The Embryonic Human Brain

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THE EMBRYONIC HUMAN BRAIN

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The brain at the end of the embryonic period (stage 23, 8 postfertilizational weeks). The color scheme used here (telencephalon in yellow, diencephalon in blue, mesencephalon in brown) will be repeated in a number of illustrations throughout the book.

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THE EMBRYONIC HUMAN BRAIN AN ATLAS OF DEVELOPMENTAL STAGES THIRD EDITION

RONAN O’RAHILLY, M.D., D.Sc., Dr.h.c. FABIOLA MULLER,¨ Dr.habil.rer.nat. School of Medicine University of California at Davis Davis, California and Institut d’Embryologie Sp´eciale Universit´e de Fribourg, Fribourg, Switzerland

A JOHN WILEY & SONS, INC., PUBLICATION

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Illustrations on the cover: Ultrasonic in vivo image at 6 weeks showing the fourth ventricle. cf. Fig. 23-35. Courtesy of Dr. Harm-Gerd Blaas. Perspektomat reconstruction at 8 weeks, stage 23. See Fig. 2-1. Oblique section at 7 weeks, stage 20. See Fig. 20-4.

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Library of Congress Cataloging-in-Publication Data:

ISBN-13: 978-0-471-69462-5 ISBN-10: 0-471-69462-2

Printed in the United States of America

10987654321

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In memory of Ernest Gardner, M.D., neuroscientist, colleague, and friend

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...ceferoitvngrandbon-heur pour le genre humain, fi cette partie, qui eft la plus delicate de toutes, & qui eft fujette á des maladies tres-frequentes, & tres-dangereufes, eftoit auffi bien connuë, que beaucoup de Philofophes & d’Anatomiftes fe l’imaginent. Niels Stensen, Discovrs svr 1’Anatomie du cerveau, 1669.

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CONTENTS

Preface to the Third Edition ix

1. Historical Aspects 1 2. Techniques 5 3. Prenatal Measurements 9 4. Embryonic Staging 11 5. Prenatal Age 15 6. Terminology 17 7. Early Stages 21 8. Stage 8: The First Appearance of the Nervous System 25 9. Stage 9: The Major Divisions of the Brain 31 10. Stage 10: The Neural Tube and the Optic Primordium 39 11. Stage 11: Closure of the Rostral Neuropore 51 12. Stage 12: Closure of the Caudal Neuropore and the Beginning of Secondary Neurulation 61 13. Stage 13: The Closed Neural Tube and the First Appearance of the Cerebellum 75 14. Stage 14: The Future Cerebral Hemispheres 84 15. Stage 15: Longitudinal Zoning in the Diencephalon 93 16. Stage 16: Evagination of the Neurohypophysis 103 17. Stage 17: The Future Olfactory Bulbs and the First Amygdaloid Nuclei 115 18. Stage 18: The Future Corpus Striatum, the Inferior Cerebellar Peduncles, and the Dentate Nucleus 133 19. Stage 19: The Choroid Plexus of the Fourth Ventricle and the Medial Accessory Olivary Nucleus 149 20. Stage 20: The Choroid Plexus of the Lateral Ventricles, the Optic and Habenular Commissures, and the Interpeduncular and Septal Nuclei 169 21. Stage 21: The First Appearance of the Cortical Plate in the Cerebral Hemispheres 187 22. Stage 22: The Internal Capsule and the Olfactory Bulbs 205 23. Stage 23: The Brain at the End of the Embryonic Period 219 24. Trimester 1, Postembryonic Phase 263 Early Postembryonic Phase 265 Later Postembryonic Phase 285 25. Trimester 2 297

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viii CONTENTS

26. Trimester 3 and the Newborn 305 Supplement: Early Postnatal Life 319

Bibliography 323 Glossary 331 1 1 Appendix 1: Changing Lengths of the Brain and its Subdivisions from 3/2 to 5/2 Weeks (Stages 9–16) 341 Appendix 2: Computer Ranking of the Sequence of Appearance of Features of the Brain 343 Appendix 3: Sequence and Stage of Appearance of Median Features of the Brain 349 Appendix 4: Sequence and Stage of Appearance of Tracts of the Brain 351 Appendix 5: Sequence and Stage of Appearance of Features Associated with the Rhombencephalon 353 Index 354 P1: FAW/FAW P2: FAW JWDD017-FM JWDD017-ORahilly August 11, 2006 13:18 Char Count= 0

PREFACE TO THE THIRD EDITION

he main objectives of this monograph are to provide The authors’ scheme of the neuromeres, which differs T and to interpret drawings, photographs, and photomi- from others in being based on the human, is detailed here. crographs of the human embryonic brain. The drawings Other topics emphasized include segmentation, not only include at least a lateral view and a median reconstruction of the neural axis both rostrally and caudally, but also that of the brain at each stage, as well as a clear indication of the of occipitocervical differentiation. Stem and crest cells in plane of section of further illustrations, either drawings or the olfactory region are elaborated, and the cerebellum, photomicrographs. Summarizing statements of the mor- the amygdaloid complex, the hippocampal region, and the phological status of the brain at each stage are supplied, corpus striatum are given special attention. and brief statements concerning relevant anomalous con- This edition has been enhanced by the use of color, ditions are included. as well as by the inclusion of more that 100 new illus- The embryonic period proper (the first eight postfer- trations and 26 new tables. Moreover, some representative tilizational weeks) is particularly important because (1) the examples of ultrasonic images have been interspersed. The embryonic brain is extremely difficult to comprehend and definitions formerly given in Chapter 6 have been expanded to visualize, (2) serial sections of first-class quality that considerably and collected as an important Glossary near show the human embryonic brain are rarely accessible, the end of the book. and (3) most major congenital anomalies appear during The Bibliography has been enlarged and brought up that time. A briefer account of the fetal period has been to date. It comprises more than 350 references to the chief included and emphasizes the continuity of development. studies of the prenatal human brain. The profuse literature Despite a general, superficial similarity in the devel- relating to other species, however, is beyond the scope of opment of the brains of various vertebrates, significant, this book. subtle differences exist so that, undoubtedly important as A set of standardized abbreviations, mostly self- are the findings in other species, contributions specifically evident, is used throughout for the illustrations, and a list to the prenatal human brain are as essential as they are of them is placed immediately inside the front cover. fascinating. The number assigned to chapters 8–23 and the first The external and internal structure of the develop- number given to each illustration indicate the developing brain, the primary concern of this book, is an essential mental stage. prolegomenon for subsequent investigations ranging from The authors wish to acknowledge the valuable sup- immunocytochemistry to imaging in vivo. Structural rep- port for their research provided by the U.S. National Insti- resentation, however, needs to be completed by interpre- tutes of Health over many years. Except where otherwise tation. In the present context two necessary components indicated, the photomicrographs as well as many of the of precise interpretation are (1) morphological staging (as photographs are from the Carnegie Collection. The scan- distinct from mere seriation, such as length or supposed ning images are included through the kindness of Dr. med. age), without which individual events cannot be arranged Harm-Gerd Blaas and other colleagues who are credited in in correct sequence, and (2) accurate three-dimensional the appropriate places. It is a pleasure to thank all at Wiley- reconstructions, without which erroneous assumptions of Liss for their encouragement and assistance. interpretation can be (and frequently are) made. These desiderata, which have been used by the authors in their RONAN O’RAHILLY research over many years, are a unifying feature of this FABIOLA MULLER¨ treatise: (1) the Carnegie system of staging originated by Villars-sur Glâne, Switzerland Streeter and named and developed by the authors is funda- July 2006 mental to the presentation, and (2) most of the drawings here are based on extremely precise graphic reconstructions prepared by the authors. No similar work is available.

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ABBREVIATIONS

a. Artery I.-v.f. Interventricular foramen Aff. Afferent Lat.f. Lateral longitudinal fasciculus A.-H. Adenohypophysis Lat.em. Lateral ventricular eminence Amyg. Amygdaloid region, nuclei, complex L.l.f. Lateral longitudinal fasciculus Bas.a. Basilar artery LMP Last menstrual period BM Basement membrane Long.fiss. Longitudinal fissure BV Blood vessel L.t. Lamina terminalis C Cervical M or Mes. Mesencephalon Cbl Cerebellar plate, cerebellum M1, M2 Mesencephalic neuromeres Ch. Chiasmatic plate M.l.f. Medial longitudinal fasciculus Ch.tymp. Chorda tympani Mam. Mamillary region, nuclei, body CN Cranial nerve Mam. teg.tr. Mamillotegmental tract CNS Central nervous system Med. fore.b Medial forebrain (or prosencephalic) Comm. Commissural plate bundle C-R Crown-rump length Med.tectobulb.tr. Medial tectobulbar tract D1, D2 Diencephalic neuromeres Med.em. Medial ventricular eminence Di Diencephalon Mes. tr. 5 Mesencephalic tract of trigeminal Dors.f. Dorsal longitudinal fasciculus nerve Eff. Efferent n. Nerve End.div. Endolymphatic diverticulum Nas. Nasal plate, pit, sac, septum Ep. Epiphysis N.-H. Neurohypophysis Ext.cbl External cerebellar swelling Not. Notochord Ggl Ganglion NTD Neural tube defect GL Greatest length Nu.mes.5 Mesencephalic trigeminal nucleus Hab.-interp.tr. Habenulo-interpeduncular tract Nu.post.X Nucleus of posterior commissure Hem. Cerebral hemisphere Olf.bulb Olfactory bulb Hipp. Hippocampus Olf.n. Olfactory nerve Hyp.-th.sulc. Hypothalamic sulcus Olf.tub. Olfactory tubercle Hyp.-th.-teg.-tr. Hypothalamotegmental tract Opt. Optic sulcus, vesicle, cup Infund. Infundibulum Opt.stalk Optic stalk Int.cbl Internal cerebellar swelling Ot. Otic plate, pit, vesicle Interest.nu. Interstitial nucleus Par. Parencephalon Isth. Isthmus rhombencephali Post.-lat.fiss. Posterolateral fissure Isth.rec. Isthmic recess Post.X Posterior commissure

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Pros. Prosencephalon Th.v. or Tha1.v. Ventral thalamus Red. nu. Red nucleus Tr. Tract(us); transversum Rh. or Rhomb. Rhombencephalon; rhombomere V Ventricle Rh. A to D Specifically identified rhombomeres V3, V4 Third ventricle, fourth ventricle Rh. 1 to 4 Specifically numbered rhombomeres Velum tr. Velum transversum Rh.lip Rhombic lip V.-n. Vomeronasal nerve, ganglion Sp.ggl Spinal ganglion X3 Commissure of the oculomotor nerves Subarach. Subarachnoid space X4 Commissure of the trochlear nerves Subth.nu. Subthalamic nucleus X sup.coll. Commissure of the superior colliculi Sulc.lim. Sulcus limitans 1–12 Cranial nerves Supramam.X Supramamillary commissure 5i Intermediate trigeminal fibers 5m Motor trigeminal fibers Supra-opt.X Supra-optic commissure 5s Sensory trigeminal fibers Syn. Synencephalon 7i Nervus intermedius Tel. Telencephalon 8c Cochlear component of Tel.med. Telencephalon medium or impar vestibulocochlear nerve Tent. Tentorium cerebelli 8v Vestibular component of Th.d. or Tha1.d. Dorsal thalamus vestibulocochlear nerve

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CHAPTER1 HISTORICAL ASPECTS

he Greek anatomist and physician, Erasistratus SPECIFIC REFERENCES (ca. 300–250 BC), distinguished two convoluted TO THE PRENATAL Tparts of the brain, a greater and a lesser. Later, it became HUMAN BRAIN clear that “the cerebrum and cerebellum are different in function as in form,” as Charles Bell wrote in 1811. Some key studies are mentioned here for convenience, but Although Malpighi in the 1670s observed the neural the list is not intended to be complete. folds in the chick embryo, their significance escaped him, One of the earliest specific accounts of the prenatal and he thought that the brain developed between them human brain (Fig. 1–1) is that by Friedrich Tiedemann (Adelmann, 1966). Even von Baer was unaware that the (1816), which was translated into French (1823) and En- neural folds are the primordium of the CNS, a role that was glish within a decade. The monograph is arranged accord- first appreciated by Rusconi and Reichert. Pander, however, ing to nine prenatal months, but early examples of the understood that the neural folds form a tube. Neverthe- human embryonic brain were inevitably lacking. less, the CNS was thought to be merely a fluid at first, In 1896, the detailed atlas of the gross morphology of and “the monotonous chronicle of vesicles and bubbles” the brain by Gustaf Retzius appeared. In addition to the (Adelmann) continued into the nineteenth century—if not, adult organ, more than 35 plates included the fetal brain indeed, beyond it. from “the third to the tenth month,” the smallest being The vesiculae cerebrales, said to have been first from two 35 mm fetuses. Retzius referred to the work of noted by Coiter in 1573 (Tiedemann, 1816), were pro- His on the embryonic brain; and he also cited Hochstetter. moted by Meckel the younger, von Baer, and Bischoff, In 1900 and 1901, Florence Sabin prepared solid although the concept is largely a myth (Streeter, 1927). (Born) reconstructions of the brain stem of a newborn, and The current acceptance of three main divisions in the the published illustrations were accompanied by a detailed brain (prosencephalon, mesencephalon, and rhomben- description of some 90 pages. cephalon) dates mainly from von Baer, who also identi- In 1904, Wilhelm His, the real founder of human em- fied the five subdivisions that appear a little later (telen- bryology (O’Rahilly, 1988), wrote an account of the pre- cephalon, diencephalon, mesencephalon, metencephalon, natal human brain from 3.1 to 160 mm CR. His had been and myelencephalon). In 1893, Wilhelm His, senior, the very interested in photography, and a striking feature of his founder of human embryology, added a sixth part, the isth- book is the high quality of the photomicrographs. It is to mus rhombencephali, which becomes very evident during be regretted that neither this work nor his Anatomie men- development. schlicher Embryonen has been translated into English.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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2 Chapter 1: HISTORICAL ASPECTS

Figure 1–1. Two early works on the prenatal development of the human brain: Tiedemann (1816) and His (1904).

