterior columns can be seen by comparing Figs. 37, 38, and 39.
Fig. 39. — Cervical spinal cord of a human fetus 80 mm. long. Enlarged 30 : 1.
As has already been shown the roof plate as such disappears with the formation of the posterior median septum. The floor plate, however, persists and is formed in part by the ependymal cells which extend from the lumen radially outward to the surface of the cord, forming the bottom of the anterior longitudinal fissure. In addition to the ependymal cells the floor plate is made i up of the processes from the heteromeric neuroblasts of the mantle zone, whose decussation eventually constitutes the anterior commissure. Neuroblasts of this character are found in considerable numbers in the inner portion of the mantle zone and are analogous to the internal arcuate fibres found in the hindbrain. The processes forming the anterior commissure cross the median line in the mantle zone. A marginal layer can scarcely be said to exist in the region of the floor plate.
The development of the marginal layer (Eandschleier of His) and its conversion into the white substance of the cord are dependent upon the foreign cells whose axons penetrate this zone and thread their way through its meshes forming the longitudinal fibre tracts of the cord. These axons may be classed into five main groups: (a) dorsal root fibres arising from the spinal ganglia; (b) short intersegmental fibres (ground bundles) arising from neuroblasts of the mantle zone and serving to connect adjacent levels of the cord; (c) long suprasegmental fibres connecting the cord nuclei with higher centres; (d) long descending fibres connecting nuclei of the hindbrain with lower levels in the cord; and (e) long fibres forming the descending palliospinal tracts. Of these fibre groups (a) and (b) make their appearance first (end of first month). Very soon afterward groups (c) and (d) appear (beginning of third month). The last fibres to appear are those belonging to group (e) (end of fifth month). The axons belonging to group (a) form a tract of fibres (funiculi posteriores) that always remains separated from the remaining fibres. Groups (b-e) partly merge into one another forming the anterolateral funiculi and thus cannot be so sharply outlined. In shrunken specimens the radial fibres of the marginal zone contract and cause the longitudinal fibres to present the appearance of being arranged in distinct bundles. The posterior funiculi in such specimens stand out with exaggerated distinctness.
The anterolateral funiculi do not meet in the middle line owing to the interposition of the floor plate. The latter plays only a passive part in the further growth and thus subsequent to the growth of the adjacent mantle and marginal zones there is formed the deep anterior median fissure, in which are found the nutrient blood-vessels of the cord. The formation of this fissure is readily seen by comparing Figs. 36 to 39.
The growth of the posterior funiculi is dependent on the addition of new fibres derived from the spinal ganglia and also on the extension upward of overlapping fibres from lower segments of the cord. At the end of the first month they form an oval bundle in the marginal zone, and when a piece of cord is examined with a low-power lens these fibres can be seen forming a white longitudinal band on the dorsolateral surface of the cord. In the median line the marginal zone is very thin or absent, so that the nuclear substance of the ependymal and mantle layers can be seen projecting between the posterior funiculi of the two sides. As these bundles enlarge they become thicker and spread toward the median line, where they eventually meet. As they meet in the median line they bend forward, as is shown in Fig. 35, and fill in the space left by the receding ependyma. It may be supposed that their presence plays a part in the stimulation of the production of the posterior median septum, which forms between the right and left halves. As these fibres crowd ventralward the posterior gray columns extend dorsolateralward and the resulting form of the combined posterior funiculi is wedge-shaped as found in the adult. In the cervical region in embryos between 20 and 60 mm. (Figs. 37 and 38), there is a V-shaped portion of these funiculi in the dorsal part at the median line that differs in appearance from the remainder. This is regarded (His) as the primitive column of Goll. The difference in appearance is doubtless due to the fact that it consists entirely of longitudinal fibres destined for the gracile nucleus at the cephalic end of the cord, and is not constantly giving off collaterals to the gray substance as the other fibres of the funiculus seem to do. In the process of shrinkage such collaterals draw in or flatten the remaining funiculus, while it leaves the dorsomedian wedge (column of Goll) unaffected. The latter consequently stands out prominently in all shrunken specimens. In older cords, as the supporting framework becomes more complete, the contrast between these two portions becomes less noticeable.
The myelinization of the fibres of the cord does not begin until about the fifth month of fetal life and is not completed until between the 15th and 20th year (Flechsig, '90, Popoff, '88, Bechterew, '87, and Trepinski, '98). It becomes first apparent in the anterior and posterior roots and the ventral commissure. Very soon afterward the ventrolateral ground bundles begin to show scattered myelinated fibres and likewise a portion of the posterior funiculi.
Three typical stages in the process of myelinization of the cord are shown in Fig. 40. On comparing these it will be seen that the formation of myelin occurs along certain tracts or systems of fibres, and owing to this difference in the time at which they acquire their myelin we are able to map out the different levels of the cord into definite functional areas. One of the latest systems to become myelinated is the pyramidal tract, which can still be seen at the seventh month (Fig. 40) as an open area. It becomes myelinated between the ninth month and second year.
Fig 40. — Diagram showing the myelinization of the spinal cord at different periods in fetal life. Rz. ant., anterior root zone; Rz.med. median lu "t zone; Rt post med., median posterior root zone; Rz. post tat., lateral posterior root zone (Lissauer); Z. med., median zone; Pyr. tat., fasciculus cerebroepinalis lateralis; Pyr. ventr., fasciculus cerebrospinalis v entrails. (After Trepinski.)
Though the anterior and posterior roots show the beginning of myelinization about the same time, the process is simpler in the anterior roots, and their myelinization is uniformly completed at a time when not more than one-half of the fibres of the posterior roots show any myelin. The fibres of the posterior roots become myelinated in a series of rather definite stages. Each root can thus be subdivided into a number of different fibre groups. Likewise on the basis of this difference in their myelinization the fibres of the posterior funiculi have been subdivided into five different embryonic fibre systems, which present a characteristic grouping in the different levels of the cord, as shown in Fig. 40. These systems are as follows :
- Anterior root-zone, consisting of fibres from posterior roots which after a longer or shorter course in the posterior funiculi disappear in the anterior portion of the posterior horns (Rz. ant.. Fig. 40). It extends throughout the whole length of the cord and is the first system in the posterior funiculi to begin myelinization.
- Middle root-zone consists of a group of fibres derived from the posterior roots, which lie between the anterior and posterior root-zones. This zone may be divided into two divisions, first and second, the former becoming myelinated in embryos 19 to 20 cm. long and the other somewhat later. The fibres of the first system after a short course enter the column of Clark, and in regions where this is absent they are lost in the gray substance connecting the anterior and posterior horns.
- Posterior root-zone is divided into a median portion and a lateral portion. The fibres of the median portion pass mostly forward and after entering the posterior horn they extend to the region of large ganglion cells in the anterior horn. The fibres of the lateral portion are apparently derived from the posterior roots and end in the substantia gelatinosa, constituting Lissauer's column.
- Median zone lies against median septum and is most distinct in the cervical and upper two-thirds of the thoracic region. The course of its fibres is not known, but it is apparently distinct from the fasciculus gracilis.
- Fasciculus gracilis (column of Goll), commencing at the tenth thoracic segment, extends upward in a compact bundle to reach the nucleus gracilis. The source of its fibres is not known.
It will be seen that three of these systems are derived from fibres in the posterior roots, and in two of them the source of the fibres is not definitely known. In the order of their myelinization the different systems may be grouped as follows : First stage Anterior root-zone Second stage Middle root-zone (first division) Median zone Third stage Fasciculus gracilis, Middle root-zone (second division) Posterior root-zone (median division) Fourth stage Posterior root-zone (lateral division) The caudal end of the spinal cord exhibits certain departures from the uniform development characterizing the rest of it, to which special attention may be directed. If one examines a sagittal series through an embryo 11 cm. long, as shown in Fig. 41, it can be seen that the extreme tip of the cord lying in the tail anlage has been closed off to form a simple epithelial sac. The lumen of the cord above this point becomes obliterated and there results a slender solid strand of nervous tissue which we know as the filum terminale. The epithelial sac becomes the vestiges medullaires coccygiens of Tourneux and Herrmann, whose development is described by Tourneux (Precis d'embryologie humain, second edition, 1909, pp. 348, 349) as follows: At the beginning of the third month the neural tube still extends to the extreme end of the vertebral column into the tail bud, and its slightly enlarged tip is closely united to the deep layers of the skin. Toward the end of the third month the spinal column, developing faster than the soft parts, draws along the part of the neural tube that is adherent to it and whose extreme tip remains attached to the skin. As a result of this unequal growth the terminal or coccygeal portion of the neural tube becomes bent in the form of a loop, the more deeply situated limb of which is attached to the posterior surface of the coccyx (segment coccygien direct), and the other more superficial limb extends obliquely from a caudal and ventral position to one more dorsal and cranial (segment coccygien reflechi). During the course of the fourth month the more deeply situated limb, the segment coccygien direct, atrophies and disappears, while the more superficial one, the segment coccygien reflechi, continues to develop into the fifth month and gives origin to cell cords or cell masses which contain cavities lined either with prismatic or pavement epithelium; these are the vestiges medullaires coccygiens or paracoccygiens. These structures from the sixth month on suffer a progressive atrophy, but it is possible to recognize traces of them up to the time of birth.
Fig. 41. — Schematic median section through the caudal end of a human fetus 11 cm. long (crownrump), showing the formation of the vestiges meclullaires coccygiens and its relation to the filum terminale(After Unger and Brugsch.)
The caudal end of the central canal extends through the conus medullaris to the beginning of the filum terminale. At its lower end it undergoes a conical expansion out of which open irregular side pouches and occasionally an elongated blind sac giving the canal the appearance as though the lower end were bent on itself (see Fig. 42). This caudal enlargement of the canal is known as the ventriculus terminalis.
During the earliest stages, up to the time of the highest development of the anlage of the tail, the spinal cord, chorda and mesoderm develop at the same rate. With the reduction of the tail bud the reduction first occurs in the mesoderm, and thus the spinal cord temporarily becomes longer than the vertebral column. With the formation of the coccygeal process there begins a relative increase in the rate of growth of the vertebral column. At the third month, Fig. 43, the cord is about the same length as the vertebral canal, but from the third month on into adult life the vertebral column becomes increasingly longer than the cord. The cord is more precocious than the skeletal system and reaches its full size before the latter has finished its growth.
Fig. 42. — Caudal end of the central canal of the spinal cord in a human fetus 9 cm. long (crown-rump), showing the formation of the terminal ventricle. (After Unger and Brugsch.)
Fig. 43. — Spinal cord exposed from behind in a three months old embryo, at which time the cord still extends to the caudal tip of the vertebral canal. (After Kolliker.)