In 1919, Ferdinand Hochstetter published a well- a comparative study by Friant. The work of Fontes was known monograph on the human brain from 23 somitic unknown to Friant, as it still is to most authors. pairs (stage 12) to 125 mm CR. It includes attractive il- In 1948, a very valuable series of reconstructions of lustrations of solid (Born) reconstructions and a series of the cranial arteries (in relation to the cranial nerves) was photomicrographs of high quality. In 1923, the same au- published by Padget, who subsequently (1957) produced a thor wrote an account of the development of the epiph- comparable work on the cranial venous system. The stages ysis cerebri. In 1929, he produced a further work, on the of the Carnegie embryos she studied are known. It needs mesencephalon and rhombencephalon, based on a study of to be appreciated that her “age groups” (of Streeter) are embryos from 6 mm GL to 250 mm CR. The illustrations now the Carnegie stages and that her “stages” are phases include solid (Born) reconstructions and many photomi- of vascular development (Table 16–1). crographs of first-class sections. Hochstetter wrote also on In 1962, the very important study by Bartelmez and the choroid plexuses (1913) and on the development of the Dekaban appeared and was based on the Carnegie Collec- meninges (1939). tion. This was the first detailed investigation of the internal A classical study of the neuromeres in the human was structure of the human brain in staged embryos, from stage completed by Bartelmez in 1923, and many further details 10 to stage 22, with the omission of stages 9, 18, 21, and were provided in a neglected study by Bartelmez and Evans 23. The account is more complete than that of Streeter in 1936. The neuromeres were investigated again in the (revised by O’Rahilly and Muller, ¨ 1987a) and was not sur- 1950s and 1960s by Bergquist and Källén. passed until the study of many embryos at each stage by In 1938, a detailed investigation of the development Müller and O’Rahilly began to be published in 1981–1990. of the human CNS was written by Barbé. This work, ex- In 1965, an excellent and well-illustrated study of the tending to 340 pages, covers the range from 14 mm CH globus pallidus and the corpus striatum was published by to 470 mm CH (320 mm CR). Many photographs and pho- Richter. This important work was based on 13 embryos and tomicrographs are included. Unfortunately neither His nor 35 fetuses from 18.5 to 370 mm CR. Hochstetter is mentioned. In 1969, a very valuable and well-illustrated investi- In 1944, a richly illustrated work on the external fea- gation of the development of the human cerebral hemi- tures of the later fetal brain (from “4 months”) was pub- spheres was published by Kahle. The work is arranged from lished by Fontes. A few years later (n.d.), some excellent the “second month” to the “eighth month” and includes external photographs (from “3 months”) were included in examples from 3 mm GL to more than 275 mm CR. P1: FAW/FAW P2: FAW JWDD017-01 JWDD017-ORahilly April 17, 2006 12:44 Char Count= 0

SPECIFIC REFERENCES TO THE PRENATAL HUMAN BRAIN 3

In 1970, Windle published a noteworthy study of the tem was consolidated by Lemire, Loeser, Leech, and Alvord. “development of neural elements in human embryos of Streeter’s “horizons” and postovulatory ages were used. four to seven (postovulatory) weeks.” The examples range Important studies that have appeared since 1980 will from about 3 to 16.5 mm GL. Although Streeter’s “hori- be cited in appropriate places in the various chapters of zons” were stated to be “helpful,” the embryos studied were this text. unfortunately not staged. On the positive side, however, the The present work, published originally in 1994, is the use of Ranson’s pyridine–silver method enabled early neu- ﬁrst book devoted to the staged, embryonic human brain. It rons and neuroﬁbrillary differentiation to be investigated should be stressed, however, that very much further work thoroughly. on the fetal brain needs to be undertaken before a level of In 1975, much useful information concerning the nor- detail comparable with that now available for the embry- mal and abnormal development of the human nervous sys- onic brain can be attained. P1: FAW/FAW P2: FAW JWDD017-02 JWDD017-ORahilly April 17, 2006 12:45 Char Count= 0

CHAPTER2 TECHNIQUES

number of matters related to human embry- 1 cm. This, coupled with the circumstance that many fea- ology in general, which also have particular tures are not at first sight identifiable (although most are Arelevance to human neuroembryology, will be summarized present), as well as the rapidity with which changes occur, in the first few chapters. necessitates the preparation of enlarged reconstructions in The present work is based largely on personal in- order to investigate topographical relationships. vestigations of the embryonic brain, stage by stage, car- ried out over several decades and published in more than TRIDIMENSIONAL SERIAL 50 research articles. The source material was mostly the RECONSTRUCTIONS Carnegie Embryological Collection and involved a careful study of 340 serially sectioned embryos (including These are made by projecting serial sections at a previ- 51 instances of silver impregnation), the preparation of ously determined magnification (Fig. 2–1). Many different graphic reconstructions from 89 brains, and the examina- techniques have been used (Gaunt and Gaunt, 1978) and tion of 55 solid, three-dimensional reconstructions (modi- several kinds of particular relevance here will be mentioned fied method of Born). No similarly detailed and adequately briefly. illustrated documentation of the developing human brain had been previously attempted, and comparable detail for (A) Solid reconstructions are those that can “sit on a ta- the fetal brain is not yet available. Moreover, because most ble.” They are associated with the name of Gustav studies of the developing brain of other mammalian species Born, who established the technique in 1876. It was are based on timing, but not on staging, comparative tab- adopted enthusiastically by Wilhelm His, the founder ulation in neuroembryology is still in its infancy, and a of human embryology (O’Rahilly, 1988). Such a recon- standard for the human is an advisable preliminary. struction consists of stacked plates, each representing When the first morphological indication of the ner- one or more enlarged serial sections. The laminae can vous system is distinguishable, the greatest length of the be made of various substances. Originally wax was cho- embryo is only 1 mm. Hence histological study is essen- sen, whereas those used here are made of plaster and tial. Throughout the embryonic period, serial sections of were prepared by Mr. Osborn O. Heard. An example excellent quality are indispensable. The examination of iso- is shown in Figure 2–2. According to Carnegie us- lated or haphazard sections, or of those of poor histological age, precise reconstructions are never referred to as quality, is almost useless and is frequently misleading. “models.” At the end of the embryonic period proper, the diam- (B) Plane reconstructions, those designed to be repro- eter of the cerebral hemispheres is of the order of only ducible on paper, are of several varieties.

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6 Chapter 2: TECHNIQUES

A B

C Figure 2–2. Example of a plaster reconstruction (made by Mr. Osborne Heard using a modiﬁed Born technique), showing a right lateral view of the brain at stage 17 (6 weeks). The rounded part in the lower right-hand corner is the right cerebral hemisphere. The large “V” in the upper middle portion is the fourth ventricle. The numerous horizontal lines show the plane of the histological sections and the way in which the plates were stacked.

the work of one of the authors (F.M.).A further technical advance, based on a modified pantograph, was introduced by Forster (1968) under the name Per- spektomat and is patented. It was applied to human embryology by Muller ¨ and O’Rahilly (1980, Figs. 5– 9) and is particularly useful for complicated structures, for correcting a markedly oblique plane of section, and for dissected views (Fig. 2–1). Figure 2–1. (A) The principle involved in solid three-dimensional 2. Computerized graphic reconstructions are being reconstruction from serial sections. If each section, of thickness t,be used increasingly. Although most of those so far projected at a magnification n, then each plate of the reconstruction published are inadequate in precision and refine- should have a thickness T equal to txn. (B) The plates were originally, and sometimes still are, made of wax and were stacked as shown in ment, the standard may be expected to improve an embryo of stage 23 (8 weeks). Individual organs and structures considerably. can be reconstructed by this wax-plate technique (of Born). (C) The It cannot be emphasized too strongly that first- same principle used for a graphic reconstruction (made by F. Muller ¨ class histological quality is essential for precise re- with Perspektomat) showing a right lateral view of the brain at stage constructions, and that reconstructions are abso- 23. The right cerebral hemisphere has been sectioned to reveal the lateral ventricle. The numerous horizontal lines indicate the plane lutely necessary for a valid three-dimensional inter- of the histological sections. The bar represents 1 mm. pretation. Moreover, examination of sections taken in the three major planes is needed in order to follow certain structures, especially tracts, which 1. Point plotting graphic reconstructions, which were disappear completely from view when sectioned also used extensively by His and later by Florian (as through a right-angled bend. well as by Beau, 1939, for the developing mam- 3. Ultrasonic reconstructions can be prepared from malian rhombencephalon), are made by superim- images obtained in vivo by ultrasound (Fig. 23–35), posing the outlines of structures—the contours be- as demonstrated by Blaas and associates (e.g., Blaas ing obtained by projecting serial sections. Hidden et al., 1995a, 1995b, 1998). Moreover, this proce- lines are omitted. An example is shown in Figure dure can be used in instances of prenatal anoma- 10–5. All the median views in the embryonic pe- lies, even during the first trimester (e.g., Blaas et al., riod and many of the lateral views in that period 2000a, 2000b). in this book are carefully prepared graphic reconstructions based on detailed examination of serial Techniques other than those concerned with re- sections. These drawings and reconstructions are construction include (1) histochemistry and electron P1: FAW/FAW P2: FAW JWDD017-02 JWDD017-ORahilly April 17, 2006 12:45 Char Count= 0

TRIDIMENSIONAL SERIAL RECONSTRUCTIONS 7

microscopy, which so far have been used to only a limited Important extent in human neuroembryology, (2) immunocytochemistry applied to staged embryos and correlated with in situ Imaging is valuable in prenatal diagnosis, but knowl- hybridization for expression of genes, (3) ultrasonic imag- edge of the time of first appearance of various features, ing and magnetic resonance imaging (MRI), which are used as well as the detailed morphology of the developing extensively in clinical practice. The results of these various brain, depends on precise reconstruction from serial techniques confirm the findings of embryological investi- sections. gations and reconstructions. P1: FAW/FAW P2: FAW JWDD017-03 JWDD017-ORahilly April 17, 2006 12:45 Char Count= 0

CHAPTER3 PRENATAL MEASUREMENTS

considerable variety of measurements has A GL B been proposed and, as is also true of postna- GL tal measurements, a range of values caused by variability C A C needs to be taken into account. The most useful measurement in prenatal life is the greatest length (GL), taken as a caliper length without inclusion of the flexed lower limbs. The crown–rump (CR) length, which is frequently similar, is a commonly cited but unsatisfactory measurement (O’Rahilly and Muller, ¨ 1984a). In the embryonic period (the first 8 weeks), however, embryonic length (particularly when taken to one or even R two decimal places) is of very little value. During that time the only reliable and indeed necessary index of develop- R mental status is provided by morphological staging (see Figure 3–1. Outlines of embryos at (A) stage 15 and (B) stage 17 Chapter 4). Furthermore, it should be emphasized that the showing that the crown–rump length (CRL) and the greatest length term “stage” should not be applied to a mere measurement, (GL) do not necessarily coincide. nor to a supposed age. Thus, the “19 mm stage” should be replaced by “at 19 mm GL”, and “the 7-week stage” by “at 7 The crown–heel (CH) length includes the lower limbs (postfertilizational) weeks.” The greatest length is replaced and is replaced after birth by the standing height. Another after birth by the sitting height. useful measurement is the foot length (FL). At 8 postfertil- The greatest length (Fig. 3–1), as would be expected, izational weeks the CH length is about 45 mm, and the FL shows variability in relation to age, and precision in esti- is approximately 4.5 mm. Additional measurements used mating age can be increased by using several different mea- in imaging techniques include the biparietal diameter, the surements, as has been found in ultrasonographic studies. head circumference, the (calcified) femoral length, and the 1 At 4 2 postfertilizational weeks the GL is about 5 mm, and abdominal circumference. at 8 weeks, the end of the embryonic period proper, it is Where the head is defective (e.g., in anencephaly), the approximately 30 mm. fetal height can be estimated from the distance between the

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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10 Chapter 3: PRENATAL MEASUREMENTS

spinous process of thoracic vertebra 1 and the coccyx, and Important from measurements of the arm, thigh, and leg (Alexandre r and Pineau, 1970). The most useful single prenatal measurement is the Body weight, which is about 2 to 3 g at 8 postfertiliza- greatest length (GL) exclusive of the lower limbs. r tional weeks, is variable. Later, an estimate can be obtained In the embryonic period, morphological stages are in vivo by special formulae based on linear measurements much more reliable than measurements. (e.g., biparietal diameter and abdominal circumference). r The GL can be determined in vivo by ultrasonog- Brain weight, which is also variable, has been studied raphy or magnetic resonance imaging; for greater in the fetal period by a number of authors (e.g., Tanimura precision in estimating age the GL can be combined et al., 1971; Gilles et al., 1983), and summarizing graphs with other measurements. are available (Lemire et al., 1975). P1: FAW/FAW P2: FAW JWDD017-04 JWDD017-ORahilly April 17, 2006 12:46 Char Count= 0

CHAPTER4 EMBRYONIC STAGING

renatal life is conveniently divided into embry- As information concerning ages becomes more precise, no onic and fetal periods. The embryonic period better example can be found of the value, indeed necessity, Pis that during which new features appear with great rapid- of the morphologically based staging system, which retains ity, enabling subdivision to be made into morphological its validity throughout. Moreover, comparisons are made stages. It occupies the first 8 postfertilizational weeks. The of a number of different features (e.g., somites, neuropores, vast majority of congenital anomalies appear during that eyes, limbs), so that individual differences are rendered less time. The fetal period is characterized more by the elabora- significant and a certain latitude of morphological variation of existing structures and, because of the less striking tion is taken into account. developmental changes, it has proved so far to be resistant Although external body form is of immediate access, to a morphologically based staging system. and can even be recorded in vivo by ultrasonography, never- In human embryology, staging, as distinct from mere theless it needs to be stressed that, particularly in certain seriation of embryos, was introduced by Mall in 1914. The stages (e.g., 20–22), internal morphology is an essential system now used internationally, termed Carnegie stages component of the Carnegie system. In some instances it by O’Rahilly, was prepared by Streeter in the 1940s. The has been found of interest to “estimate the stages” of em- early stages (1–9) were defined by O’Rahilly, who published bryos studied by ultrasound in vivo, but “exact staging by them in 1973 (O’Rahilly and Muller, ¨ 1987a).1 Other systems ultrasonography is not possible” (Blaas et al., 1998). are now obsolete. Moreover, stages should not be assigned on the basis of In the Carnegie system the embryonic period proper, mere length or age, both of which are too variable. An em- i.e., the first 8 postfertilizational weeks of development, is bryo of 20 mm, for example, could almost as easily belong subdivided into 23 stages based on external and internal to stage 19 as to stage 20, because the lengths usually given morphological criteria. These stages are used throughout for the various stages are guidelines and do not show the this book (Table 4–1). complete range of values. Similarly, even were an embryo The great advantage of morphological stages is that, in known to be precisely 49 postfertilizational days in age, it large measure, emancipation from the variables of age and could as easily belong to stage 19 as to stage 20. measurement can be achieved for the embryonic period. In addition, the admittedly subtle but useful distinction between the embryonic and fetal periods is based on a histological criterion (the onset of marrow formation in 1 It is relevant to record that the late George Corner told O’Rahilly that the humerus), and neither length nor external form would he disliked Streeter’s term “horizon” and was pleased to see it replaced be an adequate criterion. by “stage” in the 1973 monograph by O’Rahilly, who introduced the term Carnegie stage to encompass his own studies (stages 1–9) as well as those In summary, staging is now an essential procedure in of Heuser and Corner (stage 10) and of Streeter (stages 11–23). the scientific study of the human embryo, but it is necessary

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12 Chapter 4: EMBRYONIC STAGING

TABLE 4–1. Developmental Stages and Features of the Nervous System

Carnegie Greatest Approximate First appearance Pairs of stage length (mm) age (days) Key features of nervous system of neuromeres somites

8 1 23 Neural folds and groove in stage 8b 9 2 25 Mesencephalic flexure; neural groove P, M, Rh. A–D 1–3 evident; otic disc 10 3 28 Fusion of neural folds begins; optic T, D1, D2 4–12 primordium; otic pit 11 3.5 29 Rostral neuropore closes; optic vesicles Rh. 1–8 13–20 and optic neural crest; nasal discs 12 4 30 Caudal neuropore closes; secondary M1, M2 21–29 neurulation commences; adenohypophysial pouch 13 5 32 Closed neural tube; retinal and lens discs Par., Syn., 30–? develop; hypothalamic cell cord; medial Isthmus and lateral longitudinal fasciculi; primordium of cerebellum 14 6 33 Future cerebral hemispheres; pontine Rostral & caudal flexure; torus hemisphericus & medial Par.; all 16 ventricular eminence; optic cup and lens neuromeres vesicle present 15 8 36 Nasal pit; di-telencephalic sulcus; lateral ventricular eminence; hippocampal thickening; medial forebrain bundle; longitudinal zoning in diencephalon (marginal ridge) 16 10 39 Olfactory tubercle; dorsal thalamus; epiphysis cerebri; neurohypophysial evagination 17 13 41 Vomeronasal organ and nerve; forebrain septum; 2 to 4 amygdaloid nuclei; subthalamic nucleus; posterior commissure; red nucleus; internal and external cerebellar swellings 18 15 44 Paraphysis; future corpus striatum with intrastriatal sulcus; hippocampus C-shaped; inf. & superior cerebellar peduncles; primordium of nucleus dentatus 19 17 46 Olfactory bulb; nucleus accumbens; globus pallidus; choroid plexus of fourth ventricle; substantia nigra; medial accessory olivary nucleus 20 20 49 Choroid plexus of lateral ventricles; septal nuclei; interpeduncular nucleus; optic fibers in chiasmatic plate 21 23 51 Cortical plate in area of future insula; optic tract & lateral geniculate body 22 26 53 Olfactory striae; claustrum; internal capsule; adenohypophysial stalk incomplete 23 29 56 Insula indented; external capsule; caudate nucleus & putamen discernible; anterior commissure begins; mesencephalic Blindsacke¨ ; external germinal layer in cerebellum

Note: The greatest lengths and the postfertilizational ages given are approximate only. The latter have been revised to conform to current ultrasonic information. P1: FAW/FAW P2: FAW JWDD017-04 JWDD017-ORahilly April 17, 2006 12:46 Char Count= 0

COMPARATIVE STUDIES 13

to take both external and internal morphological criteria development of the brain may parallel “equivalent stages” into consideration. Neither length nor age, nor a combina- of the entire embryo, particularly those based on general tion of them, defines a stage in the accepted embryological external morphology. meaning of the term. Some preliminary data for equivalent stages, as dis- At present, staging is limited to the embryonic period tinct from equivalent ages, in the rat, mouse, and human proper. Despite attempts to do so, no satisfactory staging were proposed for the early development of the brain in re- system has yet been devised for the fetal period. Prenatal lation to anencephaly (Muller ¨ and O’Rahilly, 1984, Tables 2 life, however, can conveniently be considered in terms of and 3). Subsequently, a general atlas of some 15 species ar- trimesters: (1) including the embryonic period proper (up ranged according to the Carnegie staging system appeared to about 30 mm GL), and extending to some 90 or 100 mm, (Butler and Jurlink, 1987); that valuable work could serve (2) proceeding to about 250 mm, and (3) continuing until as a point de départ for the construction of staged inter- birth (very approximately 336 mm GL). species comparisons of the development of the nervous Staging systems are available for a number of species, system. two well known examples being Harrison’s staging of Am- “Equivalent ages” are far less desirable insofar as a bystoma maculatus and Hamburger and Hamilton’s stag- major objective of staging is to escape as much as is prac- ing of Gallus domesticus. Such systems have arisen largely ticable from the variables of age and linear measurements. independently of each other and the numeration differs Equivalent ages for the developing nervous system have from one to another. Witschi, in the 1950s, was the major been proposed by Clancy et al. (2001) for 95 events in proponent of the attractive idea of a standard enumeration 9 mammalian species, with numerous observational gaps throughout vertebrate embryology, a suggestion that un- being filled in by mathematically estimated predictions. fortunately was ignored. The Carnegie system has already The study suffers from the following major shortcomings, been applied to a number of primate species, especially particularly with regard to the human. (1) Embryonic stag- by Hendrickx and his coworkers. Unfortunately, however, ing was completely ignored and replaced by “postconcep- most workers who study the developing mouse or rat con- tional days” that were not (for the human) based on recent tinue to use ages instead of stages. ultrasonically confirmed information. (2) The human data An ideal staging system, particularly from the view- used, admitted to be subject to “much error,” were inade- point of experimental embryology, would be based entirely quate and frequently unreliable. (3) The extensive and pre- on external morphology. This is not always attainable, how- cise data now available for the human (Appendix 2 in the ever. During some periods of development, external ap- present book) were apparently unknown to the authors. (4) pearances may not change sufficiently rapidly to reflect Comparison of the two sets of data for 37 features reveals adequately the accompanying internal changes. In the hu- that only 16 % are similar in timing, whereas in Table 1 of man, for example, difficulties may arise during the period Clancy et al. (2001) 32 % are too early (by 3-16 days) and from 7 to 8 postfertilizational weeks. Hence the internal 51 % are too late (by 2-26 days), rendering their informa- structure is also important in staging. Details of internal tion untrustworthy. development in staged embryos, however, seem to be in- In the fetal period, where staging is not available and complete or even lacking in most species other than the where development is slower and not as clear-cut, compar- human. Furthermore, it should not be assumed that a given isons are more difficult and are liable to be of very limited stage based on external appearances will reflect precisely use. Incorporated in a detailed summary of the develop- similar internal features in different species. Even external ment of the nervous system of the rat (Bayer et al., 1993) features may vary among species. For example, the upper are estimates in (presumably postfertilizational) weeks of limb buds appear in the human at stage 12, whereas in the what are assumed to be corresponding features in the hu- mouse they are said to begin at stage 11 and in the pig man. The “assumptions,” “approximations,” and “extrap- they are not distinct until stage 13; the pineal outgrowth olations” involved in such studies inevitably lead to nu- appears in the human (and in other mammals) at stages merous pitfalls. (The inadequate account of the embryonic 15–16, whereas in the chick it is said to be seen at what period in the above mentioned article had already been would correspond to stage 13. superseded by the works cited here in Table 23-2). COMPARATIVE STUDIES Important r Morphological staging is essential for precise em- A valuable investigation of the brain of the rhesus monkey bryological studies. r was undertaken by Gribnau and Geijberts, and efforts have In the embryonic period, external and internal been made to compare the development of the brain in criteria are used in the assignment of 23 interna- various mammals (e.g., by Ashwell et al., 1996), but a com- tionally accepted morphological stages. parative study similar in detail to the present work on the r human awaits the future. Such investigations are needed In the fetal period, a satisfactory system of morpho- in order to assess to what extent “equivalent stages” in the logical staging is not at present available. P1: FAW/FAW P2: FAW JWDD017-05 JWDD017-ORahilly April 17, 2006 12:47 Char Count= 0

CHAPTER5 PRENATAL AGE

renatal age extends from fertilization to birth too low. According to studies with transvaginal sonography and hence should be given as postfertiliza- (Dr. Josef Wisser, personal communication, 1992), embryos Ptional weeks (or days). Ovulation is close to the time of of stages 6 to 16 may commonly have ages 1 to 3 (more fertilization (which, incidentally, is not a moment), so that usually 3 to 5) days more than the previous embryological postovulatory weeks or days (i.e., the time since the last norms. ovulation) are an acceptable indication of age. It has already been pointed out that, in embryological “Gestation” merely means pregnancy (“being with usage, (1) external body form and (2) internal morpho- child”) and lacks any technical precision, so that “gesta- logical status are the criteria for staging, and (3) greatest tional age” and “gestational weeks or days” are completely embryonic length, although it is not a determining factor, ambiguous, scientifically useless, and should be abolished is not entirely neglected. A further characteristic, (4) post- (O’Rahilly an Muller, ¨ 2000). In obstetrics, menstrual weeks fertilizational age, is rarely available and generally has to are generally and conveniently used and are assumed to be be estimated from the other three parameters. approximately a fortnight greater than the (postfertiliza- Considerable progress in imaging (e.g., by the use of tional) age. The use of the LMP measures the period of transvaginal sonography) has enabled an estimate, but only amenorrhea, when for the first two weeks no embryo ex- an estimate, of the stage of a given embryo to be made in isted (!), so that menstrual weeks are not age. Hence the vivo. This is based on parameters 1 and 3 mentioned above, designation menstrual “age” should not be used. In other and No. 4 is sometimes also known. No. 2, internal mor- words, an 8-week embryo may be assigned 10 menstrual phological status, however, is not adequately identifiable, weeks, but not said to have a menstrual “age” of 10 weeks. at least at the histological level, and hence precise staging In the embryonic period, once the stage of an embryo is remains an embryological rather than a clinical procedure. known, its presumed postfertilizational age can be assessed This distinction is particularly important in very early and from an appropriate table or graph (O’Rahilly and Muller, ¨ in very late embryonic stages. 1987a), such as Table 4–1. It is likely, however, that varia- The ages at which the chief features of the brain can tion may be greater than previously thought, and some of be detected in present usage in vivo by ultrasound during the ages accepted for early embryos may perhaps be slightly the first trimester are listed in Table 5–1.

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16 Chapter 5: PRENATAL AGE

TABLE 5–1. Chief Features of the Brain Found by Ultrasound During Trimester 1a

Postfertilizational Weeks (Age) Postmenstrual Weeks Features

5 7 First indication of brain 5–6 7–8 Cerebral hemispheres, lateral ventricles, wide interventricular foramina Future third ventricle Mesencephalon and future aqueduct Rhombencephalon and fourth ventricle 6–7 8–9 Choroid plexuses of lateral ventricle Telencephalon, diencephalon, mesencephalon, metencephalon, myelencephalon Cerebellum, pontine ﬂexure, lateral recesses of fourth ventricle 7–8 9–10 Falx cerebri C-shaped lateral ventricles Narrower third ventricle Isthmus prosencephali (between third ventricle and aqueduct) 8–10 10–12 Growing thalami Cerebellar hemispheres seem to meet Cerebellar peduncles Tentorium cerebelli Fourth ventricle divided by choroid plexus

a Based on data in Blaas (1999) and Timor-Tritsch et al. (2001).

Important Concluding Note r Prenatal age is postfertilizational by definition, al- It is recommended that decreasing confidence be given though an acceptable alternative is postovulatory. to the number of days assigned to an individual embryo r In the embryonic period, age is assessed from the or fetus, and that increasing precedence be awarded to standard morphological stage of the embryo. weeks and half-weeks. r When the embryonic length (GL) is within the range 3–30 mm, a very good estimate of age can be obtained by adding 27 to the length. r In the fetal period, age is estimated from measurements such as the greatest length (GL) taken in vivo by ultrasonography or magnetic resonance imaging. In obstetrics a useful preliminary criterion, although it is not age, is the postmenstrual interval. The term “menstrual age” is incorrect and the scientifically useless qualification “gestational” should not be used. P1: FAW/FAW P2: FAW JWDD017-06 JWDD017-ORahilly April 17, 2006 12:48 Char Count= 0

CHAPTER6 TERMINOLOGY

he nomenclature used in this book is mostly that Three main planes are used in anatomy: horizontal which is accepted internationally and is in cur- and two vertical planes, coronal and sagittal. One of the Trent anatomical usage. Examples of terms not employed, sagittal planes is median. One of the horizontal planes, including some comparative terms that are inappropriate the orbitomeatal, is used to ensure that the head is in the to the human (e.g., branchial instead of pharyngeal) are anatomical position. Strictly coronal planes are vertical given in Table 6–1. planes that are at a right angle to both the orbitomeatal Eponyms are by no means always justifiable histori- and the median plane. Prenatally, however, the situation is cally; they convey no morphological information, they add complicated by the curvature of the body and the flexion of unnecessary complications, and hence are to be avoided the head. Consequently, a transverse section of the trunk wherever possible. The island of Reil, for example, is much (a horizontal section in the adult) is not parallel to the more simply rendered as merely the insula. Similarly, the orbitomeatal plane (Fig. 6–1). Similarly, a coronal section fissures of Rolando and Sylvius, which are actually sulci of the prenatal trunk does not correspond to a coronal (!), are much better given as the central and lateral sulci, section of the adult head. These considerations, which are respectively. important in prenatal imaging, need to be kept in mind, In early development, such terms as anterior and pos- even though a satisfactory resolution of the problem has yet terior should be avoided. Appropriate terms for the em- to be achieved. When an unspecific plane is encountered in bryo include rostral and caudal, dorsal and ventral. As ultrasonic studies, the term “anyplane” is sometimes used. in adult anatomy, the unofficial and unnecessary terms The terms used for the divisions and main subdivi- midsagittal, for median, and parasagittal, for merely sagit- sions of the brain, as provided by Wilhelm His in prepara- tal, should not be used. Sagittal planes, including the tion for the Basel Nomina anatomica of 1895 are summa- median plane, are used as in adult anatomy. Trans- rized in Table 6–2 and Figure 6–2. The terms are basically verse and coronal planes, however, generally refer to those given by von Baer, with the addition of the isthmus the trunk prenatally and are frequently unclear when rhombencephali. applied to the flexed head, as found in the embryo A Glossary of terms relating to human neuroembryol- (Fig. 6–1). ogy is provided later in the book.

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TABLE 6–1. Examples of Improvements in Terminology

Undesirable Terms Comment Preferable Terms

Anterior and posterior Best avoided for the early embryo Rostral and caudal Basal ganglia Ganglia are in the peripheral nervous system Basal nuclei Central fissure In forebrain, fissure (see Glossary) has restricted usage Central sulcus Cerebral vesicles Based on avian species Forebrain, midbrain, and hindbrain Cerebrum When considered to be the telencephalon only, it is in Telencephalon contradiction with the essential and comprehensive adjective cerebral Chorda dorsalis Acceptable but clumsy term Notochord Ganglionic eminences Ganglia are in the peripheral nervous system Ventricular eminences Gestational age Scientifically useless term Postfertilizational age Lateral fissure In forebrain, fissure (see Glossary) has a restricted usage Lateral sulcus Medullary folds and groove Medulla has other implications Neural folds and groove Menstrual age Menstural weeks acceptable, but they are not age (Post)menstrual weeks Midline; midsagittal Unofficial and unnecessary terms Median Parasagittal Misinterpretation of term sagittal Sagittal Yolk sac Yolk is not involved Umbilical vesicle

A The A sagittal median plane GL plane

A coronal plane

A transverse plane

B Axis of mesencephalic flexure A coronal A transverse plane plane

Figure 6–1. The main planes of reference and the The chief terms of position shown in an embryo of stage 23 orbitomeatal (8 weeks). (A) The body as a whole. (B) The head, plane including the brain.

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TERMINOLOGY 19

TABLE 6–2. The Main Developmental Subdivisions of the Brain as Given by His

Divisions Subdivisions Cavities

E Prosencephalon n Telencephalon Lateral ventricles c Diencephalon Third ventricle e p h Mesencephalon a Mesencephalon Aqueduct l o Rhombencephalon n Isthmus rhombencephali Metencephalon Cerebellum Pons Fourth ventricle Myelencephalon Medulla oblongata Central canal

Cerebral hemisphere 3 6 DIVISIONS SUBDIVISIONS

Telencephalon Pros- encephalon Diencephalon

Mesencephalon

Isthmus Midbrain Brain Pons Rhomb- stem encephalon Metencephalon Medulla

Myelencephalon

Figure 6–2. The location of the three Spinal divisions and six subdivisions of the brain as cord seen in the newborn. P1: JYS JWDD017-07 JWDD017-ORahilly April 17, 2006 12:51 Char Count= 0

CHAPTER7 EARLY STAGES

ecause the ﬁrst morphological indication of according to whether (5a) the trophoblast is solid, (5b) the the nervous system appears at stage 8 (ap- trophoblast contains lacunae, or (5c) the lacunae form a Bproximately 3 postfertilizational weeks), the following brief vascular circle. The amniotic cavity and umbilical vesicle statement concerning stages 1 to 7 is provided. Full details (so-called yolk sac) appear during stage 5. At stage 5c a of these early stages have been published in a monograph thickening of the hypoblast at one end of the embryonic by O’Rahilly and Muller ¨ (1987a). disc may possibly indicate the rostral end of the body even Some evidence exists in mammals (and probably in- before the appearance of the primitive streak (Luckett, dis- cluding the human) that a labile axis of bilateral symmetry cussed by O’Rahilly, 1973). is determined by the site of penetration of a spermatozoon Stage 6 (about 17 days) is marked by the appearance 1 (reviewed by Denker, 2004). of chorionic villi. During this stage, at approximately 2 2 Stage 1 is the unicellular embryo that is formed at postfertilizational weeks, axial features (particularly a cel- fertilization, normally in the lateral end (ampulla) of the lular proliferation termed the primitive streak) develop, uterine tube. A new, genetically distinct human organism and hence the embryo acquires right and left sides, as well is thereby formed, although the embryonic genome does as rostral and caudal ends. The embryonic disc is now about not become activated until the next stage. 0.2 mm in length. Twins (other than certain conjoined ex- Stage 2 (2–3 days) is the cleaving embryo that proceeds amples) arise before the appearance of axial features, i.e., along the uterine tube. during approximately the ﬁrst fortnight. Retinoic acid is Stage 3 (4–5 days) is characterized by the appearance of believed to be implicated in the patterning of the rostro- a cavity within the cellular mass, at which time the embryo caudal axis and the induction of the expression of Hox is termed a blastocyst and lies in the uterine cavity. The genes. embryonic disc now presents dorsal and ventral surfaces. Stage 7 (Fig. 7–1, about 19 days). An axial structure The inner cell mass, mainly the epiblast, has been used known as the notochordal process is characteristic of this for the production of embryonic stem cells that retain the stage, when the embryonic disc measures approximately ability to develop into all types of cells, including germ 0.4 mm. Although no morphological sign of the nervous cells. system is yet present, the site of the future neural plate is Stage 4 (6 days) is the attachment of the blastocyst to dorsal and lateral to the notochordal process. the uterine lining (endometrium), an event that heralds Stage 8 (about 23 days) is the subject of the following the beginning of implantation within the uterine mucosa. chapter. The epiblast is now being transformed into the Stage 5 (7–12 days), the continuation of implanta- neural plate in the region rostral to the neurenteric canal. tion, is complicated and is subdivided into three substages, Canalization of the notochordal process occurs (i.e., the

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22 Chapter 7: EARLY STAGES

notochordal canal develops) in embryos approximately A Embryonic disc 1 mm in length. When, during stage 8, the notochordal process attains a length of 0.4 mm, the neural groove, which is Dorsal view the ﬁrst morphological indication of the nervous system, Median becomes recognizable. plane The cells and tissues that give rise to the nervous system are given in Table 7–1. Allantoic The most frequently encountered errors in descrip- diverticulum tions of the initial development of the human brain have recently been listed (O’Rahilly and Muller, ¨ 1999). 65 4 3 2 1 Important

Amniotic The embryo shows dorsal and ventral surfaces at stage cavity 1 B Dorsal surface 3 (about 1 2 postfertilizational weeks), and right and left sides, as well as rostral and caudal ends, at stage 6 (about 1 2 2 weeks.)