Owing to this unequal growth during the latter part of fetal life there is a gradual change in the position of the cord in the vertebral canal. Since the cephalic end of the cord is fixed this unequal growth results in its caudal end being drawn upward away from the lower end of the canal. At the time of birth that part of the cord from which the coccygeal nerves arise is found opposite the third lumbar vertebra; in the adult it is opposite the first lumbar. In this process of shifting, the caudal tip of the cord remains attached to the coccyx, and becomes stretched out into the slender filum terminale. Likewise the nerve roots, their ganglia, with the exception of the ganglion coccygeale, having already become attached in the intervertebral foramina, become stretched out and come to lie in an oblique direction, the most caudal root being longest and most oblique. There is thus formed the cauda equina.
Concerning the development of the blood-vessels of the spinal cord the reader is referred to the corresponding section in the chapter on the development of the blood and vascular system.
The development of the membranes of the cord has been worked up in greater detail in other mammals than in man. According to Sterzi (1900), in the sheep embryo 15 mm. long there is a meningeal mesenchyme, which in embryos 20 mm. long forms a definite membrane. In the 80 mm. embryo this membrane becomes differentiated into an outer layer or dura mater and an inner layer or meninx secundaria, the two being separated by an intradural space. The dural layer is separated externally by the epidural space from an endorhachide, which resembles the dura but is always distinct from it. Finally in the 157 mm. embryo the meninx secundaria is further differentiated into an outer layer or arachnoideal coat and an inner layer or pia mater as seen in the adult.
Development of the Hindbrain from the End of the First Month on
Up to the end of the first month the rhombencephalon passes through the same general process of development that has been described for the spinal cord. It undergoes the same differentiation into ependymal, mantle and marginal zones. Its walls also are divided into two lateral plates, united ventrally by a floor plate and dorsally by a roof plate. The latter is very broad and is thinned out so as to form an extensive membrane covering in the lumen of the tube. The lateral walls, as in the case of the spinal cord, are subdivided longitudinally by the sulcus limitans into a median basal plate which is chiefly motor, and a dorsolateral alar plate which is chiefly receptive. From the first month on, however, the exuberant growth of intersegmental neurons composing the reticular formation and the development of the suprasegmental ganglion masses and their respective tracts rapidly diminish the resemblance between hindbrain and spinal cord.
At about the fifth week certain alterations occur in the outward appearance of the rhombencephalon, indicating the changes going on within its walls. The most conspicuous is the bending of the axis of the tube resulting in the pontine flexure, as shown in Fig. 30. Whether this is simply due to an overgrowth of the tube in its long axis or whether there is the additional factor of unequal growth of different portions of the wall has not been clearly shown.
Along with the bending there occur noticeable changes in the broad ependymal roof of the fourth ventricle. As shown in Fig. 31, B, and C, the fourth ventricle is completely covered in by the expanded roof plate consisting of a thinned-out layer of ependymal cells, which is attached laterally to the border of the alar plate,
Fig. 44. Reconstruction showing cephalic portion of the rhombencephalon and adjoining midbrain at end of second month (human embryo 30 mm. long, Mall collection. No. 86). The thickened alar plates form the anlage of the cerebellum and the two halves are still separate. Caudally they are continuous with the nucleus of the acoustic nerve.
the transitional line forming the rhombic lip. Owing to the changes occurring in the alar plate that, particularly in the cephalic half of the rhombencephalon, cause it to become everted and folded back on itself, the rhombic lip becomes partly fused to what was originally ventricular surface of the alar plate. The changes occurring in the rhombic lip may be seen by comparing Figs. 34, 44, and 45, where it is represented as a cut edge, the whole ependymal roof being removed. It is this rhombic lip that forms the taenia of the fourth ventricle and the obex at its caudal apex.
At the same time with the formation of the pontine flexure there is produced a transverse fold (plica chorioidea) in the ependymal roof. This extends outward on each side into the lateral recess which is formed by the overgrowth of that part of the alar plate that is to form the cerebellum and tuberculum acusticum (see Fig. 45). This marks the beginning of the chorioid plexus of the fourth ventricle. The chorioid plexus is formed by ependymal epithelium and its covering of vascular mesoderm. They unite in forming minute villous-like folds which project within the lumen of the ventricle. These folds are first found along the line of the transverse chorioid fold, and from there the formation spreads caudally until nearly the whole posterior medullary velum is converted into a chorioid mass, the tela chorioidea inferior. Originally the fourth ventricle is completely roofed in as has been seen, but later there are found apertures which are formed secondarily, one in the caudal portion, the foramen of Magendie, and one in each lateral recess, the foramina of Luschka. The presence of these foramina has been denied by some investigators.
Fig. 45. — Reconstruction showing the outer form of the hindbrain at the end of the third month (human fetus 9.5 cm. long, Mall collection, No. 146. 1
Before referring to further changes in the outward form of the rhombencephalon we will consider the histological changes that produce them.
As has already been seen, by the end of the first month the primary neurons belonging to the cranial nerves are clearly differentiated. In Figs. 86, 32, and 96 their relation to each other and to the walls of the neural tube are shown. Their relation to the rhombic grooves is shown in Fig. 33. The further growth of the rhombencephalon results from the elaboration of neuroblasts from the ependymal and mantle zones which form the following structures: (a) receptive nuclei for the cranial nerves, comparable to the dorsal horns of the spinal cord, the axons of which form the median and lateral lemniscuses; (b) intersegmental neurons, constituting the reticular formation for co-ordination of different groups of primary neurons; (c) suprasegmental nuclei with afferent tracts which are laid down subsequent to and hence are external to the reticular formation, of which the olive is a conspicuous example; (d) efferent tracts from cerebellum and midbrain; and (e) the descending pyramidal tract from the cerebral cortex.
The neuroblasts derived from the basal plates are chiefly those that form effector fibres for the cranial nerves. As they will be described at length with the peripheral nervous system, their description here will be omitted. It should be pointed out, however, that their growth is relatively precocious, and that the differentiation of the basal plate begins first and is finished before that of the alar plate. The ependymal layer comes to the resting stage early, about the end of the second month. The subsequent development of the basal plate, aside from the part it takes in the differentiation of the formatio reticularis, is passive, and is dependent on the invasion of neuroblasts from the alar plate and the ingrowth of foreign fibres in its marginal zone.
The differentiation of the formatio reticularis is not confined to the basal plate, though it is first apparent there. As in the spinal cord, it consists of intersegmental neurons derived from the mantle zone, the processes of which to a large extent cross the median line as internal arcuate fibres. The crossing of these fibres marks the beginning of the raphe. After crossing they form a. longitudinal bundle in the marginal zone analogous to the ventral ground bundle in the spinal cord, and corresponding in position to the median longitudinal fasciculus of the adult oblongata, though, as will be pointed out, the latter contains other fibres in addition to these. The processes of some of the more lateral neuroblasts, instead of crossing within the mantle zone, penetrate the marginal zone and make their way along its surface, thus forming external arcuate fibres. In addition to the internal and external arcuate fibres (heteromeric), the formatio reticularis is early characterized by radially directed neuroblasts whose processes extend toward the marginal zone to form tautomeric intersegmental fibre tracts. The reticular formation is eventually subdivided into a gray portion (formatio reticularis grisea) containing cell bodies and shorter tracts, located in mantle zone, and a white portion (formatio reticularis alba) consisting of long tracts and located in the marginal zone. The great development of the reticular formation is an important determinative factor in the morphology of the adult oblongata. Three stages in its development are shown in Figs. 46 and 47. In the same figures is shown the conversion of the original floor plate into the median septum and raphe. It will be noticed that, as in the case of the spinal cord, the marginal zones of the two sides do not fuse, being always separated by the prominent radial processes of the ependymal cells, which extend from the lumen to the surface of the Drain.
Fig. 46. — Transverse section of medulla oblongata of a human embryo at end of fifth week (10.5 mm. long), showing ventromedial migration of neuroblasts from the alar lamina and rhombic lip. (After His, 1891.)
It is in the development of the alar rather than the basal plates that the rhombencephalon departs so widely from the type found in the spinal cord. While the initial changes have been taking place in the basal plate the cells of the ependymal zone of the alar plate have been actively separating off to join the mantle zone, preparatory to forming receptive nuclei for the peripheral nerves, as well as other nuclear masses, making up intersegmental and suprasegmental tracts and centres. Originally, as has been seen, the afferent peripheral fibres on entering the wall of the neural tube unite to form longitudinal tracts which extend upward or downward in the marginal zone over a varying number of s< ments. In the rhombencephalon such tracts are represented by the tractus solitarius, spinal limb of the n. trigeminus, and fibres coming up from the posterior funiculi of the spinal cord. Later there are added the fibres of the restiform body and fibres from the lateral funiculi of the cord. Thus originally we have here as in the spinal cord a central gray portion sharply marked off from a peripheral white portion, the latter consisting of distinct funiculi. This resemblance is, however, very soon diminished by the profuse growth of the alar mantle zone which invades the marginal zone partially enveloping the tracts and spreading them apart.
Fig. 47. — Transverse sections of the medulla oblongata, showing the development of the formatio reticularis and olivary nucleus. A, embryo 13.6 mm. long (5 weeks). Enlarged 40 : 1. B, embryo 22 mm. long (8 weeks). Enlarged 10 : 1. (After His, 1891.)
The profuse proliferation of the neuroblasts in the alar mantle zone is indicated in Fig. 46, and by comparing this with Fig. 47, A and B, the eventual fate of these cells can be seen. They form clusters along the tractus solitarius, and the descending fibres of the n. vestibularis and n. trigeminus which become the receptive nuclei for these particular fibres (nucleus tracti solitarii, nucleus vestibularis spinalis and substantia gelatinosa). At the caudal end in a similar way the gracile and cuneate nuclei are formed in which the fibres from the posterior funiculi of the cord terminate. From these receptive nuclei axons are developed which make their way largely as internal arcuate fibres through the formatio reticularis, decussating to the opposite side to form a longitudinal tract near the median line (lemniscus medialis) which forms an afferent path to the midbrain and thalamus.
In addition to these receptive nuclei there are other nuclei formed from the alar neuroblasts that serve as connecting paths to the suprasegmental centres, cerebellum and forebrain. The most conspicuous of these are the pontine nuclear mass and the nucleus of the olive. These are formed by virtue of the extensive power of migration possessed by the cells of the alar plate. The formation of the olivary nucleus is shown in Figs. 46 and 47. The migratory process begins at the beginning of the second month. At this time massed cells can be seen making their way through the mantle zone toward the median line, the cells from the median portion of the alar plate passing median to the tractus solitarius and the cells from the lateral border passing lateral to it and separating it from the marginal zone to which it originally belonged. Toward the end of the second month a distinct group of these migratory neuroblasts have assembled near the median line, constituting the anlage of the median accessory olive (Fig. 47, B). By the third month subsequent groups are added laterally to form the convoluted inferior olivary nucleus. The majority of the olivary neuroblasts are probably the products of proliferation of migratory cells after the completion of their migration. Their axons decussate and join with spinal cord fibres to form the restiform body. The restiform body can be recognized by the eighth week.
At the extreme lateral border of the alar plate at the rhombic lip are found cells which retain their primitive embryonic appearance into adult life. Others invade the marginal zone and emerge on the surface of the wall. Some of them then migrate toward the median line by a superficial path peripheral to the marginal zone. The exact fate of these cells remains to be studied. It is possible that the more caudal ones take part in the formation of the arcuate nuclei, and possibly also the olivary nuclei. The more cephalic ones just back of the acoustic region form a narrow migratory path from the rhombic lip around to the ventral surface of the pontine flexure. This path persists in the adult as a fibroganglionic band known as the corpus pontobulbare, described by Essick (compare Fig. 49). It is possible that it is the proliferation of these cells that produces the nuclei of the pons. It is also possible that the pontine neuroblasts come from the mantle zone of that region and reach the surface by emerging through the marginal zone, as apparently happens with the cortical cells of the cerebellum. The pons makes its appearance between the second and third month. The axones from its proliferating neuroblasts decussate across the median line in front of the formatio reticularis and the lemniscus medialis, and pass to the cerebellum on the opposite side forming the brachium pontis. As the pons is developing the corticospinal fibres (pyramidal tract) make their way along its ventral surface and become enveloped among its proliferating cells and fibres. Accompanying the corticospinal tract are other fibres from higher centres which terminate among the cells of the pons and thus become connected with the cerebellum.
The alar plates of the cephalic end of the rhombencephalon undergo extensive and specialized development. They form that which eventually becomes the largest part of the hindbrain, i.e., cerebellum, and in addition the acoustic nucleus. As can be seen by comparing Figs. 34, 44, and 45, the acoustic nucleus is formed from the thickened rhombic lip at the pontine flexure, at the point where the lateral recess develops. The rhombic lip becomes everted and is folded against and is partially fused with the lateral surface of the remaining alar plate, as is schematically shown in Fig. 48. The fibres of the acoustic nerve enter at the lower edge of this mass. As the trunk of the nerve differentiates itself into cochlear and vestibular portions (embryos 20-30 mm. long), the terminal nucleus also becomes differentiated into a median portion (vestibular) and a lateral portion (cochlear). These become more sharply separated from each other by the development of the restiform body whose fibres pass between them. The vestibular nucleus remains closely connected with the cerebellum and most of its axons terminate there. The cochlear nucleus remains quite independent of the cerebellum. Its axons pass across the ventral border of the reticular formation and decussate to form the trapezium. The superior olive in which many of these fibres terminate can be seen by the eighth week, apparently developing from migrant alar neuroblasts in a similar way to the inferior olive. The axones from the superior olive and trapezium extend forward along the ventrolateral border of the formatio reticularis to the inferior colliculus constituting the lateral lemniscus. This path is partly nuclear and partly fibrous, and is virtually a forward extension of the superior olive. Later the fibre element predominates through the increase in number and length of fibres, resulting in the separation of the superior olive from a smaller nucleus, the nucleus of the lateral lemniscus, which were originally one continuous structure. From its position it can be seen that the trapezium is laid down subsequent to the formatio reticularis. Still later occurs the descent of the corticospinal tract which with the growth of the pons nearly entirely covers in the trapezium on its ventral surface.
Fig. 48. — Transverse section of medulla oblongata of a human embryo 9.1 m m . long, showing folding of rhombic Up (Rl.). This feature is most marked in the region of the pontine flexure.
Before considering the development of the cerebellum it may be pointed out that the characteristic features of the adult rhombencephalon are only the result of the further growth of the structures that have been mentioned. In the floor of the ventricle we meet with swellings produced by the nuclei of the hypoglossal and abducens nerves, lateral to which is a longitudinal furrow representing the sulcus limitans. Lateral to this furrow are the structures derived from the alar plate, including the vestibular field and the terminal nuclei of the trigeminal and vagoglossopharyngeal nerves (ala cinera). Secondary tracts and nuclei invade the floor of the ventricle producing the characteristic striae acusticae, nucleus intercalatus and funiculus teres. The ventricle is closed in caudally by the rounded elevations (clava and cuneus) caused by the large gracile and cuneate nuclei. The olivary nuclei produce lateral swellings on each side (olives), and ventrally emerging through the pontine nuclear mass are the prominent corticospinal tracts (pyramids).
The character of the cerebellum at the end of the first, second and third months is shown in Figs. 34, 44 and 45 respectively. This covers the period from the time when it exists as simple bilateral alar plates to the time when it fuses across the median line as a transverse mass consisting of a median vermis and two lateral lobes. Its later enlargement and the formation of its characteristic lobes and fissures are shown in Fig. 49.
At the end of the first month the alar plates of the rhombencephalon cephalad to the pontine flexure differ very little from the rest. They are a little thicker and present a moderately convex surface toward the ventricle. Anteriorly they converge toward the median line, being united by a narrow seam just behind the exit of the trochlear nerve. Attached along their free edge is the tela chorioidea forming the roof of the fourth ventricle.
Fig. 49. — Three stages in the development of the fissures and convolutions of the cerebellum, as seen from behind. At the left are shown lateral views of the same specimens on a smaller scale of enlargement Ajs from the same model shown in Fig. 45; B and C are drawings made from dissected specimens.
During the second month the cerebellar plates, owing to the active proliferation of cells in their mantle zone, rapidly thicken and bulge inward toward the ventricle. They also come to lie transversely so that what was originally a longitudinal dimension becomes a transverse one. This change in position is apparently due to the marked increase in the pontine flexure that occurs at this time. The cerebellar plates not only increase in thickness but also in length (i.e., transverse dimension), so that they become cramped in position and show a tendency to be thrown in folds. Further irregularity may be due to unequal growth in different portions. The growth is more marked in the cephalic half than in the caudal or lateral half. Near the median line on each side can be seen a swelling that corresponds to the vermis, which like the cerebellum itself originally consists of bilateral halves separated from each other by the roof plate.
During the third month (Fig. 50) the cerebellar mass comes to bulge outward, instead of inward toward the ventricle as before, which is evidently due to the fact that the proliferating mantle zone cells find less resistance in that direction, the marginal surface being more yielding than the ependymal surface. The cerebellum now consists of two convex masses (lateral lobes) connected laterally by a ridge (brachium pontis) with the developing pons. At the same time the fusion across the dorsal median line has commenced. The fusion begins on the dorsal surface and gradually involves the whole thickness of the wall, the last portion involved being the ependymal membrane and rhombic lip. Before the fusion is completed the outer surface of this region has commenced to show transverse fissures marking off the primitive lobes of the vermis.
We have already seen how the rhombic lip takes part in the development of the acoustic nucleus ; likewise in the cerebellum it plays an important part, giving origin to the nodulus and flocculus. At the third month it forms a distinct ledge, still notched in the median line, and along its free edge is attached the tela chorioidea. In conjunction with the acoustic lip it forms the lateral recess.
Between the third and fifth months the outer form of the cerebellum is completed by the formation of its principal lobes and fissures, the steps of which process are shown in Fig. 49. This lamellation is evidently due to the fact that the cortical region undergoes greater cell proliferation than the deeper portion, and since this growth is chiefly in the longitudinal axis it results in fissures that run transversely to that axis. As the cortical differentiation and development of fissures occur together, we have in the latter an index of the former. It will thus be noticed that the vermis, and the anterior portion adjoining it are the first to show signs of this process. The floccular region begins to show fissures at about the same time. These may be regarded as the more primitive parts of the cerebellum, and are found to be the most constant in different vertebrates. The lateral lobes which form the so called hemispheres of the adult organ are still smooth at the fourth month and it is not until the fifth month that they receive their fissures, which are partly intrinsic and partly extensions of fissures from the vermis. It is evident that phylogenetically the lateral lobes are recent structures. Later they increase enormously in size and eventually cover in the entire posterior portion of the vermis. It is supposed that their extensive growth in man is correlated with the large pons, and that in turn with the large pallium. Bolk, 1906, suggests that if we are to consider the cerebellum as the co-ordinator of muscle contraction then we may assign the muscles of the median line, which are common to all vertebrates, to the vermis, and the muscles of the extremities to the lateral lobes, the high development of the upper extremities in man explaining the marked development of his lateral lobes.
Fig. 50. — Sagittal sections through the cerebellum at or near the median line, showing the development of the fissures of the vermis and the formation of the cerebellar cortex.
The lateral lobes are the lateral extensions of the median lobe. The median lobe is bounded anteriorly by the primary fissure and posteriorly by the secondary fissure. Everything in front of the primary fissure comprises the anterior lobe, and everything posterior to the secondary fissure comprises the posterior lobe (tonsil, uvula, nodule, and flocculus). The detailed development of the surface markings of the cerebellum can be seen by comparing Figs. 49 and 50. It should be noted that the great horizontal sulcus that is so prominent in the adult is relatively late in appearing; at the fifth month it only exists as a shallow furrow. The median longitudinal fissure, which is found on the posterior and inferior surface in the adult, is produced by the excessive growth of the lateral lobes whereby they close in over the vermis posteriorly. This rolling in of the lateral lobes toward the median line has already commenced at the fifth month (Fig. 49, C).
On tracing the fate of the rhombic lip in Fig. 49, where it is stippled darker than the rest of the cerebellum, it is seen that from the median portion there is developed the nodulus, which is the last portion of the vermis to show its bilateral character. From the lateral portion is developed the flocculus. The paraflocculus is derived from the lateral portion of the cerebellar plate immediately adjoining the rhombic lip.
The alar plate from which the cerebellum is formed, like the rest of the neural tube, at the outset has the typical ependymal, mantle and marginal zones, the ependymal zone toward the ventricle and the marginal zone toward the outer surface. It is through secondary development and migration that the cerebellar plate becomes covered with the layer of cells which eventually form its cortex, as will presently be seen.
At the end of the second month (30 mm.) the demarcation between ependymal and mantle zones is still poorly defined, and it is apparent that cells from the ependyma are still being contributed to the mantle zone. Later (70 mm.) the ependyma, with the exception of the portion situated at the rhombic lip, gradually enters upon its resting stage and assumes the form seen in adult specimens. The ependymal cells at the rhombic lip differ from the rest of the ependyma in that they continue to show active proliferation late in embryonic life. The same feature is shown throughout the whole rhombic lip but is more marked in the portion belonging to the cerebellum.