Umbilical vesicle

0.1 mm Median section

Prechordal plate Notochordal process Ectoderm & plate Primitive streak Mesoderm & node Site of future Endoderm cloacal membrane Allantoic diverticulum

Figure 7–1. Reconstruction of an embryo at stage 7 (nearly 3 weeks), immediately before the neural groove and folds become visible. (A) Dorsal view and (B) median view. The various features are identiﬁed in the keys below the drawing. P1: JYS JWDD017-07 JWDD017-ORahilly April 17, 2006 12:51 Char Count= 0

EARLY STAGES 23

TABLE 7–1. The Origin of the Central and Peripheral Nervous Systems, and the Associ- ated Neural Cresta

Neural C P N N plate S S

folds Neural tube

Neural ectoderm Retina Optic crest 1

Neuro- somatic Neural junction crest

Somatic- Otic Nasal ectoderm crest crest

Placodes ("islands") Primi- tive 2 streak Caudal Neural eminence cord

Stage 6b 8 8b 9 10 12 13

a In primary neurulation (marked 1 at the right) the neural tube is formed by folding of the neural plate and fusion of the neural folds. The neural discs or placodes, which develop in the somatic ectoderm, were thought of by Streeter as islands of neural ectoderm. Secondary neurulation (marked 2 at the right) is the formation of the caudal portion of the neural tube from a cellular mass known as the caudal eminence, and not by fusion of neural folds. The interrupted horizontal line indicates the cerebrospinal junction. P1: JYS JWDD017-07 JWDD017-ORahilly April 17, 2006 12:51 Char Count= 0

24 Chapter 7: EARLY STAGES NEUROTERATOLOGY

It has been shown experimentally in the mouse that excessive cell death in the primitive streak plays a major role in spina biﬁda aperta caused by nonclosure of the neural folds (Fig. 7-2).

A BC

Myeloschisis D aperta Spina bifida (NTD) Myelomeningocele cystica Meningocele occulta

Figure 7–2. The completion of a vertebral foramen and its relationship to spina bifida. (A) In the embryo, the cartilaginous neural processes have not yet united. (B) In the newborn, although three ossific centers are present, the spinous process is still cartilaginous, providing a radiological appearance of a normal spina bifida. (C) In the adult, ossification is complete. (D) Spina bifida is a failure of closure of a vertebral foramen from whatever cause. The condition may be concealed (occulta) or evident (aperta) and generally cystic (cystica). P1: JYS JWDD017-08 JWDD017-ORahilly April 17, 2006 12:52 Char Count= 0

CHAPTER8 STAGE 8: THE FIRST APPEARANCE OF THE NERVOUS SYSTEM

Approximately 1–1.5 mm in Greatest Length; Approximately 23 Postfertilizational Days

he embryo is an ovoid (frequently pear-shaped) organization are of crucial importance for an understand- disc with a longitudinal axis and distinct cephalic ing of the developing nervous system. It is of interest that Tand caudal ends. In one-quarter of examples, referred to as the primordium of the brain appears before the heart or stage 8b, the neural groove can be detected in the neural any other organs become visible. plate as a very shallow sulcus bounded by faint neural folds. Studies of early neurogenesis indicate that differences This is the ﬁrst visible sign of the future nervous system, concerning neural induction among vertebrate classes are and most of the folds represent the brain. The neural plate present from the beginning of neurulation, and that mam- is closely related to two median features: the prechordal malian neurulation is extremely complex. plate and the notochordal process. Stage 8 has been generally listed as 18 days, but is Important probably more usually about 23 days. Although few morphological features are visible at the The ﬁrst indication of the neural groove and folds is time of initial development of the brain, stage 8 and its found during this stage.

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26 Chapter 8: THE FIRST APPEARANCE OF THE NERVOUS SYSTEM

TABLE 8–1. The Neurenteric Canal and Its Site as Important Landmarks

Stage Rostral to Neurenteric Canal Caudal to Neurenteric Canal

8 Notochordal process and notochordal plate induce (in stage 8b) development Primitive streak and epiblast of neural plate from the epiblast in area of future brain as far rostrally as D2 Prechordal plate induces D1 Floor plate may perhaps be present Endoderm incomplete axially Endoderm complete 9 Notochordal plate is ventral to brain, including Rh. D Primitive streak Floor plate may perhaps be present Endoderm incomplete axially Endoderm complete 10 Rostral part of notochord develops by folding of notochordal plate Spinal part of neural plate develops from surface ectoderm Endoderm gradually continuous axially Caudal part of notochord develops directly from mesenchyme

Figure 8–1. Dorsal view of an embryo of stage 8. The rostral end is above; the caudal end is below and is anchored by the connecting stalk, at the end of which two chorionic villi have been sectioned. The amnion has been cut and removed in order to expose the dorsal surface of the embryo. X and Y are the levels of the sections shown in Figures 8–3 and 8–4. The embryo at stage 8 is a slightly vaulted, pear-shaped disc that displays a longitudinal axis. The axis is indicated (1) by the primitive groove, which begins at the primitive node and proceeds caudally, and (2) by the neural groove, which is situated in the median plane at level Y. This is the region of the neural plate, which, although sharp boundaries are not evident, comprises (a) a peripheral rim, the alar plate, and (b) a more central part capping the notochordal process and primitive node, namely the basal plate or lamina (Fig. 9–5). The neural groove, which is shown in Figure 8–4, is the first visible sign of the future nervous system and, for the most part, it indicates the site of the brain. This beautiful drawing of the Heuser embryo is by James F. Didusch, whose “work is unexcelled in the anatomical literature” (Crosby and Cody, 1991). In 1917 Max Brödel 0.14 mm referred to Didusch as “my first pupil.” P1: JYS JWDD017-08 JWDD017-ORahilly April 17, 2006 12:52 Char Count= 0

THE FIRST APPEARANCE OF THE NERVOUS SYSTEM 27

Neural plate

Notochordal

Figure 8–2. Graphic reconstruction prepared from transverse sections of an embryo of stage 8. The rostral end is to the right. From rostral to caudal, the following are indicated: prechordal plate, neural plate (dorsally), and endoderm. The neural plate is in close contact rostrally with the prechordal plate, and ventrocaudally with the notochordal process. The rostralmost portion of the neural plate corresponds to the optic area of the diencephalon, neuromere D1. The notochordal plate is the roof of the notochordal process at levels where the ﬂoor has already disappeared during the process of intercalation of the plate in the endoderm. The notochordal process is a cellular rod that contains the notochordal canal and is in close contact with the neural ectoderm dorsally and the mesenchyme laterally. Its canal begins as a pit in the primitive node and then proceeds more or less vertically, as the neurenteric canal, before continuing rostrally. The primitive streak is situated caudal to the primitive node, and it gives rise to numerous mesenchymal cells.

Amnion

Figure 8–3. Transverse section at the level of the prechordal plate corresponding to line X in Figure 8–2. This figure and Figure 8–4 were selected from a histologically superior embryo. The prechordal plate is a multilayered accumulation of cells in close contact with the floor of the neural groove of D1. It is involved in neural induction, which is probably maximal at stage 8. The plate also furnishes mesenchyme for the orbital muscles and probably for the tentorium cerebelli. The location of the prechordal plate in the human would seem to correspond to the axial mesoderm between the first pair of “somitomeres” in the mouse, in which species seven such segmental units have been detected rostral to the first somite. Bar = 0.05 mm. The prechordal plate is an important source of prenotochordal tissue. It is maintained that the prechordal plate is ventral to a single retinal field at the rostral end of the neural plate and that normally it suppresses the median part of that field, thereby causing bilateral retinal primordia to develop (Fig. 10–13).

Neural groove & fold

Figure 8–4. Transverse section at the level of the notochordal plate corresponding to line Y in Figure 8–2. The shallow neural groove, present in one-quarter of embryos of stage 8, is bounded on each side by a slightly elevated neural fold. Numerous mitotic figures are present in the neural plate and are adjacent to the amniotic cavity—that is, near the future ventricular surface of the later-appearing neural tube. The multilayered mesoderm interposed between ectoderm and endoderm is separated by the basement membranes of the two epithelia. The median part of the neural epithelium is the future floor plate. It is firmly attached to the notochordal plate and is as thick as the lateral portion of the neural plate. Bar = 0.05 mm. P1: JYS JWDD017-08 JWDD017-ORahilly April 17, 2006 12:52 Char Count= 0

28 Chapter 8: THE FIRST APPEARANCE OF THE NERVOUS SYSTEM

Chor. villi Embryonic disc

Amniotic cavity Body Umbilical stalk vesicle Allantoic diverticulum

Amnion Neural plate

Artifact Primitive pit Primitive Notochordal streak process

Neurenteric canal Endoderm

Primitive Ectoderm groove & streak

Mesoderm

Endoderm

1 Figure 8–5. The formation of the primitive streak at stage 8a. (A) Median section of an embryonic disc of nearly 1 2 mm in length. (B) A higher powered view of the section shown above. The neurenteric canal connects the amniotic cavity with the umbilical vesicle temporarily. It is an important landmark in stages 8 to 10 (Table 8–1). (C) Transverse section through the primitive groove and primitive streak, which attains its greatest length at this stage. P1: JYS JWDD017-08 JWDD017-ORahilly April 17, 2006 12:52 Char Count= 0

THE FIRST APPEARANCE OF THE NERVOUS SYSTEM 29

B A Neuroectoderm Prechordal plate A B B C

C D C Epiblast Primitive E node

D D

Primitive groove E Primitive streak

Figure 8–6. Serial sections through an excellent example of stage 8. The level of the sections is indicated on the reconstructed median section. (A) The prechordal plate in transverse section shows as many as eight rows of cells that differ from the endodermal cells in being larger and more nearly spherical, and in containing numerous granules. The neural ectoderm at this level shows a very faint indentation, the beginning of the neural groove. The prechordal and neural plates are separated by a basement membrane. (B) The neural groove in an area rostral to the notochordal process. (C) The primitive pit and its continuation with the notochordal canal of the notochordal process. (D) The primitive node. (E) The primitive groove and streak. At this caudal level the mesenchyme between the surface ectoderm and the endoderm is far greater in quantity than at rostral levels. Blood vessels are not yet present. Bar = 0.03 mm. P1: JYS JWDD017-08 JWDD017-ORahilly April 17, 2006 12:52 Char Count= 0

30 Chapter 8: THE FIRST APPEARANCE OF THE NERVOUS SYSTEM

EARLY NEURAL EVENTS identiﬁable (Fig. 9-2). The free edges of the neural folds turn mediad (sharply so in rodents at what are termed After the neuroepithelium is induced, the neural plate dorsolateral bending points) resulting in apposition of the forms and is characterized by cellular movements mediad neural folds. Normal bending of the neural folds is believed (convergent extension). The edges of the plate form bilat- to depend on contraction of actin microﬁlaments, emigra- eral neural folds (Fig. 8-4) that undergo median bending tion of neural crest, and neuroepithelial apoptosis (as stud- accompanied by expansion of the underlying mesenchyme. ied in rodents and summarized by Copp, 2005). The neural The folds are separated by the neural groove (Figs. 8-4, folds then fuse in the median plane (Figs. 10-2A, 10-5, and 9-3, and 10-11). The lengthened neural plate is broader 11-9) and this is the beginning formation of the neural rostrally, where the three major divisions of the brain are tube (primary neurulation). P1: JYS JWDD017-09 JWDD017-ORahilly April 17, 2006 12:53 Char Count= 0

CHAPTER9 STAGE 9: THE MAJOR DIVISIONS OF THE BRAIN

Approximately 1.5–2.5 mm in Greatest Length; Approximately 26 Postfertilizational Days

he embryonic disc is now an elongated body The otic discs, which are the first indication of the (inter- characterized by a long and deep neural groove. nal) ears, are first visible at this stage. TThe first somites have appeared and are occipital. The The primitive streak is replaced by the caudal emi- three major divisions of the brain are distinguishable in nence. The neural folds of the spinal cord begin to develop. the folds of the completely open neural groove: prosencephalon (mostly diencephalon), mesencephalon (at the mesencephalic flexure), and rhombencephalon (compris- Important ing four subdivisions, A to D). Rhombomere D is related to The three major divisions of the brain can be distin- the (occipital) somites and was not recognized by previous guished in the completely open neural folds, when no authors. No neural tube has yet formed, and “brain vesi- so-called vesicles are present. cles” are not present. Neural crest is beginning to develop.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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32 Chapter 9: THE MAJOR DIVISIONS OF THE BRAIN

Figure 9–1. Left lateral and dorsal views of an embryo of stage 9. Striking changes have occurred since the preceding stage. The embryonic disc is now clearly an elongated embryonic body, set off from the surface of the umbilical vesicle (the so-called yolk sac). Various features are indicated in Figure 9–2 A,B. In the lateral view, the “waist” of the embryo can be seen to be the site of considerable lordosis. The cephalic and caudal portions of the body are elevated from the surface. In the dorsal view, the region of the head, which is broadest at the level of the mesencephalon, is clearly joined to the caudal eminence by a “waist,” in which the ﬁrst (occipital) somites are appearing. Caudally the greatest width is at the level of the primitive node, the site of which is shown in Figure 9–2. (In the present ﬁgure the artist has placed it too far caudally.) Cephalic to the node, the embryo has elongated greatly. Beyond the embryo, the umbilical vessels and the allantoic diverticulum have been sectioned. The neural folds bound a long and deep neural groove. Preotic and postotic sulci are very faint (compared with those in rodents). This is another example of an elegant drawing by James F. Didusch, artist to the Carnegie Collection. P1: JYS JWDD017-09 JWDD017-ORahilly April 17, 2006 12:53 Char Count= 0

THE MAJOR DIVISIONS OF THE BRAIN 33

A ∗

Rhombencephalon

Primitive Somites streak node

C Ot.