The most characteristic feature of the cerebellum is its cortex. We have already seen that originally the outer surface of the cerebellar plate is formed by the marginal zone and is devoid of nuclei. The neuroblasts which are found there later, constituting the cerebellar cortex, reach the surface by a process of migration. The steps by which the non-nuclear marginal zone becomes converted into a ganglionic layer by the invasion of these neuroblasts are shown in Fig. 50. This figure represents sagittal sections at or near the median line in four successive stages. At 30 mm. it can be seen that a layer of closely packed cells (stratum marginale embryonale) from the rhombic lip is spreading over the surface of the cerebellar plate, covering half of it in, the remaining portion being still non-nuclear. At 70 mm. this invasion of surface cells has extended so as to cover in the whole cerebellar plate, excepting the thinned-out portion that is to become the anterior medullary velum. At the same time a second layer of cells (stratum granulare) may be seen spreading from the rhombic lip forward and lateralward in the same direction as the marginal layer but beneath the surface in the outer part of the mantle zone. The space between it and the marginal layer corresponds to the stratum moleculare. In fetuses 95 mm. long these layers form well-marked strata running parallel with the surface of the cerebellum, dipping down where there are fissures. In fetuses 12 cm. long the surface of the cerebellum is greatly increased in extent, in the first place by actual growth of the whole cerebellum and in the second place by the infolding of the surface due to the rapidly increasing number of fissures. The cortex through further proliferation presents thicker and more sharply defined strata. We now (12 cm.) have an arrangement possessing a close similarity to the adult, viz., a central portion, fibrous and sparsely nucleated, covered in by a convoluted cortex consisting of three distinct strata. Concerning the source of the cells forming the cortex there remains some doubt. It is apparent that the cortex formation begins at the rhombic lip and spreads from there forward and lateralward; that is, it spreads from the free edge of the original alar plate toward the junction of the latter with the basal plate. This applies to all three of the primitive cortical layers. It is also evident that the outermost layer (stratum marginale embryonale) is directly continuous with the ependymal zone of the rhombic lip. On this account it has been suggested by Schaper, 1894, that the rhombic lip constitutes a germinal bed from which cells are given off and that these cells migrate along the surface and so form the outer layer as indicated in Fig. 51. It is conceivable that the deepest layer (stratum granulare) is also derived in the same way, its cells migrating out from the region of the rhombic lip along the outer border of the mantle zone. There is, however, no proof that the outer cells of the mantle zone do not take part in the formation of any one or all three of the cortical layers.
The later histogenesis, as seen in G-olgi specimens in other mammals, is shown in Fig. 52. The development is not completed until very late, sometime after birth. The development of the granule cells seems to occur through a process of unipolarization, like the T-formation described in the spinal ganglion cells, and subsequent migration inward to the granular layer. The successive steps in this process are shown in Fig. 52, A, of which a is the earliest undifferentiated stage and "h" the fully formed granule cell. The dendrites of the Purkinje cells do not form until the migration of granule cells is completed. The outer layer (stratum marginale embryonale) disappears in man several years after birth.
Fig. 51. — Schematic drawing showing the differentiation and migration of cerebellar neuroblasts in the teleost. Arrows indicate the migration of cells from the rhombic lip over the surface of the cerebellar plate. The different cells are indicated in the same way as shown in Fig. 3. (After Schaper.)
Fig. 52. — Sections showing the histogenesis' of the cerebellar cortex. (After Cajal.) A, schematic section showing the migration of granule cells from the surface to the stratum granulare, and different stages in their differentiation, o being the youngest and k the fully formed cell. B, section through the cerebellar cortex of new-born dog, showing two Purkinje cells with partially formed dendrites, axones, and terminal aborizations.
Many of the mantle zone cells take no part in the formation of the cortex. Some of them form the neuroglia framework through which the fibres of the central white substance pass. Others become neuroblasts which are grouped to form the internal nuclei of the cerebellum. In embryos toward the end of the third month (50-95 mm.) the nucleus dentatus can be outlined in the interior of the lateral lobe, conforming to the outer form of the lobe. From its anterior border strands of axones emerge passing forward to be assembled in the two brachia conjunctiva, which can be traced forward to their decussation and connection with the red nuclei of the midbrain (see Fig. 53).
Later, as the nucleus dentatus becomes more sharply outlined, it assumes the convoluted form seen in the adult. Median to the dentate nucleus, in the vermis, the mantle zone neuroblasts are grouped to form the paired tegmental nuclei to which acoustic fibres can be traced by the end of the third month. Other nuclei formed supplementary to the dentate nucleus are the emboliform and globular nuclei. Of the centripetal tracts to the cerebellum the restiform body and the centripetal fibres from the acoustic and trigeminal nerves are the first to become well marked (second month). By the end of the third month the middle cerebellar peduncles containing fibres from the pontine nuclei may be distinctly traced to the lateral lobes of the cerebellum. The final development and completion of the arborizations of these fibres is not finished until sometime after birth.
Development of the Midbrain
As has been previously mentioned the midbrain is a portion of the epichordal brain and is closely affiliated in its manner of development and general form with the rhombencephalon and spinal cord. As in the latter two we can recognize on each side a basal plate and alar plate, the alar plates being large and united above by a narrow seam (roof plate). The wall forming them at first consists of a combined ependymal and mantle layer covered in by a non-nucleated marginal layer. Later the mantle layer becomes clearly differentiated from the ependymal layer, forming thereby three distinct strata (ependymal, mantle, and marginal). The differentiation between ependymal and mantle layers is completed in the basal plates about the end of the first month (Fig. 31, D). In the alar plates it is considerably later, about the third month. In their later development the alar plates form suprasegrnental ganglion masses (corpora quadrigemina) in a manner analogous to the development of the alar plates of the hindbrain that form the cerebellum.
The basal plates conform even more than the alar plates to the form seen in the rest of the epichordal system. The points of difference are mainly dependent on extrinsic factors. As in the hindbrain they give origin to motor nerves which become covered in by a modified formatio reticularis and the marginal zone is traversed by long suprasegrnental fibre tracts (peduncles of cerebrum). In Fig. 53 is shown a reconstruction of the midbrain of an embryo about three months old, in which the more prominent structures of the basal plate are indicated. The nuclei of the third and fourth cranial nerves maintain their position near the floor of the lumen like the hypoglossal and abducens nerves in the hindbrain. The trunk of the fourth nerve, however, bends around dorsally to decussate in the roof as we have already seen. It runs directly dorsalward at first, but later owing to the growth of the inferior colliculus it is crowded backward and assumes a distinctly caudalward course before its decussation.
Fig. 53. — Reconstruction of the midbrain of a human embryo 80 mm. long (Mall collection, No. 172) showing the relations of the red nucleus and the decussation of the brachium conjunctivum connecting it with the dentate nucleus of the cerebellum.
Associated with the third and fourth nerves is the median longitudinal fasciculus, which forms an intersegmental bundle belonging to the formatio reticularis, extending throughout the whole length of the mid- and hindbrains and into the anterolateral fasciculus of the spinal cord. It is apparently for the most part made up of axons which run a short course in the bundle and serve to connect the motor nuclei of the eye muscles (Nn. oculomotorius trochlearis and abducens^. It probably contains axons from other cranial nerve nuclei (Nn. facialis, acusticus, and hypoglossns). It also contains the fibres of the rubrospinal tract and fibres from the superior colliculus. Next to the entering fibres of the sensory nerves this is one of the earliest tracts in the epichordal system to become well outlined.
The origin of the nucleus ruber is not definitely known. It forms in the mantle layer as a portion of the formatio reticularis and by the end of the third month it is sharply outlined, and the decussating brachia conjunctiva connecting it with the dentate nucleus can be clearly recognized, as seen in Fig. 53. From its resemblance to the inferior olive we may assume that it develops in a similar manner. The fibres of the fasciculus retroflexus (Meynerti) traverse it on their way to the interpeduncular nucleus.
The mantle zone structures of the midbrain region become closed in ventrally and laterally by the tracts of the marginal zone. The first of these are the median lemniscus and the lateral lemniscus, which are usually included with the formatio reticularis as comprising the tegmentum. Later there are added ventrally the fibres connecting the cerebral cortex with the pons, medulla oblongata and spinal cord, which can be recognized toward the end of the third month. The subsequent increase in size of these ventral tracts produces the projecting masses known as the peduncles of the cerebrum.
The alar plates by their large size indicate that they are to form a large organ, though in man owing to the recession of the optic lobes the superior colliculus never attains the size found in lower vertebrates. The alar plates are at first separated by a narrow seam or furrow, and in young specimens, if there is any maceration, this seam (roof plate) is easily stretched and the alar plates may then overlap one another. With the subsequent thickening of the alar plates this median furrow disappears. This thickening also causes the lumen to decrease in proportionate size. Instead of a considerable cavity or midbrain ventricle we eventually have the narrow aqueduct of Sylvius connecting the third and fourth ventricles.
The details in the differentiation of the alar plates have not been fully studied in man, but we know that like the cerebellar plates they are characterized by the migration of neuroblasts to their outer surface. These neuroblasts proliferate and develop into more or less stratified ganglionic masses which, together with the deeper lying cells, form the superior and inferior colliculi. The more superficial layers correspond to the cortex of the cerebellum, and the deeper cell masses correspond to the dentate and tegmental nuclei. The fibres from the optic tract and lateral lemniscus can be plainly traced to the colliculi by the end of the third month.
The optic tract fibres disappear beneath the superficial ganglion layer of the superior colliculus, while the lateral lemniscus spreads over the surface of the inferior colliculus. At about the same time the inferior brachium connecting the inferior colliculus with the median geniculate body can be recognized as shown in Fig. 45.
Development of the Diencephalon
The division of the prosencephalon into the telencephalon and diencephalon has already been referred to. The telencephalon from the outset differs widely from the type seen in the epichordal portion of the nervous system, and at a casual glance would seem to have nothing in common with it. The diencephalon, however, forms an intermediate link, and though it merges directly into the telencephalon, yet it resembles the epichordal system in many ways, particularly in the early stages.
As seen in Fig. 54, we can speak of an alar plate and a floor plate, united dorsally by a roof plate and ventrally by a floor plate, differing from the spinal cord up to the fifth week only in the absence of a ganglion crest and motor nerves. The alar plate like the alar plate of the epichordal system is predominantly sensory. It rapidly thickens, due to the proliferation of the neuroblasts which are to form the receptive nuclei for the optic and cochlear tracts and for the fibres of the medial lemniscus. These nuclei are massed together to form the thalamus which constitutes the largest part of the diencephalon. The lateral nuclei (geniculate bodies) are spoken of as the metathalamus.
Fig. 54. — Section through the diencephalon of a five weeks human embryo. Dp., roof plate (chorioid plexus); Th., alar plate (thalamus); S.M., sulcus limitans (sulcus hypothalamicus): P. s., basal plate (hypothalamus); Ma., mammillary recess. (After His.)
The thalamus is separated from the hypothalamus by the sulcus hypothalamicus which extends forward to the optic recess. This sulcus apparently is analogous to the sulcus limitans. It persists into adult life. The hypothalamus or basal plate portion lacks the motor elements which form so large a part of the basal plate in the epichordal system. Its principal function seems to be in connection with the special structures which are developed in the floor plate, the hypophysis and mammillary bodies (see Figs. 55 and 56). It is also from this portion that the corpus Luysi is developed, and through the caudal part of its marginal zone the large tracts pass from the internaUcapsule constituting the pedunculi cerebri.
The anterior boundary of the floor of the diencephalon may be regarded as constituted by the transverse ridge formed in the floor by the optic chiasm (Johnston). This ridge extends later
ally into the basal plate as the pars optica hypothalamica. Caudal to it (Fig. 56) is a pouch representing the beginning of the infundibulum. During the fourth week an extension of this pouch (infundibular process) comes into contact with a similar pouch formed from the stomodseal epithelium (Rathke's hypophyseal pouch). The latter finally becomes detached from the oral epithelium and becomes incorporated with the infundibular process to form the hypophysis. The nervous and epithelial elements remain distinct throughout and constitute its two lobes. The epithelial pouch is at first flat and lies in front. It later develops two horns which envelop the infundibular pouch laterally. During the latter half of the second month vascular epithelial sprouts are developed from the pouch forming a mass of tortuous tubules, and finally (third month) obliterate the original cavity, converting it into a solid glandular organ. In the meantime the lumen of the nervous infundibular process has become shut off from the rest of the infundibular cavity, though the process always remains attached to the infundibulum. It becomes converted into a solid mass of tissue resembling neuroglia, and is closely united with the epithelial portion by a connective-tissue capsule and forms the posterior lobe of the organ.
Fig. 55. — Brain of a human embryo 5 weeks old (13.6 mm.), median view of the right half. model, from Spalteholz. (After His)
The diencephalic floor caudal to the infundibulum forms the tuber cinereum, and still further caudal the mammillary recess from the walls of which the mammillary bodies are formed.
Fig. 56. — Brain of a human'fetus in the third month, Jmedian view of right half. (After a His model, from Spalteholz.)
The roof plate of the diencephalon is bounded anteriorly and posteriorly by two transverse grooves. The posterior one appears toward the end of the first month and always remains a wellmarked groove. The posterior commissure crosses through its substance. The anterior boundary is formed by the velum transversum in a line with the foramen of Monro. The identity of this groove is best recognized in the early stages, 5-10 mm., after which the complications of the forebrain development obscure it. It marks the boundary between a part of the third ventricle that belongs to the telencephalon and a part that belongs to the diencephalon (see Fig. 26).
A dorsal view of the roof plate is shown in Fig. 57 and a median view in Fig. 56. It consists of a thin ependymal plate uniting the two thalamic plates. At the fourth week it is smooth. Proliferation of its cells causes it to expand and form an outward ridge which is soon thrown into longitudinal folds, as shown in Fig. 54. These folds project into the ventricle as the ectodermal lining of the tela chorioidea of the third ventricle. The increase of these folds and the development of a vascular mesodermal coat
Fiq. 57. — Dorsal view of a model of the prosencephalon of a human embryo at the beginning of the sixth week (13.6 mm.). The pallium is partly removed, exposing the interior of L the lateral ventricles. This is from the same specimen shown in Fig. 55. (After His.) complete the formation of a typical chorioid plexus. Orally this chorioid roof is continued into the telencephalon where it forms a pointed pouch overlapping the lamina terminalis and the contained commissures. At the foramen of Monro it is continuous with the similarly formed chorioid body of the lateral ventricle. At the posterior, or epiphyseal end of the roof, there is another small chorioidal pouch formed which overlaps the epiphysis. The anterior chorioidal pouch apparently corresponds to the paraphysis of the lower vertebrates.
Laterally the roof plate is attached along the borders of the thalamic plates. At the line of junction there are formed the epithalamic structures known as the ganglia habenulse and the epiphysis. The habenular apparatus bears a relation to the thalamic plate similar to that of the rhombic lip to the alar plate in the hindbrain. The habenular nuclear mass can be recognized by the fifth or sixth week as a longitudinal ridge on the dorsal surface of the diencephalon along the edge of the thalamic plate. In fetuses 80 mm. long, as seen in Fig. 53, the nucleus can be outlined and the stria medullaris and fasciculus retroflexus traced to their terminal connections. The former extends forward along the edge of the thalamic plate and spreads out over the surface of the future anterior nucleus of the thalamus.
Fig. 58. — Lateral view of brain of a human embryo about three months old (crown-rump length 53 mm.). Part of the hemisphere wall is removed, showing its thickness and exposing the [interior of the lateral ventricle. (After His.) The epiphysis is formed at the caudal end of the diencephalic roof. At the fifth week, Fig. 57, it appears as a rounded elevation of the roof. In the groove behind it the posterior commissure crosses and in the groove in front of it the dorsal or habenular commissure. It thus originally consists of a thin ependymal diverticulum between these two commissures. Subsequently its* walls are thickened and incorporate some of the adjacent vascular mesoderm to form the adult organ. In the human embryo the epiphysis never reaches the advanced stage of development seen in reptiles (pineal eye).
The ventricle of the diencephalon, at first a relatively broad space, becomes thinned down to a narrow cleft owing to the thickening and crowding in of the lateral walls. The space is still further reduced by an actual approximation and fusion of a portion of the thalamic plates. In this manner there is produced the commissura mollis, the extent varying in different subjects. It is very large in lower mammals.
We thus see that the diencephalon consists of three main regions, the hypothalamus, the epithalamus, and, largest of all, the thalamus proper (including the metathalamus or geniculate bodies). The hypothalamus and epithalamus are the most primitive in character and their fibres are the first to develop. During the second month the following tracts become established in the hypothalamus: (a) fasciculus mammillotegmentalis ; (b) fasciculus thalamomammillaris ; and (c) columna fornicis. At the same time in connection with the epithalamus there are developed: (a) stria medullaris; (b) commissura habenularis; (c) fasciculus retroflexus; and (d) commissura posterior. Advanced development of the thalamus is characteristic of the higher vertebrates. In the human embryo, though it develops somewhat slower, yet it eventually predominates over all the rest of the diencephalon. By the end of the second month the acoustic fibres have reached the median geniculate bodies, the optic tract fibres the lateral geniculate bodies, and the fibres from the median lemniscus the ventrolateral thalamic nucleus. At the same time these nuclei give off fibres that extend into the corpus striatum forming the thalamic radiation. Some of them can be seen passing through to reach the developing neopallium (compare Figs. 63 and 73).
Development of the Telencephalon
When we come to the extreme oral end of the neural tube it is no longer possible to clearly recognize an alar plate or basal plate as seen everywhere else in the tube. The sulcus limitans, however, is usually considered as curving downward along the posterior border of the optic evagination to the median line just in front of or along the transverse ridge caused by the optic chiasm. (Compare Figs. 26 and 28.) In this sense practically the whole telencephalon may be regarded as corresponding to an elaboration of the alar plate.
The broad expanse of this portion of the neural plate in the earliest stages (Fig. 23) indicates its importance. As we have already seen, before the closure of the tube is completed (Figs. 26 and 28), the telencephalon has become differentiated on each side into a bulging portion marking the future pallium or hemisphere and a basal portion which is to form laterally the corpus striatum and medially the rhinencephalon. The optic evagination is on the boundary line between the latter and the diencephalon.
The further steps in the differentiation are shown in Figs. 55, 56, 59, and 60. Comparison of these figures shows that though these primary regions of the telencephalon undergo great change in size, form and position, yet they maintain their identity throughout. It is the extensive development of the pallium that is the most striking feature ; whereas the rhinencephalon, which is so massive in lower vertebrates, at its most favorable embryonic stage in the human embryo composes not more than one-twentieth part of the bulk of the telencephalon, and in the adult a far smaller proportion. The corpus striatum is closely united with the thalamus, and it is through this that the connection between telencephalon and diencephalon is principally maintained. It shares with the thalamus in the development of the pallium. Through these two centres pass all the paths of communication to and from the cortex, excepting the insignificant portion belonging to the olfactory system.
Fig. 59. — Lateral view of the forebrain of a human embryo 10.2 mm. long. Taken from a model. It shows the beginning of the overlapping of the diencephalon by the pallium. Compare with Figs. 29 and 86. After His.)
Corpus Striatum and Pallium. — The change occurring in the telencephalon toward the end of the first month is a very important one and should be carefully noted in order to understand the development of this region of the brain. As can be seen by comparing Figs. 28 and 55, it represents the transition from the neural tube type to the typical paired hemispheres opening out laterally through the foramen of Monro. The latter is produced not as an actual constriction but secondarily through the fact that its boundaries remain nearly stationary while the pallial walls undergo enormous expansion. The expansion of the pallial walls is shown in Figs. 59 and 60. From around the borders of the corpus striatum they expand orally, dorsally and caudally, gradually covering in the whole diencephalon and more caudal parts of the brain. In Fig. 60 we can recognize the oral end as the frontal lobe, its inclosed cavity being the anterior horn of the lateral ventricle. The caudal end curves downward to form the temporal lobe, its inclosed cavity being the descending horn of the lateral ventricle. Later, fetuses 10 cm. long, the caudal portion presents two lobes or poles, the temporal lobe having become more ventral and the new occipital lobe forming the extreme caudal end, its cavity corresponding to the posterior horn of the lateral ventricle (see Figs. 76 and 77).
During the expansion of the pallial walls the median lamina uniting them does not share in the growth, and there is thus formed Pallium the great longitudinal fissure between the two hemispheres, which eventually becomes occupied by a mesodermal septum, the falx cerebri. The lamina uniting the two hemispheres is continuous anteriorly with the lamina terminalis. and might properly be regarded as belonging to it. Posteriorly it is continuous with the diencephalic roof plate. We have already seen how the latter becomes folded and vascularized to form a chorioidal roof for the third ventricle. A similar change occurs in the pallial wall near its junction with the diencephalon. The wall becomes very thin and folds into the lumen of the lateral ventricle, carrying with it vascular mesoderm (Fig. 62) and thus finally forms a chorioidal body within the ventricle. If the chorioidal body is removed there is left a cleft in the wall, the approximate position of which is shown in Fig. 64, and which corresponds to the fissura chorioidea. That portion of the hemisphere wall ventral to the fissure apparently never undergoes active development. In the portion dorsal to it is developed the hippocampal system. Anteriorly the chorioidal formation is continuous with the chorioidal roof of the third ventricle. The whole chorioidal mass forms an irregular Y, the stem being the roof of the third ventricle and the two arms being the chorioidal bodies of the lateral ventricles. The arms begin at the foramen of Monro and differ from the stem in being better developed and projecting into the ventricle. The relations of these structures are considerably modified later by the changes occurring in the lamina terminalis due to the formation of the interforebrain commissures which will be spoken of again in connection with the hippocampus. In all other regions of the neural tube we find chorioidal formation limited to the roof plate and this gives a ground for considering the roof plate of the telencephalon as bifurcated and represented by the two chorioidal fissures. There is, however, no other evidence of such a bifurcation of the oral end of the tube.