Figure 9–2. (A) dorsal, (B) right lateral, and (C) median views of an embryo of stage 9. The cephalic end is to the right. The first (occipital) somites are stippled. The otic discs are indicated by interrupted lines; C is a graphic reconstruction prepared from transverse sections. Although no part of the neural tube has yet formed and no so-called brain vesicles are present, the three major divisions of the brain recognized by von Baer are distinguishable. The prosencephalon is almost exclusively diencephalic. The mesencephalon is at the site of a marked bend, the mesencephalic flexure. In C, the rhombencephalon, which extends from the otic to the somitic region, can be seen to comprise four subdivisions: rhombomeres A, B, C, and D, the last (first recognized by Muller ¨ and O’Rahilly, 1983) representing the hypoglossal region. These rhombomeres are real entities (as shown by immunological methods in the chick). The asterisk indicates the future cerebrospinal junction. A faint groove is visible between the mesencephalon and Rh.A. It is clearest in a dorsal view (Fig. 9–2A), where it separates the wider midbrain from the narrower hindbrain. It corresponds to the preotic sulcus in rodents. The first sign of the production of neural crest can be found in a few embryos of stage 9. It occurs at the level of the mesencephalon and the rhombencephalon. In addition, the production of general mesenchyme continues. The prechordal plate participates in the formation of the head and probably provides cardiac mesenchyme. The primitive streak, however, seems to have ceased as a site of proliferation, and its functional role has been replaced by that of the caudal eminence. The primitive node is shown in its correct position (more rostrally than in Fig. 9–1). P1: JYS JWDD017-09 JWDD017-ORahilly April 17, 2006 12:53 Char Count= 0

A E

F B

D H Mesenchyme

Allantoic diverticulum Epiblast

Neural fold & groove

A Head fold

B Mesencephalon

C Rhombomere B Ot. D S1 Rhombomere D

E, F Primitive pit & node G Primitive groove H Caudal eminence Allantoic diverticulum

Figure 9–3. Sections through an embryo of stage 9, a stage that is rarely seen. Key drawings, a median section and a dorsal view, are the authors’ reconstructions. The levels of the sections reproduced are indicated from A to H. The degree of lordosis of human embryos of this stage seems to be less pronounced than in those of some other primates and of rodents. (A) The head fold, including the most rostral part of the neural plate, a little caudal to the prechordal plate and rostral to the cardiac primordium. The foregut is a closed tube at this level. The amnion and the amniotic cavity are well shown in this and in the next section. (B) The deep neural groove here is at the level of the mesencephalon. The floor plate lies on the broad notochordal plate, which is intercalated in the endoderm. The paired pericardial cavities are clearly visible. (C) Rhombomere B. The neural groove is widely open to the amniotic cavity. The floor plate is in contact with the notochordal plate and has the same thickness as the lateral walls of the future neural tube. The thick ectodem lateral to the sumit of each neural fold is the otic plate. (D) Rhombomere D at the level of the caudal part of somite 1. This embryo possessed two somitic pairs. (E) The primitive pit and the umbilical vesicle communicate with each other through the neurenteric canal. (F) The primitive node and the beginning of the primitive groove. Venous channels on each side are the umbilical veins and that on the left side of the embryo (right side of the photograph) is wider, an asymmetry also seen in other embryos of this stage. (G) The primitive grove is deeper here. Mesenchyme invaginating from the primitive streak is visible. (H) Caudal region of the primitive streak. Invaginating cells and a pseudostratified epiblast are visible. Mesenchyme forms also from the surface of the body stalk near the allantoic diverticulum as emphasized in the key drawing.

34 P1: JYS JWDD017-09 JWDD017-ORahilly April 17, 2006 12:53 Char Count= 0

Umbilical vesicle

C, D B

Allantoic diverticulum

Neural ectoderm

Umbilical vesicle

C D

Figure 9–4. Regression of the primitive streak in stage 9. (A) A coronal section. The epiblast has mostly been replaced by cuboidal surface ectoderm. The dark tissue rostral to the umbilical vesicle (and mostly at the right side of the photograph) is neural ectoderm. (B) A transverse section through the rostral part of the primitive streak. The median, invaginating ﬂask-shaped and spherical cells are still numerous, and the epiblast is still thick laterally. The open arrow indicates the primitive groove. (C) A transverse section through the neurenteric canal (black arrow) in an other embryo in which the cuboidal surface ectoderm has almost replaced the former epiblast. (D) The neurenteric canal (black arrow), epiblast, and mesenchyme of the primitive streak in the embryo shown in B. Modiﬁed from Muller ¨ and O’Rahilly (2004a, Cells Tissues Organs) by permission of S. Karger AG, Basel.

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36 Chapter 9: THE MAJOR DIVISIONS OF THE BRAIN

Neural Figure 9–5. Transverse sections at stages 8 to 11 to show groove Stage in a purely didactic manner the formation of the neural tube and the notochord. The neural primordium is closely related ventrally to the precursor of the notochord (stages 8–10). Later, when the notochord becomes surrounded by 8 the developing centra of the vertebrae, the latter become and remain an important ventral relation of the spinal cord. Blue, the future alar plate (dorsal lamina); Orange-brown, the future basal plate (ventral lamina) of the neural tube. The ﬂoor, basal, alar, and roof plates all express different genes. Inductional processes between the future notochord Notochordal 9 plate and the neural tube would likely be greatest during stages 8 and 9, when the future notochord is present as a plate Neural and hence presents a relatively wide surface. The contact fold is particularly close at stages 8–10 because, as has been shown in the macaque, a basement membrane is lacking between the two tissues at that time.

Floor plate

Roof plate 10

Neural crest Neural tube

Somites

Notochord P1: JYS JWDD017-09 JWDD017-ORahilly April 17, 2006 12:53 Char Count= 0

NEURAL TUBE AND NEURENTERIC CANAL 37

Immature Figure 9–6. A portion of the wall of the neuron neural tube (small drawing at left) showing interkinetic nuclear migration. M G2 G When DNA is replicated (S phase), the S 1 S nuclei migrate towards the lumen, where BM Marginal zone a terminal bar net (TBN) is situated. A Intermediate mitotic ﬁgure is shown at the ventricular zone surface during the mitotic (M) phase. Synthesis After division, the nuclei migrate away of DNA from the lumen (G1 phase). The ventricular (matrix), intermediate (mantle), and marginal zones are indicated. Ventricular zone Mitotic zone TBN Cavity of neural tube

Amniotic Neurenteric cavity canal Neural Amnion plate

Notochordal plate Umbilical vesicle

Figure 9–7. The neurenteric canal at stage 9. P1: JYS JWDD017-09 JWDD017-ORahilly April 17, 2006 12:53 Char Count= 0

38 Chapter 9: NEUROTERATOLOGY

S1 D

Notochordal plate NORMAL

C GUT GUT Neural plate E

A Noto- chordal AMNIOTIC DIASTE- plate and CAVITY MATO- notochord MYELIA UMBILICAL VESICLE F DORSAL ENTERIC Endoderm UMBILICAL CYST B VESICLE

GUT

Figure 9–8. The neurenteric canal and anomalies that are probably related to it. (A), (B) Median and transverse sections through a four-somite embryo of stage 10 showing the neurenteric canal. (C) After normal closure of the canal. (D) A few weeks later (at stage 23). (E) The formation of a split notochord. (F) Persistence of the neurenteric canal. P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

CHAPTER10 STAGE 10: THE NEURAL TUBE AND THE OPTIC PRIMORDIUM

Approximately 2–3.5 mm in Greatest Length; Approximately 29 Postfertilizational Days

hen approximately five somitic pairs are placodes, which have been considered as special “islands” present, the neural folds begin to fuse in the in the somatic ectoderm. adjacent rhombencephalic and spinal regions, frequently W Summary in several places simultaneously. A portion of the neural tube is thereby formed, and mitotic figures are found near Two de novo sites of fusion of the neural folds appear its cavity. The diencephalon consists of the future thala- in succession: α in the rhombencephalic region (stage mic region (D2) and an optic portion (D1) in which the 10) and β in the prosencephalic region, adjacent to the optic sulcus appears. The right and left optic primordia, chiasmatic plate (stage 11). Fusion from site α proceeds which are visible for the first time at this stage, are con- bidirectionally (rostrad and caudad), whereas that from nected by the chiasmatic plate (primordium chiasmatis; β is unidirectional (caudad only). The fused regions torus opticus). The lateral parts of the forebrain beyond terminate in neuropores, of which there are two: rostral the chiasmatic plate belong to the telencephalon, which and caudal. Fusion β begins later than fusion α, but the is visible for the first time at this stage. Several regional rostral neuropore closes before the caudal. components of the neural crest can now be distinguished, Accessory loci of fusion are (1) inconstant, (2) vari- and the formation of the crest in the head is probably at its able in position, and (3) exhibit no specific pattern, so greatest. that they are not “multiple sites” of fusion. Stage 10 is usually listed as 22 days, but may be as much as a week older. The neural crest, widely dispersed groups of cells, Important arises at the neurosomatic junction. In the head they in- The telencephalon medium can be distinguished from clude mesencephalic, trigeminal, facial-vestibular, glos- the diencephalon at this stage, i.e., much earlier than sopharyngeal, vagal, and hypoglossal crest, and at least commonly stated. half of these also receive contributions from epipharyngeal

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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40 Chapter 10: THE NEURAL TUBE AND THE OPTIC PRIMORDIUM

Figure 10–1. A 10-somite embryo of stage 10. (A) Left dorsolateral view. Various features are identified in the inset, according to the authors’ interpretation, including the eight rhombomeres (numbered) and the first four somites (in gray). M, midbrain. Ph., first pharyngeal arch. The beginnings of the telencephalon (Fig. 10–3) are not visible in these views. (B) Left lateral view. These two superb illustrations were made by James F. Didusch for Dr. George Corner.

S4 S4

M 1 Ph. 1 2 2 3 3

4 4

5 5 6 6

7 7

8 8

Figure 10–2. Dorsal and right lateral views of an embryo of stage 10. The number of somitic pairs at this stage ranges from 4 to 12; the embryo shown here has 10 pairs. An extensive portion of neural tube has already formed, leaving parts of the neural groove exposed. (A) The dorsal view shows the neural folds fused in the adjacent rhombencephalic and spinal regions. Fusion begins when approximately 5 somitic pairs are present. Accessory loci of fusion are sometimes seen. The neurenteric canal is still present in the least advanced embryos. The caudal eminence (a continuation of the primitive streak) constitutes about one-ﬁfth of the embryonic length. It continues the production of mesenchyme and its surface ectoderm forms the caudal part of the future neural plate during stage 10. (B) The right lateral view shows the developing pharyngeal arches and the cardiac region, represented here by the pericardial cavity. The surface ectoderm is contributing to the otic plate (dotted outline) and the epipharnygeal area of the future vagal ganglia. P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

THE NEURAL TUBE AND THE OPTIC PRIMORDIUM 41

Tel.

Figure 10–3. Graphic reconstruction prepared from transverse sections to show a median view. An end-on view is shown on the right. The major divisions of the brain are distinguishable in the largely still-open neural groove. The mesencephalic flexure has decreased (from approximately 150◦ to 104◦) since the previous stage, contributing to a ventral bending of the prosencephalon and the shaping of the future head. The diencephalon comprises two portions: D2, the future thalamic region, and D1, in which the (left) optic sulcus can be seen for the first time. D1 possesses a thick floor that forms the median bridge between the two, laterally placed, optic primordia. This is the chiasmatic plate (primordium chiasmatis) or torus opticus. The optic sulci may extend to the median plane and end in a pit, the “postoptic recess” (Johnston, 1909), which is the caudal boundary of the chiasmatic plate. The lateral parts of the forebrain extend further rostrally than the chiasmatic plate. This is the telencephalon, evident for the first time at this stage in embryos of 7–12 somitic pairs. At this stage and in stages 11 to 14 (Bartecko and Jacob, 1999) the notochord extends rostrally to the oropharyngeal membrane (Muller ¨ and O’Rahilly, 1985), so that induction of the floor plate is possible as far rostrally as neuromere D2. This is the future epinotochordal part of the brain. Neuromere D1, which is induced by the prechordal plate (Fig. 10–7), is prenotochordal in position. Pax 3 is expressed in the neural groove and in the closed part of the neural tube at stage 10 (and at stage 15 in the brain stem and spinal cord) in the human embryo (Gérard et al., 1995). Pax 6 is important for the development of the eye. P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

42 Chapter 10: THE NEURAL TUBE AND THE OPTIC PRIMORDIUM

D D A B C

M C P B Rh. A

10 16 neuromeres: 123 4 5678 Telencephalon Diencephalon 1 Rostral parencephalon 11 M2 Caudal parencephalon M1 Synencephalon Mesencephalon 1 T Mesencephalon 2 Isthmus Rhombomeres 1-8 D2 D1 12 Isth. D2

Cbl Par.

Syn.

Par.c.

Par.r. 14

Figure 10–4. The neuromeres of the human embryo at stages 9 to 14. Neuromeres are morphologically identiﬁable transverse subdivisions perpendicular to the longitudinal axis of the embryonic brain and extending onto both sides of the body. Primary neuromeres are six larger divisions that appear early (stage 9) in the open neural folds: prosencephalon (P), mesencephalon (M), and rhombomeres A, B, C, and D. Secondary neuromeres are smaller subdivisions that are found both before (stages 10 and 11) and after (stages 12–14) closure of the neural tube. In all, 16 secondary neuromeres develop: telencephalon medium (T), diencephalon 1 (D1), rostral parencephalon, caudal parencephalon, synencephalon, mesencephalon 1 (M1), mesencephalon 2 (M2), isthmus rhombencephali, and rhombomeres 1 to 8. These are detectable at stages 14 to 17. A longitudinal organization begins to be superimposed on the neuromeres at stage 15, and ﬁve longitudinal zones can be discerned in the diencephalon (Table 18–1). Although in some instances territories of gene expression follow the morphological neuromeres, in others they may cross interneuromeric boundaries. P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

THE NEURAL TUBE AND THE OPTIC PRIMORDIUM 43

5 7 A A 8

Rhomben- 10,11 cephalic crest B

B 12 C

Spinal

0.1 C N e u r a l t b

D D E Spinal crest

E 0.1

Figure 10–5. The neural crest at stage 10. The levels of the neural tube are shown in the left-hand column. At rostral levels (A), crest material appears before closure of the neural groove, whereas at levels B to E, the contrary holds. The crest cells, which leave the neural plate where the basement membrane is interrupted, contribute to ganglia of cranial nerves and migrate to the general mesenchyme to provide ectomesenchyme for the skull and face. Also arising at the neurosomatic junction are otic crest and nasal crest, and the latter gives origin to vomeronasal crest and terminalis crest. Finally, arising from the retina, which is in continuity with the neural ectoderm of the diencephalon, is the optic crest (Table 10–3). P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

44 Chapter 10: THE NEURAL TUBE AND THE OPTIC PRIMORDIUM

Neural crest

10 Ð 8 7 6 M

Di.

Figure 10–6. In the upper part of the photomicrograph, the mesencephalic neural crest can be seen migrating on each side from the neural ectoderm. The sites of neural crest emigration show discontinuity of the basement membrane. The optic sulcus is indicated by an arrow.

Figure 10–7. Neural crest is visible above as it emerges from rhombomere 1. The median plane is occupied by the Chiasmatic ﬂoor of the neural groove. The prechordal plate shows as a plate small dark projection on each side of the lower portion of the photomicrograph above the chiasmatic plate. The very large bilateral blood vessels on each side of the neural plate are the ﬁrst aortic arches, which arise from the paired dorsal aortae, visible in Figures 10–11 and 10–12. P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

THE NEURAL TUBE AND THE OPTIC PRIMORDIUM 45

Crest

Ao.

Pharynx Notochord

Figure 10–8. The facial crest, rather than migrating from the neurosomatic junction, appears to arise directly from the neural ectoderm of the future neural tube (arrows in the key). Such an origin resembles that of the mesencephalic (Fig. 10–6) and trigeminal (Fig. 10–7) crest, although it is less pronounced here.

TABLE 10–1. The Terminology, Development, and Derivatives of the Neuromeres in the Human Embryo

Primary Secondary Neuromeres Neuromeres Derivatives Stages Stage 9 10 11 12 13 14 Telenceph. T medium P D1 D2 Parenc. Rostral Dienceph. Caudal Synenc. M1 M a M2 Mesenceph. a Isthmus Isthmus Rh. A Rh. 1 Rh. 2 Cere- Rh. 3 bellum Rh. B Rh. 4 Pons Rh. 5 Rh. C Rh. 6 Rh. 7 Med- ulla Rh. D Rh. 8

a The distinction between M1 and M2 can be followed up to and including stage 17. P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

46 Chapter 10: THE NEURAL TUBE AND THE OPTIC PRIMORDIUM

Stage 6

Epiblast

9 M Rh. A Rh. D

10 Caudal Tel. eminence M Rh.

Epiblast; diencephalon Primitive node & streak Prechordal plate; mesenchyme Hypoblast; endoderm; telencephalon Notochordal process/plate

Figure 10–9. Development of axial structures from stage 5c to stage 10: the prechordal plate, primitive streak, notochordal process/ plate, and ﬂoor plate. Stage 6. The prechordal plate appears before the notochordal process. Stage 7. The primitive streak and node are forming. Stage 8. The notochordal process and plate develop. Rostral to the neurenteric canal the neural plate replaces the epiblast. The notochordal plate reaches approximately from the neurenteric canal to the prechordal plate. The thick arrows in stages 8–10 indicate the site of the neurenteric canal. Stage 9. The notochordal plate extends from the neurenteric canal to the prechordal plate. The epiblast on both sides of the primitive streak becomes surface ectoderm. The ﬂoor plate extends from D2 to Rh.D. The asterisks in stages 9 and 10 indicate the summit of the neural fold over the mesencephalon. Stage 10. The surface ectoderm of the caudal eminence develops into neural plate. The lengths of the structures represent calculated means of percentages of several embryos. The longitudinal extent of the prechordal plate and of the primitive streak is greatest in stage 8, after which they undergo a progressive diminution. In stages 9 and 10, however, the primitive streak is replaced by the caudal eminence (measured from the neurenteric canal caudally). The notochordal plate reaches as far rostrally as the prechordal plate (stages 8–10), although this relationship changes in later stages. P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

Median plane? Figure 10–10. Schematic representation of some important Stage 5c tissues from stage 5c to stage 10. Epiblast Stage 5c. The bilaminar embryonic disc may possibly be Basement membrane beginning to show a longitudinal axis. Stages 6–10. Schematic representations of median sections Hypoblast showing the prechordal plate and the caudally adjacent structures. Stage 6b. Epiblastic cells invaginating through the primitive streak form the mesendoderm of the prechordal plate. Primitive streak Stages 7 and 8. A primitive node is present and the notochordal 6b process rostral to it is continuous with the prechordal plate. Stage 10. A sagittal block seen from the median plane. The now rotated prechordal plate is independent of the foregut endoderm. Primitive node The notochordal plate is inserted into the medial portion of the pharyngeal endoderm and reaches as far rostrally as the adenohypophysis, which, together with the prechordal plate, lies at the summit of the newly formed oropharyngeal membrane. From Muller ¨ and O’Rahilly (2003a, Cells Tissues Organs) by 7, 8 permission of S. Karger AG, Basel.