Lobus temporalis Lobus parietalis Lobus frontalis
Fig. 60. — Lateral]view of the forebrain of a human embryo 13.6 mm. long. Taken from the same specimen shown in Fig. 57. Comparison with Fig. 59 shows the growth of the pallium and the manner in which it overlaps the diencephalon, (After His.)
Attention has already been called to the ridge formed by the corpus striatum in the floor of the telencephalon (Figs. 28, 57, and 55). It can be seen at the outset that the corpus striatum is directly continuous with the thalamic plate of the diencephalon. In its development it resembles the thalamus and becomes closely co-ordinated with it, but the two always remain distinctly separated from each other, at first by a deep groove and later by the taenia semicircularis. It consists at first of a ridge which spreads out anteriorly in three limbs (Fig. 28), marking off the two divisions of the rhinencephalon. Later, with the expansion of the pallium, the ridge becomes more prominent. It is elongated caudally and curves around the developing stalk of the hemisphere to the tip of the inferior horn, forming the tail of the caudate nucleus. As the wall thickens it projects into the ventricle, and the lateral surface of the same portion of the brain wall, Fig. 60, presents a shallow fossa which continues to become deeper as the surrounding pallium develops. The thickening of the wall at first involves chiefly the ependymal zone, which undergoes an exuberant growth, and exactly in the area corresponding to the future caudate nucleus. Gradually from the ependymal zone a mantle zone is elaborated and furnishes the neuroblasts which become assembled into a typical corpus striatum. The fibre strands from and to the thalamus become arranged in a sharply marked lamina which subdivides the corpus striatum into the caudate and lenticular portions, thus forming the limbs of the internal capsule. It should be noted that this subdivision of the corpus striatum and the formation of an internal capsule are due to the manner in which the fibres traverse it. In some mammals the fibres pass diffusely through the striatum and then the capsule-like arrangement of the fibres is absent.
The division between thalamus and corpus striatum is most evident in midembryonic life. At the end of the third month a deep groove separates them. Subsequently as they become larger and as the nerve-fibres connecting them increase, this groove becomes flattened out, and they come to form one solid ganglionic mass separated from each other only by the taenia semicircularis. It is thought by some that in this process an apposition and fusion occurs between the anterior end of the thalamus, the medial pallia!
Fig. 61. — Schematic horizontal sections through the forebrain of human embryos, showing three stages in the fusion of the thalamus and corpus striatum. A, embryo of about 6 weeks (15 mm.); B, fetus during the fourth month; C, fetus during fifth month (crown-rump length 150 mm.). F. M., foramen of Monro. (After Goldstein.)
Fiq. 62. — Transverse section through forebrain of human embryo of about six weeks (16 mm. long), showing on one side the fusion of thalamus and corpus striatum. Compare with Fig. 61, A. (After His.) wall and the corpus striatum, as shown in Fig. 61. The same result, however, would occur if it were a simple thickening of the wall produced by the massive connections developed between thalamus and corpus striatum. In Fig. 62, on comparing the two sides it would seem as though such a fusion had occurred; but it should be remembered that the two sides are not cut at the same level, that one is through the foramen of Monro and the other just below or caudal to it.
At the end of the fifth month, as seen in Fig. 63, the relation and form of the corpus striatum are practically those of the adult. The form of the internal capsule can be clearly made out. It contains: (a) fibres connecting the thalamus with the corpus striatum and pallium; (b) optic and acoustic fibres from the metathalamus to the pallium; (c) projection fibres from the pallium (pyramidal tract). The stria semicircularis, though it is on the border line between diencephalon and telencephalon, probably belongs to the latter. It can be recognized early (80 mm.), as it curves around the thalamic border. It is shown in Figs. 66, 67, and 68.
Fig. 63. — Horizontal section through the forebrain of a fetus about five months old (crown-rump length 160 mm.). This represents a stage intermediate between B and C in Fig. 61. (After His.)
Rhinencephalon. — The olfactory apparatus consists of a basal portion and a cortical or pallial portion. The basal portion includes the olfactory bulb, olfactory stalk, the median and lateral olfactory tracts and the region of the anterior perforated space which merges on the one hand with the tip of the temporal lobe and on the other with the preterminal body which partly forms the septum pellucidum.
All of these parts are derived from the basal portion of the telencephalon median to the corpus striatum (see Fig. 55). The cortical portion of the rhinencephalon belongs to the pallium and is designated as archipallium in contradistinction to the remainder or neopallium. It consists of an extension of the basal preterminal area dorsalward and forms the median margin of the pallium along the dorsal border of the chorioidal fissure. In the adult we know it as the hippocampus, the dentate fascia, and it probably includes a strip of cortex bordering along the hippocampus. It differs from the basal portion in that the cells composing it are arranged in the form of a cortex with characteristic strata.
Fig. 64. — Median wall of the telencephalon of same specimen shown in Fig. 58, showing the fissura chorioidea and under it a narrow strip of the lamina infrachorioidea. The fissura prima extends upward from the olfactory lobe marking off the anterior border of the prseterminal body. In front of it is the accessory' arcuate fissure. The calcarine fissure is sharply marked. The hippocampal fissure curves around parallel with the inner margin of the specimen. (After His.) In Figs. 66, 67, and 68 the median view of the brain is shown in its later stages of development exposing this general region. That portion of the pallium possessing a uniform cortical layer is shown in lighter color than the remainder and corresponds in general to the neopallium. The darker portions form the archipallium and thus represent the olfactory apparatus. If we are to consider that portion of the cortex adjoining the hippocampus as olfactory and belonging to the archipallium (G. Elliot Smith), then to complete the pallial portion of the olfactory system the dark shading should be spread wider to include this. The basal portions of the olfactory apparatus are shown in the same figures. Lateral views of the same stages are shown in Figs. 76 and 77. The relations of the basal portions can be best seen, however, in a ventral view, as given in Fig. 65, where its different parts are indicated. The boundaries of the olfactory apparatus in this figure are marked by the dorsal border of the lateral olfactory gyrus and the gyrus ambiens.
The olfactory apparatus can be traced back to a still youn._ stage in Figs. 55 and 60, which present median and lateral views of the brain at the end of the fifth week. At this period, as seen in a lateral view, there is a distinct field marked off ventral to the Sylvian depression which represents the basal portion. It consists of two elevations. The anterior one is formed by a shallow pocket opening out of the ventricular cavity. The further evagination of this results in the formation of the hollow olfactory bulb whose form in later stages we have already seen. It can be readily understood how this extending tubular process becomes narrowed down in its proximal portion to form the olfactory stalk, commonly spoken of as the first pair of cranial nerves. In man the lumen of this process is eventually obliterated.
Fig. 65. — Ventral view of brain of a four months old human fetus, showing the olfactory apparatus. v After Kollmann.) The posterior olfactory elevation becomes a thickened portion of the wall instead of an evagination and represents the anterior perforated space. Mesially (Fig. 55) it extends upward, bordering along the lamina terminalis, and forms the preterminal body of Elliot Smith; and is directly continuous with the olfactory pallium along the fissura chorioidea. In the older stages the olfactory tracts were already laid down. At this stage they are just beginning to appear. According to His. a little before this time, in embryos Nl. 10.9 mm., filaments can be recognized connecting the nasal epithelium with the olfactory pocket i anterior olfactory elevation) of the brain wall, i.e., before we can yet speak of an olfactory bulb or stalk. About the same time the fibres of the median olfactory tract begin to extend dorsalward from the olfactory pocket to the preterminal body. By the time the olfactory bulb has become partially constricted from the general brain wall fibres can be seen extending- backward from it along the dorsolateral border of the posterior olfactory elevation (anterior perforated space) and constituting the lateral olfactory tract, whose fibres are distributed to the archipallium covering the apex of the temporal lobe.
In embryos under four weeks old the rhinencephalon can only be recognized as the space between the lamina terminalis and the internal ridge formed by the corpus striatum (Fig. 28). According to His the three limbs of the striate ridge mark out the two fossae which we have seen as prominences on the lateral surface corresponding to the olfactory bulb and the anterior perforated space.
Interforebrain Commissures.- — In connection with the olfactory apparatus there are the tracts connecting it with the hypothalamus (fornix) and the commissural tracts uniting the opposite sides of the telencephalon (anterior commissure, commissure of fornix and corpus callosum). The development of these structures can best be understood by comparison of Figs. 66, 61, and 68, which represent three stages in their development.
In these figures the lamina terminalis is shown as though cut in the median sagittal plane, while the commissures are left longer so that their cut ends project from the surface. It will thus be seen that they all cross through the substance of the thickened lamina terminalis and are thus confined to the original walls connecting the two hemispheres. The use of the term " lamina terminalis " is made in a broad sense. It is not restricted to the ependymal seam that originally closes off the anterior end of the tube, or its immediate derivatives ; but includes also a certain amount of neuroglial tissue from the adjacent wall which becomes incorporated with it. In this sense we may speak of a fusion of the median walls of the precommissural bodies, but the process only occurs in a narrow line immediately in front of the lamina terminalis and the derived tissue becomes a definite part of the latter. Its further enlargement is produced by the stretching of its boundaries by the entering commissural fibres. A narrow lamina terminalis suffices originally, as only a few slender bundles cross at first. As further fibres are added the fibre mass spreads open a space for itself, in which process a portion of the precommissural body is appropriated, and the eventual lamina terminalis presents a large surface in the cut median section, including the whole corpus callosum and the septum pellucidum. The widening of the boundaries of the lamina terminalis occurs rapidly in fetuses between 80 and 150 mm. It is distended dorsalward and anterolateralward through the growth of the corpus callosum, the shape of which in turn is determined by the expanding pallium. As a result of this tension there is a new arrangement of its tissue, and in the readjustment a ventricle is formed, the so-called fifth ventricle or cavum septi pellucidi. This becomes lined with a smooth neuroglial membrane. The ventricle is only present where there is a large corpus callosum.