Not. process

Not. plate 10 Pros.

O. ph.

Epiblast Hypoblast; endoderm Primitive streak & node Prechordal plate Notochordal process/plate Adenohypophysis

TABLE 10–2. The Neural Crest and Related Tissues in the Embryonic Period

Stages Site of Origin Destination References

9, 10 (1) Neural ectoderm of open neural folds Mesencephalic neural crest to head Muller¨ and O’Rahilly (1983) of mesencephalon and Rh. A and B Mesenchyme for skull and face. Cranial Muller¨ and O’Rahilly (1985) (2) Neural tube Rh. C, D ganglia; succession: facial, trigeminal, vagal, occipital, glossopharyngeal 11 (3) Otic groove Vestibulocochlear ganglia Muller¨ and O’Rahilly (1986a,b) (4) Optic vesicle Bartelmez and Blount (1954) (3) Rhombomere 2 Mandibular arch 12 (1) Otic vesicle Vestibulocochlear ganglia O’Rahilly (1963) (2) Optic vesicle Pigment cells of uvea Bartelmez and Blount (1954) (3) Rhombomeres Proximal part of cranial ganglia Muller¨ and O’Rahilly (1987) Pharyngeal arches (3) Epipharyngeal discs Distal part of cranial ganglia 13–23? Nasal disc (1) Future glial cells for olfactory ﬁbers (1) Studies in mouse (2) Terminal-vomeronasal crest (2) O’Rahilly (1965); Muller¨ and O’Rahilly (2004b) (3) LHRH precursors (3) Verney et al. (2002); Zecevic and Verney (1995) (4) TH-IR neurons accompanying lateral (4) Verney et al. (1996) olfactory ﬁbers

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48 Chapter 10: THE NEURAL TUBE AND THE OPTIC PRIMORDIUM

10 Ð 12 11

Di.

Figure 10–11. The neural groove of rhombomere 2. Ventral to it, the folding notochordal plate is visible and, on each side, a dorsal aorta. Transverse anastomoses between the right and left dorsal aortae have been recorded at stage 11, and fusion has deﬁnitely begun at stages 13 and 14.

Ot.

Figure 10–12. The neural tube of rhombomere 5. Mitotic ﬁgures are visible near the cavity of the tube. The otic plates appear on each side as ectodermal thickenings. Extramural blood vessels are forming ventrally and laterally, adjacent to the wall of the brain, but they do not yet give off intramural branches. A histological distinction between the perineural arteries and veins becomes apparent by stage 20 and for the intramural vessels during trimester 2. P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

NEUROTERATOLOGY 49

TABLE 10–3. The Authors’ Interpretation of the Neural Crest and Related Tissues in the Human Embryo

Stage 8 Stage 10 Stage 12 Neural Neurosomatic ectoderm “Islands” in junction somatic ectoderm Stage 11

Epipharyngeal Retina Cranial neural crest discs Mesencephalic Optic crest Trigeminal 5 Stage 13 Otic Facial 7 crest Vestibular Nasal crest Glossophar- yngeal 9 Vomeronasal Vagal 10 crest Hypoglossal

Terminalis Spinal neural crest crest

Neuroteratology

Cyclopia (the term is based on a mythical race of Sicilian limbs (the origin of symmelia) has been noted (O’Rahilly giants) is characterized by a single median eye and orbit. and Muller, ¨ 1989b). The sine qua non is the presence of a single median (bony) Axial cells of the prechordal plate and the noto- orbit. The condition is accompanied by holoprosencephaly, chord express SHH in normal embryos and induce neural and the nose is usually represented by a proboscis placed development, including the subdivision of the single reti- above the median eye. The impression of a fusion of for- nal field into two separate domains. Experimental work merly paired optic primordia is no longer considered to re- with molecular markers indicates that disturbances can flect the origin of the condition. In cyclopia sensu stricto be produced during or even before stage 8 (Goodman, the ocular structures are single rather than paired. The 2003). prosencephalon fails to “diverticulate” into the right and Synophthalmia is a variety of cyclopia sensu lato in left optic evaginations. Such a disturbance could arise as which some or all of the ocular structures are paired within early as stages 6 to 8 if the single retinal field, which is a single globe. Although the prosencephalon “diverticu- normally converted to paired primordia, is not so trans- lates” into two optic primordia, these fail to lateralize. Such formed because of a lack of inhibition of the median part a disturbance could arise as early as stage 9, when the fu- by the prechordal plate. (Fig. 10–13A). The teratogenetic ture optic area is probably changing from a median to bi- termination-point is probably 3 weeks for cyclopia sensu lateral regions (see Fig. 10–13). For an unknown reason, stricto (a median eye in a single orbit) and 4 weeks for cy- several embryos of stage 16 showing this variety of cyclopia clopia sensu lato (paired ocular structures in a single orbit, have been available and have been described (Muller ¨ and Fig. 16–14). A parallel situation in the development of the O’Rahilly, 1989c). P1: JYS JWDD017-10 JWDD017-ORahilly June 13, 2006 10:33 Char Count= 0

50 Chapter 10: THE NEURAL TUBE AND THE OPTIC PRIMORDIUM

A Figure 10–13. Early development of the optic primordia and the floor plate. CYCLOPIA (A) Dorsal view of an embryonic disc at SINGLE stage 8 and a projection of the Prechordal RETINAL prechordal plate, which occupies about plate FIELD 15–20% of the width and 12% of the length of the embryonic disc. It is maintained that a single retinal field exists at the rostral end of the neural plate (future neuromere D1). Persistence of this single field would lead to cyclopia. (B) Subsequently SYNOPHTHALMIA (although probably still in stage 8), the prechordal plate is believed to be responsible for suppressing the median B TWO part, so that bilateral retinal fields are RETINAL formed. Lack of inhibition of the FIELDS median component would lead to synopthalmia. (C) The retinal fields are completely separated from each other, which is the normal arrangement. (D) Dorsal view of an embryo of stage 10 in which the retinal fields occupy neuromere D1. (E) Median view at C stage 10 showing neuromere D2, distinguishable from its relationship to NORMAL the neurophypophysial (NH) and adenohypophysial (AH) primordia. The notochordal plate extends as far rostrally as the caudal boundary of NH and it induces the floor plate in the overlying neural ectoderm. The prenotochordal part of the brain comprises neuromeres T, D1, and the rostral portion of D2.

D E D2 D1 M N-H

Ch. T

A-H Not. Prechordal plate Oropharyngeal membrane P1: JYS JWDD017-11 JWDD017-ORahilly April 17, 2006 12:54 Char Count= 0

CHAPTER11 STAGE 11: CLOSURE OF THE ROSTRAL NEUROPORE

Approximately 2.5–4.5 mm in Greatest Length; Approximately 30 Postfertilizational Days

he rostral, or cephalic, neuropore closes during Notochordal and neural axial structures are still closely stage 11. The closure, in which the neural ecto- related. Tderm also participates, is basically bidirectional; that is, it proceeds from the region of D2 (its “dorsal lip”) and simultaneously from the telencephalon (its “terminal lip”). Also Precision during this stage, the ﬂoor of the telencephalon medium The neuropores are rostral (or cranial) and caudal, not becomes distinct as the future lamina terminalis and com- anterior and posterior, which have specialized meanings missural plate. The optic vesicle is being formed from the in human anatomy. There is at present no embryological optic sulcus in Dl, and is providing optic crest. Both adeno- evidence in the human that a speciﬁc pattern of multiple hypophysial and neurohypophysial primordia can be dis- sites of closure of the neural tube exists, such as has been tinguished, and they are in contact from the beginning of described in the mouse. their development; the hypophysis arises as a single organ.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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52 Chapter 11: CLOSURE OF THE ROSTRAL NEUROPORE

12 10 9Ot. 8.7 5

Ch.

Opt.

Figure 11–2. Right lateral view of the brain of another embryo. The features shown are the optic vesicle, the trigeminal and facio- vestibulocochlear ganglia, the otic vesicle, the glossopharyngeal and vagal ganglia, and the hypoglossal cell cord, which will form the connective tissue of the tongue. Cells given off from the wall of the devel- Figure 11–1. Right lateral view of an embryo of stage 11 with the oping otic vesicle appear to be crest cells that form a ventral sheath; brain superimposed (interrupted line), and showing the rostral and these latter will contribute perhaps more to the otic capsule than caudal neuropores. The number of somitic pairs was 17; the range to the facio-vestibulocochlear ganglia. Trigeminal and otic arteries in number at this stage is 13–20. The umbilical vesicle and the body are present and later (stages 13–15) form parts of the caroticobasilar stalk have been sectioned at the right. anastomosis (Fig. 21–23). P1: JYS JWDD017-11 JWDD017-ORahilly April 17, 2006 12:54 Char Count= 0

CLOSURE OF THE ROSTRAL NEUROPORE 53

Figure 11–3. Graphic reconstruction prepared from transverse sections showing a median view of the brain. The asterisk indicates the junction with the spinal cord. The rostral, or cephalic, neuropore is indicated by a thick line between two arrowheads. Each of the two neuropores, rostral and caudal, measures about 0.5 mm in length (mean of 24 embryos). The rostral neuropore closes within a few hours during stage 11, when about 20 somitic pairs are present. (The embryo illustrated here has 17.) The thin surface ectoderm overlying the dorsal aspect of the neural tube has not been included in the drawing. D1 still consists mostly of optic primordium. The chiasmatic plate is first at the rostral end of the neural plate (13 pairs of somites), as in stage 10. When 14 or more somitic pairs have appeared, however, fusion at the “terminal” lip (Fig. 11–7A) of the neuropore results in the formation of a floor for the telencephalon medium. This represents the future lamina terminalis and commissural plate. In D2, the neural floor adjacent to the adenohypophysial primordium is the neurohypophysial region. Both components of the hypophysis cerebri develop in contact with each other, so that no migration or growth of one to meet the other occurs. The level of the adenohypophysial primordium is caudal to that of the chiasmatic plate, and its site is clearly defined by the oropharyngeal membrane, which has not yet ruptured (in 11 out of 16 embryos). The percentage of length occupied by the mesencephalon in relation to that of the whole brain remains almost constant from stage 9 up to and including stage 11. The rhombencephalon takes up approximately three-quarters of the brain in length. The relative increase in prosencephalic length is slightly less than in stage 10. Cranial ganglia and neural crest are projected onto the median view. Eight rhombomeres are distinguishable (Fig. 10–4B). The notochord or the notochordal plate is still closely related to the neural tube or the neural plate, so that it is possible that induction of the floor plate could continue along almost the whole length of the neural axis. P1: JYS JWDD017-11 JWDD017-ORahilly April 17, 2006 12:54 Char Count= 0

54 Chapter 11: CLOSURE OF THE ROSTRAL NEUROPORE

D1 D2 M

Rh. 1

Figure 11–4. Sagittal section through an embryo at stage 11 (17 somites) showing the rostral neuropore, through which the lumen of the neural tube still communicates with the amniotic cavity. (The thin line of the amnion is visible above.) Further caudally, the wall of the neural tube shows portions of several rhombomeres. Also recognizable are the oropharyngeal membrane and foregut, and the heart, which presents myocardial mantle, cardiac jelly (appearing here as an almost clear space), and endocardium. P1: JYS JWDD017-11 JWDD017-ORahilly April 17, 2006 12:54 Char Count= 0

CLOSURE OF THE ROSTRAL NEUROPORE 55

Figure 11–5. Drawings of the rostral end of the neural tube in seven embryos of stage 11, to show the progressive closure of the rostral neuropore. Under each is shown a horizontal section taken at the level indicated by the horizontal lines. The embryos shown had 13, 14, 16, 17, 17, 17, and 20 somitic pairs, respectively. Modiﬁed from Streeter, as reproduced by O’Rahilly and Muller ¨ (1987a). The rostral neuropore, which is still open when 19 pairs of somites are present, is closed when 20 pairs have formed (O’Rahilly and Gardner, 1979, Table 2). See also Figure 12–12. The rostral neuropore is not considered to be the “front” end (das wahre ursprungliche ¨ Ende) of the neural tube, which is frequently taken to be the infundibulum or the infundibular recess (Dart, 1924, in agreement with von Baer). There is much to be said, however, for Johnston’s (1909) view that “in all vertebrates the anterior end of the head is the point at which the brain plate meets the general ectoderm at the same time that it comes into contact with the anterior end of the entoderm. This point is marked in the adult by the optic chiasma.” Abbreviations: A-V, atrioventricular canal; C-T, conotruncus; LV, left ventricle; RA, right atrium; RV, right ventricle; SV, sinus venosus. P1: JYS JWDD017-11 JWDD017-ORahilly April 17, 2006 12:54 Char Count= 0

56 Chapter 11: CLOSURE OF THE ROSTRAL NEUROPORE

Figure 11–6. Drawings and photomicrographs to illustrate the closure of the rostral neuropore in an embryo of stage 11. Basically, the neuropore closes bidirectionally, i.e., from (site β) its “dorsal lip” (near D2) and simultaneously from (site α) its “terminal lip” (in the telencephalon, adjacent to the chiasmatic plate). The surface ectoderm participates in the closure at the terminal lip, and the area of fusion of the neural folds lies between the two nasal discs. The right and left components of the neural ectoderm (stippled) and those of the surface ectoderm (in blue) seem to fuse simultaneously across the median plane. The bar represents 0.02 mm. A key drawing showing the lips and the plane of sections A and H is provided in Figure 11–7 A. From O’Rahilly and M¨uller (1989a). The phenomenon of closure at the “terminal lip” is ignored in most publications on embryology. In the chick embryo, near the time of fusion of the neural folds, occlusion of the lumen of the neural tube occurs and has been considered to be necessary for the growth of the brain. In the human embryo, however, occlusion is infrequent during stage 11 and has been found only when the rostral neuropore is still open (Muller ¨ and O’Rahilly, 1986a), thereby precluding any hydrodynamic function. Moreover, growth of the brain is practically at a standstill during stages 11 and 12 (Muller ¨ and O’Rahilly, 1987, Table 3). The closure at the dorsal lip is much simpler. It concerns the fusion of both the unilaminar surface ectoderm and the unilaminar neuroectoderm, represented schematically in Figure 10-5E. P1: JYS JWDD017-11 JWDD017-ORahilly April 17, 2006 12:54 Char Count= 0

CLOSURE OF THE ROSTRAL NEUROPORE 57

Figure 11–7. Views of the rostral neuropore and the beginning optic vesicles at stage 11. (A) End-on and median views as a key to Figure 11–6. Tel. indicates the surface ectoderm overlying the telencephalon. In the median view, the thin surface ectoderm overlying the dorsal lip has not been included in the drawing. The two horizontal lines show the plane of sections A and H. (B) End-on and right lateral views as a key to the plane of section of the photomicrograph, C. (C) The A optic vesicles are being formed by further deepening of the optic sulci in D1. Optic crest is developing from the external layer of the optic vesicle and is met by migrating mesencephalic neural crest. The two form the sheath of the optic vesicle, i.e., of the future optic cup. The basement membrane is interrupted where the cells of the optic crest leave the neural ectoderm. Optic crest is formed by mitotic division in the superﬁcial cells of the optic vesicle, an exception to the general rule that mitosis in the neural tube B occurs adjacent to the ventricle. The rostral neuropore is visible at the bottom of the photomicrograph. Bar: 0.15 mm.

Mesencephalon

Neuropore C Optic sulcus P1: JYS JWDD017-11 JWDD017-ORahilly April 17, 2006 12:54 Char Count= 0

58 Chapter 11: CLOSURE OF THE ROSTRAL NEUROPORE

DE Figure 11–8. Development of the AB C notochord and the ﬂoor plate. (A) After the notochord has developed from the dorsal part of the notochordal process of stages 7 and 8, its cross-sectional shape changes. (B) It appears as the notochordal plate in stage 9 (Fig. 9–5B). (C, D) It has the form of an inverted U in stages 10 and 11 (Figs. 10–11 and 11–9). (E) Next it appears as a rod in stage 12 (Fig. 10B).

Notochord Figure 11–10. Secondary development of the body. The caudal part Figure 11–9. The notochord in this embryo of stage 11 with 16 of the notochord, caudal to the site of the former neurenteric canal, pairs of somites still has the form of an inverted U at the level of which is formed from the caudal eminence, in an embryo with 17 rhombomere 5. Bar: 0.05 mm. pairs of somites. The neural groove above is still open. Bar: 0.04 mm. P1: JYS JWDD017-11 JWDD017-ORahilly April 17, 2006 12:54 Char Count= 0

CLOSURE OF THE ROSTRAL NEUROPORE 59

A Figure 11–11. The early blood vessels. The movement of the blood would be merely ebb and Aorta Otic disc ﬂow. The still open brain would not yet be dependent on a blood supply. (A) At stage 9 (2, 3 somites). (B) At stage 10 (10 somites). (C) At stage 11 (14 somites). Aorta

Heart

B Capital v. Omphalo- mesenteric v.

Aorta Umbilical v.

RV LV Internal Umbilical carotid a. plexus

Cardinal vv.

2 1

Cono- truncus L. & R. ventricles P1: JYS JWDD017-11 JWDD017-ORahilly April 17, 2006 12:54 Char Count= 0

60 Chapter 11: CLOSURE OF THE ROSTRAL NEUROPORE

NEUROTERATOLOGY: of the rat). It has been speculated (by Hoving, 1993) that ENCEPHALO(MENINGO)CELE insufficient cell death (apoptosis) at the terminal lip of the rostral neuropore (e.g., from retinoic acid deficiency) Encephalocele and encephalomeningocele may arise, at might result (immediately after fusion of the neural folds) least in some instances, from a failure in separation of in persistent attachment of the surface ectoderm to the the brain from the surface ectoderm in later stages. This neural ectoderm, producing a subsequent cranial defect failure in separation would be caused by a disturbance of and a fronto-ethmoidal encephalocele. the mesencephalic neural crest, which is at the height of An interesting example of a telencephalic diverticulum its formation at stage 10. This mesenchyme is believed to in a 35 mm fetus has been recorded (Bossy, 1966). It was be the main source for the development of the face, and situated in the region of the former situs neuroporicus insufficient production of it may lead to a narrow facies, as and was considered to represent cerebral dysraphia with seen in the fetal alcohol syndrome. secondary encephalocele. Encephaloceles are, in the Western Hemisphere, most Nasal Glioma. Insufficient cell death in the region of frequently found in the occipital region. They may perhaps the rostral neuropore causes a persistent “surplus of un- be caused by a lack of the basal mesenchyme originally intended surviving cells” that “might be represented by between the neural tube and the notochord; its quantity is heterotopias like nasal gliomas” (Hoving, 1993). accumulating rapidly. Fronto-ethmoidal encephaloceles may be at or near the situs neuroporicus (as proposed by Hoving from studies P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

CHAPTER12 STAGE 12: CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION

Approximately 3–5 mm in Greatest Length; Approximately 31 Postfertilizational Days

relationships to the cranial ganglia: Rh.5 is associated with he rostral neuropore is closed, although the si- the otic vesicle, and Rh.D is level with the four occipital tus neuroporicus can frequently be detected and somites. The first nerve fibers are differentiating, partic- Tis probably at the future commissural plate in the mid- ularly those of the future lateral and ventral longitudinal dle of the embryonic lamina terminalis. The closure (dur- fasciculi. The hypoglossal nucleus has appeared and four ing stage 11) allows the formation of the telencephalon to five intramural hypoglossal roots are present. The cau- medium to occur. The mesencephalon consists of two dal neuropore closes during stage 12, and its final prenatal neuromeres (M1 and M2), and the mesencephalic flex- site is at the level of somitic pair 31 (future vertebral level ure is a right angle. The rhombomeres have important S2).

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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62 Chapter 12: CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION

Figure 12–1. Right lateral view of an embryo of stage 12 with the brain superimposed. The number of somitic pairs was 28; the range in number at this stage is 21–29.

Di.

Figure 12–2. Right lateral view of the brain. The features shown are the optic vesicle, the trigeminal and facio-vestibulocochlear ganglia, the otic vesicle, and the glossopharyngeal and vagal-accessory ganglia. The brain now occupies about 40% of the length of the neural tube. Expansion of the brain stretches the surface ectoderm (O’Rahilly and Muller, ¨ 1985) so that entrance of mesenchymal cells may be hindered. The prechordal mesenchyme is caudal to the optic vesicles, where the orbital muscles will develop. The optic neural crest (Fig. 12–5) is now at the height of its development. The neural crest contributes to the trigeminal and facio-vestibulocochlear ganglia. Crest cells from the region of ganglia 9–11 migrate, by way of pharyngeal arch 3, towards the aortic sac. Moreover, the surface (epipharyngeal) ectoderm gives rise to cells that may contribute to the facial, inferior glossopharyngeal, and vagal ganglia. The hypoglossal cell cord is forming from the occipital somites and, in the more advanced embryos of this stage, it begins to enter pharyngeal arch 4. P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION 63

Figure 12–3. Reconstruction of the brain. The asterisk indicates the junction with the spinal cord. The rostral neuropore has closed. The site of final closure (the situs neuroporicus) is probably at the future commissural plate in the middle of the embryonic lamina terminalis. The initial formation of the telencephalon medium normally depends on the closure of the rostral neuropore during stage 11. The prosencephalon now consists of three parts: the telencephalon, D1, and D2. The telencephalon medium, which is rostral to the well-defined neuromere D1, is recognizable externally by its situation between the nasal discs (Fig. 12–7). D1 is still characterized mainly by the optic vesicles. The semilunar opening of the optic ventricle into the third ventricle is indicated by shading. D2 is related to the adenohypophysial primordium and now shows the first sign of the mamillary recess. The mesencephalon consists of two neuromeres: M1 and M2. The mesencephalic flexure is a right angle between the forebrain and the hindbrain. The sulcus limitans is seen to traverse the midbrain. The various rhombomeres have distinctive features. For example, the floor is expanded at the level of Rh.2, 4, and 6. Rh.5 is related to the otic vesicle, and the ganglia of the future cranial nerves (which are projected onto the median view) are important relationships of Rh.2, 4, 6, and 7. Rh.D is at the level of somites 1–4. The first nerve fibers are now differentiating. Apart from short fibers in ganglia 5 and 7/8, the fibers are mostly related to cells that will form the nucleus of the lateral longitudinal fasciculus. Moreover, fibers of the future ventral longitudinal fasciculus are discernible in Rh.7. Four intramural hypoglossal roots are present, i.e., the hypoglossal nucleus has developed and some hypoglossal neural crest is still present dorsally. The relative length of the rhombencephalon has been decreasing since stage 9.

Figure 12–4. An almost median section of the brain showing rhombomeres 2–7 and two occipital somites. P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

64 Chapter 12: CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION

Optic crest

Opt. D1 Chiasmatic plate

Oropharyngeal epithelium

Figure 12–5. Optic vesicles and D1 in a horizontal section. A mesenchymal sheath separates the optic vesicles from the surface ectoderm. Optic neural crest is evident and gives the optic vesicle the appearance of a “frightened hedgehog” (Bartelmez) externally (Fig. 12–2). Little or no mesenchyme is present between the dorsal part of D1 and the surface ectoderm.

Fig. 12 Ð 5

M 5

7,8v

Fig. 12 Ð 6

Ot.

Figure 12–6. Rhombencephalon. Several cranial ganglia and the otic pits are visible. The surface ectoderm covering the ventral part of pharyngeal arch 1 (arches 2 and 3 are also visible here) is thicker and gives off cells that join the trigeminal ganglion. The ectoderm is a part of the ectodermal ring (O’Rahilly and M¨uller, 1985). P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION 65

Situs neuroporicus Tel. medium Nasal disc Figure 12–7. Optic vesicles and D1 in a horizontal section of another embryo. Optic neural crest is evident. At this time the Optic diencephalon consists of two neuromeres: D1, related to the crest optic vesicle, and D2, related to the adenohypophysis. The site of the closed rostral neuropore is conspicuous. The nasal disc becomes bilaminar and becomes shifted laterally. Bar: 0.1 mm. Sternberg (1927), who placed the rostral neuropore in the region of, and probably dorsal to, the commissural plate, ventured to identify the situs neuroporicus even up to the end of the embryonic period, at which time he showed it between the eyes and at the root of the nose. D1

5 Rh. Fig. 12 Ð 8 2 Fig. 12 Ð 7 7,8v

Rh. 5

Figure 12–8. Rhombencephalon of still another 10,11 embryo. Several cranial ganglia and the otic vesicles are visible. The uppermost part of the photomicrograph depicts the mesencephalon and Occipital is followed by rhombomeres, which are clearly somite delimited by evaginations. The trigeminal ganglion is related to Rh.2, the facial to Rh.4, the glossopharyngeal to Rh.6, and the vagal and accessory to Rh.7. The part of the brain that is related to the four occipital somites is Rh.D. Bars: 0.1 mm. P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

66 Chapter 12: CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION

Figure 12–9. The optic vesicles and the optic crest. (A) Transverse section of another embryo showing the optic vesicles on both sides of the diencephalon. In the lower half the first pharyngeal arch and part of the heart are visible. The levels of the sections are indicated in the inset. (B) In an embryo of stage 11, when the rostral neuropore is still open (arrow), as shown also in Figure 11–7C. The neuropore is covered by amnion, and the ependymal fluid within the future ventricular system is continuous with the amniotic fluid. Mesenchyme is not yet visible between the optic vesicle and the surface ectoderm. Some cells of the optic crest are emerging caudally, but are seen better in B. The vesicle is limited by the caudal limiting sulcus (O’Rahilly, 1966), beyond which blood vessels can be seen. (C) In an embryo of stage 12, when the rostral neuropore has already closed. The striking feature of the optic vesicle here is the emergence from its wall of cells of the optic crest. P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION 67

Di.

B, C Neuropore

Figure 12–9. (Continued ) P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

68 Chapter 12: CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION

Figure 12–10. Development of the ganglia of cranial nerves. Neural crest gives rise to the main, proximal portions of the ganglia of nerves 5, 7, 9, and 10, whereas epipharyngeal discs (incorporated in the ectodermal ring) contribute to the distal portions. Shown here are examples from an embryo of 22/23 pairs of somites. (A) Transverse section showing the otocyst and the facial ganglion, both of which are very close to the wall of the rhombencephalon. (B) Transverse section through rhombomere 7 and the pharynx, showing the superior vagal ganglion (10s), which arises from neural crest, and the inferior ganglion (10i), which is arising from the epipharyngeal disc (asterisk) of pharyngeal arch 3. Bar: 0.15 mm. (C) A more rostral section, through a part of the otic vesicle (Ot.), showing the geniculate (or facial) ganglion, which arises from both neural crest and the epipharyngeal disc (asterisk) of pharyngeal arch 2. Bar: 0.2 mm. Abbreviations: Ao., dorsal aorta; 5, 7/8, 9/10, cranial ganglia; 10s, superior vagal ganglion. P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION 69

C B 10s 10i 9, 10

7, 8 Ot.

5 Not.

Aortic arch 2 Aortic Ao. sac

2 1

Ot.

Figure 12–10. (Continued ) P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

70 Chapter 12: CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION

Figure 12–11. The early blood vessels of the head. (A) The vascular system at stage 12 in an embryo with 28 paired somites. The surface of the brain and the cranial ganglia have a good blood supply. Three aortic arches (the second is marked 2) are present. The capital plexuses (a, b, c) and the capital vein are now well-developed, and the cardinal venous system is established: precardinal, postcardinal, and common cardinal. Bar: 0.15 mm. Based on Streeter in O’Rahilly and Muller ¨ (1987a) and on Padget (1957). Abbreviations: a, b, c, rostral, middle, and caudal capital venous plexuses; Ao., dorsal aorta; Ot., otic vesicle; 5, trigeminal ganglion. (B) The blood ﬂow indicated by arrows. Oxygenated blood from the placenta reaches the body by way of the umbilical vein. The rectangle at the left shows the order of the various chambers and their abbreviations: sinus venosus, right atrium, left atrium, left ventricle, right ventricle, conus cordis, and truncus arteriosus.

Common cardinal vein LA

TA CC RV LV SV LA RV RA SV Omphalo- mesenteric plexus PLACENTA Umbilical vein Aorta

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→

Figure 12–12. The closure of the neuropores in the human, based on data from 19 embryos. The future neuropores are recognizable as soon as fusion of the neural folds begins, when approximately five to seven pairs of somites are visible (Heuser and Corner, 1957). In the rostral region the dorsal lip formed by the roof progresses rapidly and has a much longer track than the terminal lip, formed by the floor. This can be seen from the steep rise of the line representing the roof. The line of the floor, by contrast, remains horizontal during stage 10 and then rises during stage 11, indicating the bidirectional closure of the rostral neuropore. Although closure seemingly may occur in several places independently at stage 10 at least in some instances, no regular pattern of multiple sites, such as has been described in the mouse, has yet been shown in the human embryo (O’Rahilly and Muller, ¨ 2002). Two instances of dysraphia (open circles) are included for comparison. In the first example an embryo of 14 somitic pairs showed complete failure of fusion of the neural folds (Dekaban, 1963), although the terminal lip had progressed normally. In the second case, believed to be future anencephaly (Muller ¨ and O’Rahilly, 1984), an embryo of stage 13 showed a well-developed terminal lip but a marked deficiency in the progression of the dorsal lip (Fig. 13–9). Both these examples show that development of one lip can proceed more or less independently of the other. The triangles represent the situs neuroporicus; the asterisk, the cerebrospinal junction. The caudal region differs considerably from the rostral. Both the floor and the roof become increasingly elongated as further pairs of somites (the stepwise line) become visible. They remain approximately parallel, however. The neuropore, which remains small throughout, becomes displaced more and more caudally until it disappears at a level corresponding approximately to future sacral vertebra 2. This is taken to be the level of the junction between primary and secondary neurulation. Fetal ascensus of the spinal cord would be expected to result in a higher level postnatally. P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

Dorsal lip

Terminal lip

V e r t e b r a e Neuropore closed Secondary neurulation

Figure 12–12. (Continued ) Once the caudal neuropore is closed, the whole caudal area of the embryo is covered by surface ectoderm. The continuing formation of the spinal part of the neural tube takes place without involvement of ectoderm and is termed secondary neurulation. The caudal part of the tube is present ﬁrst as a concentration of tissue in the caudal eminence. Secondary neurulation is the continuing formation of the sacrocaudal part of the spinal cord without direct involvement of the surface ectoderm, i.e., without the intermediate phase of a neural plate. It begins once the caudal neuropore has closed during stage 12. The caudal eminence is a mass of pluripotent mesenchymal tissue covered by ectoderm. It is recognizable already at stages 9 and 10, and gradually replaces the primitive streak. It provides structures that are comparable to those formed more rostrally by the three germ layers. The derivatives include the caudal portion of the digestive tube, blood vessels, notochord, somites, and spinal cord. At stage 12 the caudal eminence gives rise to a compact cellular mass known as the neural cord, which forms the nervous system in the sacrocaudal part of the body. The cavity (central canal) of the spinal cord, present already more rostrally, extends into the neural cord. The caudal eminence gives rise to at least somitic pair 32 (corresponding to future sacral centra 3 and 4) and those following. The mesenchyme for somitic pairs 30–34 is the material for sacral vertebrae 1–5. Secondary neurulation is important in regard to timing and localization of spina biﬁda aperta.