It should be mentioned that, according to some authors (Goldstein, 1903), the commissures are developed entirely within the lamina terminalis, in the narrower sense, the adjacent walls not contributing anything to it. On the other hand, according to Zuckerkandl, 1901, there is an approximation and fusion of a considerable area of the median walls with resorption of the previously interposed mesodermal falx. This forms a "massa commissuralis" through which the fibres subsequently cross. In the process of fusion he describes an active proliferation of the cells of the wall, forming "wulstartige Vorspriinge, ' ' which meet and fuse in the median line. The description given above corresponds essentially with that given by G. Elliot Smith (1895) and Marchand (1909).
Of the three commissures the anterior commissure and the commissure of the fornix are the more primitive, and they both serve as commissures for the archipallium. The fibres of the fornix make their appearance early along the chorioidal margin of the hippocampus and form a bundle increasing in size as it extends forward. It passes over the foramen of Monro to reach the precommissural body where it gives off and receives fibres. It then extends ventralward to the hypothalamus in the region of the mammillary body (pillar of the fornix). In the region of the precommissural body the two fornix systems exchange fibres forming a commissure between the two hippocampal gyri. Originally this commissure lies directly dorsal to the anterior commissure, as seen in Fig. 66. Subsequently it is drawn backward' owing to the change in the position of the hippocampi, which in turn are carried backward by the ventral extension of the temporal lobe.
The development of the corpus callosum is closely connected with that of the fornix commissure, being practically a derivative of it. The latter is a commissure of the archipallium and the former of the neopallium, the one starting where the other stops. Owing to the great development of the neopallium in man the corpus callosum soon predominates.
In fetuses 80 mm. long (Fig. 66) its fibres can be recognized in the medial wall of the hemisphere streaming toward the upper part of the lamina terminalis, where it crosses together with the commissure of the fornix, forming a rounded bundle on the dorsal surface of the latter. The first discoverable fibres contributed to it are found in the median wall in the vicinity of the point of crossing. As further fibres are added they form a layer that can be gradually traced spreading backward and lateral ward through the pallium to the regions more distant from the lamina terminalis. It is quite probable that the growth of these fibres starts simultaneously in all parts of the pallium, and it is natural that it is in the region of the lamina terminalis that the accumulation of them is first sufficient to be recognized as a definite layer. The form of the corpus callosum in fetuses 95 mm. long is shown in Fig. 70, where its relation to the brain wall can be seen. It lies nearer the ependyma than the outer surface. The model represents only that part that could be distinguished as a stratum. It is probable that callosal fibres reach much further than this.
Fig. 66. — Median view of a model of the telencephalon of a human fetus three months old (80 mm. long, Mall collection, No. 234a). It shows the cut ends of the commissural bundles crossing in the lamina terminalis. The thalamus is removed, exposing through the fissura chorioidea, the lateral ventricle and nucleus caudatus. Comparison of this figure with Figs. 67 and 68 shows the development of the corpus callosum and its relation to the commissure of the hippocampus.
Fig. 67. — Median view of a model of the telencephalon of a human fetus about 4 months old (95 mm. long, Mall collection, No. 146). It shows the same structures seen in Figs. 66 and 68. The lamina terminalis has become thickened at the expense of the corpus praeterminale, and a cavity has developed in it forming the cavum septi pellucidi. The fissura hippocampi has deepened, it being the first step in the covering in of the fascia dentata.
Fig. 68. — Median view of a model of the telencephalon of a human fetus of the fifth month C150 mm. long, Mall collection). Here the commissural systems are practically those of the adult. The fascia dentata extends up over the splenium of the corpus callosum and reappears at the front end (genu) and is continuous with the preterminal body and enlarged lamina terminalis. Compare with Figs. 66 and 67
The addition of fibres occurs interstitially, the new fibres growing in everywhere between the old ones. As seen in cross section, it very early takes on a typical form. In fetuses 95 mm. long, Fig. 67, we can recognize the anterior end as the genu and the posterior end as the splenium, the latter always remaining in contact with the fornix commissure. With the further growth of the pallium and the addition of new fibres to the corpus callosum we have in 150 mm. fetuses, Fig. 68, relations which are practically those of the adult. It will be seen that like the pallium it has grown both posteriorly and anteriorly. As the splenial end spreads caudalward it covers in the diencephalon, carrying the commissure of the fornix with it. The latter gradually becomes flattened out on the under surface of the corpus callosum to form the psalterium.
The striae of Lancisi represent tissue connecting the dentate fascia with the precommissural body. By comparison of Figs. 66, 67, and 68 it can be seen how the two are closely connected at first (practically continuous). The tissue connecting them may be regarded as regressive fascia dentata. It soon is stretched out in a narrow strand by the enlarging corpus callosum. Some of the fibres in this substance are frequently laid down in advance of the corpus callosum, so that the fibres of the latter pass between them and incorporate them. Thus the anterior end of the adult corpus
Taenia semicircularis Commissura anterior W * Fig. 69. — Right half of the anterior commissure dissected out from the brain of anl80 mm. pig fetus, viewed from above and from the median side. Its constituent elements are shown andjits connection with the taenia semicircularis callosum is found to be traversed by some of these fibres, on their way through the wall of the septum pellucidum to the precommissural body.
The anterior commissure, as it appears when dissected out in the pig embryo, is shown in Fig. 69. It consists of two divisions, an anterior or olfactory division and a posterior division. The olfactory division arises principally (in pig embryos) in the brain wall in the neighborhood of the olfactory evagination. The posterior division arises between the corpus striatum and the overlying cortex and thus corresponds in position to the fossa of Sylvius. It forms a concave lamina in which the corpus striatum rests. Owing to the fibres streaming from the corpus striatum to the pallium it is difficult to determine whether its fibres are derived mesially from the corpus striatum or laterally from the superimposed cortex. In Fig. 69 it is shown how the fibres composing it form confluent fan-like bundles which point ventralward and become incorporated into two main bundles, anterior and posterior, which in turn unite and point toward the lamina terminals to meet the similar formation from the opposite side. In the earlier stages it is possible to recognize the anterior commissure fibres before they have reached the median line. As it approaches the median line it receives a communication from the taenia semicircularis. In Fig. 70 is shown the relation of the anterior commissure in a 95 mm. human fetus, being essentially like that seen in dissections of pig fetuses. Of the olfactory division some strands apparently come from the olfactory stalk, and others from the hemisphere wall in the immediate neighbourhood.
Fig. 70. — Anteromedian view of a model of the fibre tracts of the same brain shown in Fig. 67. One half of the brain stem is preserved intact. In the front part of the telencephalon everything is removed excepting the fibre tracts, exposing the corpus callosum, pillar and commissure of the fornix, two divisions of the anterior commissure and the internal capsule. The last subdivides the corpus striatum into the caudate and lenticular nuclei. On the left side the connection from the taenia semicircularis to the anterior commissure is shown.
Development of the Wall of the Hemisphere
Up to the end of the second month the wall of the hemisphere remains thin and relatively undifferentiated. The increase in thickness and development of the wall that begins to be noticeable at that time does not occur uniformly in all regions at the same time, but is always more advanced in the basal portions adjoining the corpus striatum, and from there it gradually extends toward the median line over the whole pallium. In the accompanying table is given the thickness of the wall and its constituent zones in
taken at appro-ximateiv the same region.
tube,, of an outer irr t.:'z1~
- a ike the wall of the original cleated or marginal zone and .ml :'-r 7ii .ills ::rziiiz rftion of the latter are farther differentiated and are irr.izr-ri. "1 i :«:-:-;:; - :iiri :r 7iii:'.e :::e. trueture the wall eons: ~ : s : i i " i — j i - -:n~ : ::i_ .:: r-l.ii ;i :ii: us i described imder the h _ 77tSt7.:5 It :1y7.:it:ii: :ii: is i:: itmn cribrosam. This is situated in : f lateral processes from the so arranged as to form a thin nucleated and outer part of this zone.
lie region of the eorpns
.1 : i f : ii ~~' * r f i : r : f :i f sarface as far as the olfactory margin, where it form the olfactory cortex. It is formed by the mi if~f - iiim if ii: zli.sii :': ri 71 f fif 177111*. 11 i 711.1:". -_ in mil cording to Tfis (1904),
rion of this : hi. iii„j " :i- 71 -11" modified to
7i:i:i Hi" fntnTr 1 - 7-amidaI cells advance toward the onter surface as far as :i nil ::::: : mi. ""ii - 11 pact layer. This migration is most actinre daring the third month '-'. 111 :-= — f_ iii: -..- 1:1 71 7 1 "_ 1 - — 1 - 7 ::i:i
Fig. 71. — Section through hemisphere wall of a human embryo at about the sixth week (16 mm. long) before the development of the cortical layer. (After His.)
Fig. 72. — Hemisphere wall of a human fetus at about the eleventh week (crown-rump length 46 mm.), showing the wandering of the neuroblasts from the interior of the wall toward the outer surface where they form the pyramidal or cortical layer. (After His.)
of the brain wall of an embryo about 3 months old. On the inner surface of the marginal zone is a well-developed cortical layer, toward which numerous other neuroblasts can be seen wandering from the mantle zone. The mantle zone has become much broader, and can be subdivided into an inner nuclear portion, consisting of proliferating neuroblasts and spongioblasts, and an outer wider portion, or intermediate layer (Zwischenschicht), which seems to be sparsely nucleated, owing to the extensive invasion of fibres from the internal capsule. A schematic section of the wall at this time is shown in Fig. 73. On the left is shown the spongioblastic framework and its formation into different layers, the nuclei representing future neuroglial cells. On the right are indicated the wandering neuroblasts moving radially outward to form the cortical layer. In their journey they have to make their way through the meshes of the framework and through the entering fibres from the thalamus and corpus striatum. During this period of migration the pyramidal cells usually possess a bipolar character, as shown in Fig. 74. The advancing end is broader and more irregular and becomes the apical process. The slender central end (i.e., toward the lumen) becomes the axone. The development of lateral dendrites and attainment of the characteristic adult form does not occur until about the time of birth.
Fig. 73. — Schematic drawing showing structure of hemisphere wall at the end of the third month. On the left side is shown only the spongioblasts framework; on the right side are shown the wandering neuroblasts and their accumulation to form the cortical layer. The arrows indicate ectogenous fibres from the internal capsule. Compare with Fig. 72. (After His.)
Fig. 74. — Pyramidal neuroblasts during the period of migration. The lower process is broader and more irregular. It becomes the apical process. The other is more slender; it is pointed toward the ependyma and becomes the axone. (After His.)
Up to the fourth month the wall remains relatively thin and the ventricle large. From then on the wall rapidly thickens, owing mainly to the great increase in fibres in the intermediate layer. These fibres at first are all ectogenous fibres, from the thalamus and corpus striatum. Subsequently there are added the axones from
Fig. 75. — Section through hemisphere wall at the end of the fourth month (crown-rump length 120 mm.). The intermediate (Zwischenschicht) zone is rapidly becoming thicker, owing to the increase of incoming and outgoing fibres. It is this layer that eventually forms the central white substance of the brain. Its inner portion is subdivided into the following layers: a, outer transitional layer; b, outer striated layer; c, inner transitional layer; d, inner striated layer. At this period the wandering of the cortical neuroblasts is completed. (After His.) the developing neuroblasts of the cortical layer (autochthonous). It is this fibrous layer that eventually forms the massive white substance of the hemisphere. With the increase in the thickness of the wall the ventricle apparently becomes smaller. The appearance is due in part to the difference in relative growth of the two, and in part to the change in shape of the ventricle, from a wide vesicle to a narrow slit.
As shown in Fig. 75, the inner portion of the mantle zone still possesses many nuclei, belonging to the supporting framework, which are now arranged in layers. The ependyma does not appear as active as heretofore, although it apparently is still giving off spongioblasts that are to form the neuroglial elements of the white substance. The cortical or pyramidal layer has taken up all its wandering neuroblasts from the deeper layers and is sharply marked off from the subjacent intermediate layer. It is already beginning to subdivide itself into two separate layers, the outer portion being somewhat denser than the inner portion. During the sixth and seventh months, with the further differentiation of the cortical cells, they become grouped into six distinct layers, corresponding to the stratification of the adult cortex. Certain portions of the cortex exhibit modifications of this six-layered arrangement, the strata being increased or decreased in number or varying in thickness. Thus the adult cortex presents various histological areas, each possessing its own characteristic stratification. The visual cortex is a particularly marked example. Its characteristic consists in the subdivision of the internal granular layer into two layers, between which is formed a conspicuous white line, the so-called line of Gennari. Another departure from the general type is found in the hippocampus and fascia dentata, which differ in the well-known way from the cortex seen in other regions. On the outer surface of the cortical layer there is frequently seen during the fourth month, as shown in Fig. 75, an irregular fungiform clumping of cells, the so-called Eetzius papillae. These, however, are an artefact, being a result of partial maceration of the tissues.
Formation of Sulci and Convolutions
In the further growth of the brain wall the white matter continues to increase in thickness, while the cortical zone (gray matter) remains spread out in a relatively thin layer, its expansion taking place in a plane parallel with the surface of the brain wall. To accommodate this increase in the extent of its surface the outer surface of the brain wall is thrown into folds. The lines along which the principal folds form correspond (usually) to the boundaries of different histological areas, due perhaps to the difference in their time of development or possibly in consequence of their different reaction to the tension existing between the gray and white substance. Since the different histological areas represent constant functional areas, the fissures are therefore more or less constant.
The first fissures to appear (about the third month) are those associated with the primitive olfactory system, the hippocampal and rhinal. The hippocampal or arcuate fissure forms along the border of the dentate fascia, as shown in Fig. 67. An accessory arcuate fissure on the median wall dorsal to the hippocampal fissure is described by His as occurring about the same time. By other writers (Hochstetter, Goldstein) this and the so-called fissura prima are regarded as post-mortem phenomena. The fissura prima, or anterior arcuate fissure, is described by His as being the first fissure to appear (the second month). It is found on the median wall near the olfactory bulb, and extends upward in front of the preterminal body of G. Elliot Smith (that is, the trapezoid body of His). Part of it is thought to persist as the fissura parolfactoria posterior. According to His, an extension of the pia mater extends into and corresponds in form to the fissure, and he argues that therefore it must be a real fissure. His opponents deny its presence in well-preserved brains. The rhinal fissure Lobus parietal is (Fig. 76) separates the lobus piriformis from the neopallium, but in man, owing to the suppression of the olfactory apparatus, it always remains insignificant.
Fig. 76. — Lateral view of reconstruction of cerebral hemisphere of a human fetus about three months old (crown-rump length 80 mm., Mall collection, No. 234a). The rhinal fissure is situated along the upper border of the traetus olfactorius lateralis. The dark-shaded portion at the base represents that portion that is not covered in by a typical cortical layer.
The development of the Sylvian fissure is not completed until after birth, but the first stages in its formation can be seen at the third month. On comparing Figs. 76, 77, and 79 it will be seen that its formation is dependent on the fact that the brain wall in the region of the corpus striatum does not enlarge as rapidly as the parts adjacent to it. This at first expresses itself in the formation of a shallow depression, the fossa Sylvii (see Fig. 76). As the neighboring temporal, frontoparietal, and orbital portions become thicker they form in-rolling walls or lips, the so-called opercula, which finally cover in the retarded portion or insula. The lines along which the lips meet constitute the fissure of Sylvius. The temporal and frontoparietal opercula are formed first. The frontal and orbital opercula are very late in development. They do not begin to form until the insula is already partly covered in by the temporal and frontoparietal opercula, and they do not come into apposition with each other and the other two opercula, so as to close in the anterior part of the insula, until after birth. In Fig. 77 the advanced growth of the temporal, occipital, and parietal lobes, corresponding to their primitive functions, is very evident. The frontal lobe whose functional activity is the last to be required is correspondingly backward. In consequence the brain in fetuses between 50 and 150 mm. long, when seen from above or in front, as in Fig. 78, resembles in its outward appearance the smooth forward tapering brain seen in some of the lower mammals, — e.g., rabbit. Variations in the degree of development of the frontal operculum determine the shape of the two anterior limbs of the Sylvian fissure between which it lies. When well developed, it separates the two Sylvian limbs from each other so that they assume a U shape; when less developed, it forms a V shape; or, if so poorly developed that the orbital and frontoparietal opercula meet so as to occlude the frontal operculum from the main limb of the fissure, then we have a Y shape. In some forms of arrested development the anterior portion of the fissure of Sylvius is defective and the insula remains partly exposed.
Fia. 77. — Lateral view of reconstruction of cerebral hemisphere of human fetus at the beginning of the fifth month (crown-rump length 150 mm., Mall collection). A portion of the tractus olfactorius lateralis can. be .seeni'at the lower border of the insula.
Fig. 78. — Anterior view of brain of a human fetus of about the same age as shown in Fig. 76. (After His.)
The hippocampal, rkinal, and Sylvian fissures develop along boundary lines of brain areas that differ markedly both in structure and in rate of development. The calcarine, parieto-occipital, and central fissures also represent boundary lines of areas that differ histologically, but the differences are not so marked as in the former cases, and the fissures appear somewhat later, during the fifth month. They are soon followed by the collateral, inferior and superior precentral, postcentral, superior temporal, superior and inferior frontal, parolfactory, interparietal, callosomarginal, and orbital fissures, all of which appear during the sixth or seventh month. 2 The character of these fissures at the end of the seventh month is shown in Figs. 79, 80, and 81. These fissures first appear as shallow furrows, and an individual fissure may first appear as several short furrows which as they deepen subsequently unite into a continuous furrow. The calcarine fissure, somewhat like the hippocampal fissure, involves the whole thickness of the brain wall and produces an elevation within the ventricle, the calcar avis. The parieto-occipital fissure apparently also causes at first an infolding of the brain wall. This, however, disappears with the thickening of the wall. It is possible that it is to be classed as an artefact together with the so-called transitory fissures. The transitory fissures consist of sharply marked furrows frequently found indenting all parts of the cortex during the third and fourth months. They are irregular in form and position and are only found at this time. It is to be remembered that at this period the human hemisphere consists of a large thin-walled vesicle whose walls have not yet developed a firm framework, and, even with good material and with great care in its treatment, it is difficult to prevent artificial foldings of the wall when the specimen is immersed in preserving fluids.
Fig. 79. — Lateral view of the cerebral hemisphere of a human fetus at the end of the seventh month, showing the formation of the early fissures. Compare with Figs. 76 and 77. (After Kollmann.)|
- A distinction is frequently made between sulci and fissures, based on the conditions found in the adult. The term sulcus is used for the more shallow grooves, and the term fissure for the deeper ones, those which in their development involve the whole thickness of the brain wall and influence the form of the ventricle. Thus we speak of the fissure of Sylvius, the longitudinal, the hippocampal, the collateral, the calcarine, and the parieto-occipital fissures; all other grooves are designated as sulci. From the embryological stand-point it might be better still further to restrict the term fissure and limit it to the fissure of Sylvius and the longitudinal fissure. We would then have the term sulcus as representing all those furrows which are formed as actual grooves in the brain wall, and the term fissure would be limited to the clefts that result secondarily from the unequal growth of major brain regions, and are not true indentations in the original surface of the brain wall.
Fig. 80. — Median view of the cerebral hemisphere of a human fetus at the end of the seventh month, being the same specimen shown in Fig. 79. (After Kollmann.) These primary fissures constitute boundaries of primary functional areas of the pallium. Subsequently association areas are developed around them, forming new cortical territories, and as these expand new furrows develop to accommodate the growing cortex. The secondary gyri thus formed may crowd the older ones into new forms or even partly replace them by burying them under, as we have seen the insula buried by the adjoining opercula.
Development of the Myelin Sheaths
The final phase in the development of the hemisphere wall consists in the process of myelinization of its nerve-fibres. This does not begin until about the time of birth and it continues from then until the end of puberty. For the details of this process the reader is referred to the studies of Flechsig, to whom we are indebted for almost the whole of our present knowledge of this, subject. We will here only give a brief outline of the process.
The process begins in the projection fibres of the four primn sensorimotor fields : 1, the olfactory ; 2, the visual ; 3, the acoustic ; and 4, the somatic. These possess both efferent and afferent elements. In the visual and acoustic mechanisms the efferent element is very small. In the somatic area both the efferent and afferent elements are largely represented, each occupying a definite portion of the total area, the afferent forming the postcentral area (somaesthetic) and the efferent the precentral area (motor). The afferent projection fibres are probably myelinated shortly before the efferent ones.
Gyrus frontalis medius Gyrus frontalis inferior Gyrus frontalis superior Gyrus prsecentralis Gyrus centralis posterior Lobulus parietalis superior Lobulus parietalis inferior Lobus occipitalis
Fig. 81. — Dorsal view of the cerebral hemisphere of a human fetus at the end of the seventh month, being the same specimen shown in Figs. 79 and 80. (After Kollmann.) The process next spreads to a series of intermediate areas whose projection fibres serve to connect the primary cortical areas with the thalamic and pontine nuclei. The terminal areas to become myelinated are those made up almost entirely of association neurones, whose axones cross in the corpus callosum to the opposite hemisphere or extend to distant or near parts of the same hemisphere. .
In concluding this chapter, there is added a table, taken from His (1904), showing the order of development of the different fibre tracts of the central nervous system. The size and approximate age of the embryo or fetus is indicated, and in the columns the first recognizable appearance of a given tract is indicated by a check.
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- Compare also the chapter describing the development of the eye.