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72 Chapter 12: CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION

Cloacal Hindgut memb. Axial mesenchyme

H Neural cord

Hindgut

Notochord

Spinal cord

Cloacal membrane

Caudal eminence

Somitic plate H

Somite

Figure 12–13. Secondary neurulation. (A) A reconstruction of the caudal end of an embryo of stage 12 with 29 pairs of somites. The site of the now closed caudal neuropore is indicated by an arrow. Somite 25 is shown as a dotted oval outline, and the position of the more caudal somites, including future No. 30, is shown. The closure of the neuropore is opposite future somite 31. The cross sections, from an embryo with 24 pairs of somites, show some of the structures derived from the mesenchyme of the caudal eminence, e.g., the neural cord, spinal cord, and notochord of the caudal region. (B) An embryo of stage 13 with 33 pairs of somites. The somites have not been included. The cross section, from another embryo also with 33 pairs of somites, shows the somitic plates that unite ventral to the hindgut. P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION 73

Closure of caudal neuropore Weeks 23 4 5 6 Stage 3 8 10 12 17 Primary Development S1 Ð 29 Pry neurulation Secondary development Caudal S29 Ð 38 part of notochord Secondary neurulation

Figure 12–14. Primary and secondary developmental modes in the caudal region related to stages. From Muller ¨ and O’Rahilly (2004a, Cells Tissues Organs) by permission of S. Karger AG, Basel.

Neural tube Central Caudal canal neuropore Endoderm

Notochord

Mesenchyme Caudal eminence Hindgut PRIMARYIntestine SECONDARY NEURULATION Figure 12–15. Primary and secondary neurulation. Median sections showing the left half of the caudal end of the body. (A) At stage 10. (B) At stages 12, 13. Beyond the caudal neuropore, Neural cord the caudal eminence gives rise to the neural cord (blue), into which the canal penetrates (arrow). Based on reconstructions by the authors. P1: JYS JWDD017-12 JWDD017-ORahilly June 13, 2006 13:14 Char Count= 0

74 Chapter 12: CLOSURE OF THE CAUDAL NEUROPORE AND THE BEGINNING OF SECONDARY NEURULATION

SOMITES CENTRA

L 1 Occ. 4

T12 S 1 L5

S5 34 Co. 1

38 Co. 6 Median sacral a. Notochord Paramesonephric ducts Coelom 10 44

Figure 12–17. Scheme to show that the somites (green) are out-of- phase in relationship to the vertebral centra (mauve). The distribution of the ﬁrst 34 somites is indicated at the left. The maximum num- Rectum ber of somites is now believed to be 38 or 39 (Muller ¨ and O’Rahilly, 1994; O’Rahilly and Muller, ¨ 2003), but was formerly thought to be greater (shaded area).

Neural Genital tube tubercle Urogenital sinus

Figure 12–16. Median section of spinal cord and vertebral column at stage 21. The neural tube and the vertebral column are coextensive during the embryonic period.

NEUROTERATOLOGY

Agenesis of the hypoglossal nerve would be expected from attributed to an exaggeration of the normal process of cau- an isolated absence of the hypoglossal nucleus at stage 12. dal regression that occurs later in the embryonic period. Although the lingual musculature would not be affected Complete lack of the caudal eminence would result in cloa- primarily, lack of innervation would lead to atrophy and fas- cal deﬁciency and consequently an incomplete separation ciculation. The hypoglossal cell cord, which becomes rec- of the two lower limb buds, i.e., symmelia (O’Rahilly and ognizable at stage 12, gives rise to the muscles of the tongue M¨uller, 1989b). and possibly to some of those of the larynx, although their Caudal Aplasia. The caudal tip of the trunk appears connective tissue is believed to come from the neural crest. particularly tapered at 5 weeks because it contains merely Albinism is related to a defect in the production of neu- neural tube, but it is in no sense a future vertebrated “tail.” ral crest, including probably the optic neural crest, which Neuroschisis. The claim that “neural clefts (neu- latter is noticeable at stage 12. roschisis)” existed in 100 of more than 200 Carnegie em- Sacral agenesis may result from a localized defect bryos from stage 10 to stage 23 (Padget, 1970) has not been within the caudal eminence, although it has also been substantiated (O’Rahilly and Muller, ¨ 1988). P1: JYS JWDD017-13 JWDD017-ORahilly April 17, 2006 12:56 Char Count= 0

CHAPTER13 STAGE 13: THE CLOSED NEURAL TUBE AND THE FIRST APPEARANCE OF THE CEREBELLUM

Approximately 4–6 mm in Greatest Length; Approximately 32 Postfertilizational Days

Precision

ormally, at 4 to 5 postfertilizational weeks, A double m is not used in mamillary because the term in embryos of some 5 mm in length, both is derived from the Latin mamilla, which in turn is a Nneuropores are closed, so that the future ventricular sys- diminutive of mamma, which does have a double m. tem no longer communicates with the amniotic cavity. The choroid plexuses will not appear for another fortnight, so that the liquid in the neural tube is “ependymal fluid.” First Appearance of the The terminal-vomeronasal crest is arising from the nasal Cerebellum discs, the retinal and lens discs are beginning to develop, r and the adenohypophysial pouch is distinct. Three dien- Stage 13. The cerebellum commences as a thick- cephalic neuromeres are present: D1, parencephalon, and ening in the alar plate of rhombomere 1. synencephalon. The isthmus rhombencephali is visible as r Stage 14. It extends into the alar portion of the a neuromere between M2 and Rh. 1. A marginal layer isthmus. is distinguishable in the wall of the mesencephalon and r rhombencephalon. The primordia of various somatic and Stage 17. The rhombic lip begins to participate. visceral efferent nuclei, the common afferent tract, and the ganglia of most of the cranial nerves can be discerned. The first indication of the cerebellum appears in Rh.1 during Precision stage 13. Median plane is the correct term, not midsagittal nor midline. The term parasagittal is superfluous because all planes parallel to the median are simply sagittal.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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76 Chapter 13: THE CLOSED NEURAL TUBE AND THE FIRST APPEARANCE OF THE CEREBELLUM

Di.

Figure 13–1. Right lateral view of the brain. The number of somitic pairs in this extensively studied embryo is now known to have been 32. The mesencephalon is well-delimited. The cerebellum is at the alar plate of Rh.1. The roof of the fourth ventricle is translucent. The otic vesicle is closed. The wall of the optic vesicle related to the surface ectoderm becomes ﬂattened and constitutes the retinal disc, and the lens disc becomes distinguishable concomitantly. The arteries to the head at stage 13 were reconstructed by Padget (1948, Fig. 1), who included the internal carotid and the caroticobasilar anastomoses.

1 1 TABLE 13–1. Mean Measurements (in mm) in 93 Embryos of Stages 6a–13 (ca 2/2–4/2 Weeks) Stage 6a 6b 7 8a 8b 9 10 11 12 13

Greatest embryonic length 0.23 0.31 0.59 0.90 1.30 1.44 2.1 3.2 3.86 4.88 Greatest embryonic width 0.44 0.68 0.81 0.68 Prechordal plate 0.87 1.35 1.4 0.09 0.11 Length of primitive streak 0.08 0.23 0.28 0.43 0.27 Length of caudal eminence 0.57 0.31 0.34 0.67 Length of neural groove/tube 0.31 0.97 1.63 3.1 6 8.5 Length of neural cord 0.15 0.6 n 181313745131235 P1: JYS JWDD017-13 JWDD017-ORahilly April 17, 2006 12:56 Char Count= 0

THE CLOSED NEURAL TUBE AND THE FIRST APPEARANCE OF THE CEREBELLUM 77

Telencephalon medium

Figure 13–2. Graphic reconstruction from transverse sections to show a median view of the brain. The asterisk indicates the junction with the spinal cord. Both neuropores are now closed, so that, at approximately 4 to 5 postfertilizational weeks, the cavity of the neural tube is a closed (future ventricular) system, normally no longer in communication with the amniotic cavity. The contained “ependymal fluid” is presumably formed by the lining cells and later, when the choroid plexuses have appeared, will become the cerebrospinal fluid. Once the neural tube has closed, its walls become subject to the pressure of the contained fluid, provided fluid formation is greater than absorption. The telencephalon is of approximately the same length as D2. The commissural plate is the median area at the level of the nasal plates. The terminal-vomeronasal crest is appearing (O’Rahilly, 1965). Cells leave the still convex or flat nasal plates and form cellular buds, which will participate in forming the ganglia of the nervus terminalis and the vomeronasal nerve, as well as in the development of the olfactory nerve. The roof of D2 bulges slightly at the site of the future synencephalon. The adenohypophysial pouch and the mamillary region are now distinct. At the transition between D2 and M1, the interstitial nucleus is forming ventrally, and its fibers constitute the uncrossed part of the medial longitudinal fasciculus. The oculomotor and trochlear nuclei are present, the former in M2, the latter in the isthmus. The isthmus rhombencephali, so named by His, lies between M2 and Rh.1, and is clearly separated from the latter. This is a newly formed neuromere. The rhombencephalon is considerably enlarged dorsoventrally in comparison with stage 12, and the floor of the fourth ventricle is bent in the region of Rh.2. Although the wall of the brain remains histologically simple for the most part, being formed by the pseudostratified epithelium of the ventricular layer, a marginal layer has developed in the mesencephalon and rhombencephalon (Figs. 13–6 and 13–7). The primordia of the somatic and visceral efferent nuclei of cranial nerves 5, 6, 7, 9–11, and 12 (Fig. 13–6) are present. The common afferent tract is being formed by descending fibers of nerves 5, 7, 9, and 10. Rhombomeres 2 to 7 are characterized by internal grooves. The first indication of the cerebellum (marked Cbl) can be found in the alar lamina of Rh.1 in most embryos of stage 13. Loosely arranged cells begin to constitute its intermediate layer. P1: JYS JWDD017-13 JWDD017-ORahilly April 17, 2006 12:56 Char Count= 0

78 Chapter 13: THE CLOSED NEURAL TUBE AND THE FIRST APPEARANCE OF THE CEREBELLUM

TABLE 13–2. Embryonic Development of the Cerebellum

Events Figures

Cerebellum appears as a slight thickening in alar plate of Rh. 1. The roof of the fourth ventricle is attached at the caudal tip of Rh. 1 13–1 The alar plate of Rh. 1 is up to 3 times longer in rostrocaudal direction than the basal plate of Rh. 1. The cerebellar primordium is the widest part of the brain. 14–2 The roof of the fourth ventricle is now attached at the caudal tip of the isthmus. The alar plate of the isthmus becomes part of the cerebellar primordium. Its roof represents the 15–3 future superior medullary velum. The width of the cerebellum is approximately the same as that of the two cerebral hemispheres 16–2 together up to ca stage 21. The posterolateral fissure defines the future flocculus, which is the earliest part of the future vermis. 17–3 Extra- and intraventricular cerebellum can be distinguished. 17–4 The rhombic lip of Rh. 1 shows strong mitotic activity. The inferior cerebellar peduncle begins to form from vestibulo- and trigeminocerebellar fibers. 17–10 The dentate nucleus can be distinguished. 18–2 Dentatorubral fibers are present and initiate the superior cerebellar peduncle. 18–16 The external germinal layer begins. 23–19 Tegmental decussation of the superior cerebellar peduncles. 23–3

4th Isthmus ventricle

M2 Rh.2

M2 Primary meninx

Syn. AH Notochord

Tongue Ao.

Heart

Figure 13–3. Median section of the brain at stage 13. The notochord still extends as far rostrally as the caudal wall of the adenohypophysial pouch. The isthmus rhombencephali is evident. The rhombencephalon, the mesencephalon, and part of D2 (Syn.) are epinotochordal in position and possess a ﬂoor plate. The rostral parts of D2 and D1 are prenotochordal. P1: JYS JWDD017-13 JWDD017-ORahilly April 17, 2006 12:56 Char Count= 0

Figure 13–4. The development of the eye A B 1 from 4 /2 to 6 weeks. (A) Stage 13. Early indentation of the retinal and lens discs. (B) Stage 14. The optic cup and lens pit are evident. (C) Stage 15. The lens pit has become closed off from the surface, forming the lens vesicle. (D) Stage 17. Retinal pigment can be seen in the external layer of the optic cup. The inverted layer of the cup will develop in a manner comparable to that of the wall of the brain (Fig. 14–8). The cavity of the lens vesicle is beginning to become obliterated. Hyaloid blood vessels are visible behind the lens. Early development of the retina. (E) At stage 14, showing layer 1 (the future pigmented layer), layer 3 (the terminal bars of the external limiting membrane), and the thick inverted layer. (F) At stage 15, showing the onset of pigmentation (minute black dots) in layer 1 (as well as two mitotic ﬁgures). Only the most external portion of the inverted layer is included in the ﬁeld selected. C D Further development can be seen in Figure 23–13. The inverted layer develops in a manner comparable to that of the wall of the brain, as shown in Figure 14–8.

Uveocapillaris E

Inverted layer of optic cup

Lens disc

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Figure 13–5. Silver-impregnated section showing ganglion 7/8v containing two long afferent ﬁbers.

Rh.4

Figure 13–6. The bilateral hypoglossal nuclei are formed by unipolar neurons that at this stage are situated peripherally, being more laterally placed than the visceral efferent nuclei of nerves 5,7, and 9–11. The extent of the hypoglossal nucleus on the left is indicated by arrowheads.

Figs 13 Ð 6, 7

13 Ð 5

Figure 13–7. A hypoglossal root from the neural tube (at left) to somite 3 (at right). The nerve ﬁbers are accompanied by neural crest cells. The hypoglossal roots are not rigidly segmental, some somites receiving two roots. The cells of the primordial hypoglossal nucleus are relatively lateral in position, but that changes during development, as described with Figure 14–9. The hypoglossal artery participates in the carotico-basilar S.3 anastomosis, which is prominent until stage 15 (Fig. 21–22).

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THE CLOSED NEURAL TUBE AND THE FIRST APPEARANCE OF THE CEREBELLUM 81

2 M2 4 6

A-H Syn.

C D2

v d

D Nas.

Figure 13–8. The neuromeres at stage 13, as shown in a graphic reconstruction. D2 now consists of the synencephalon caudally and the parencephalon rostrally, and the isthmus rhombencephali constitutes a distinct neuromere. (A) Sagittal section near the median plane to show the rhombomeres (Rh. 2, 4, and 6 having ventral evaginations that are numbered). The mamillary region is distinguishable, and the notochord can be seen to end close to the incipient adenohypophysial pouch. (B)–(D) The dorsal and ventral eminences that represent the future dorsal and ventral thalami (d and v). The more caudal portions of the sections include the spinal cord (with the sulcus limitans), the dorsal aortae, as well as the truncus arteriosus and pharyngeal arches 1 and 2 (in B), the pharynx (in B and C), and the atria (in C). The bar for A–D represents 0.5 mm. P1: JYS JWDD017-13 JWDD017-ORahilly April 17, 2006 12:56 Char Count= 0

82 Chapter 13: THE CLOSED NEURAL TUBE AND THE FIRST APPEARANCE OF THE CEREBELLUM

NEUROTERATOLOGY: except in such conditions as anencephaly and spina bifida CEREBRAL DYSRAPHIA cystica. (ANENCEPHALY) Phases 2 and 3 of anencephaly are discussed in Chap- ters 22 and 24 respectively. The most frequent neural tube defects (NTD) are anencephaly and myelomeningocele, which are multifactorial, and the genetic and environmental influences have been MISCELLANEOUS reviewed (Detrait et al., 2005). ANOMALIES Cerebral Dysraphia. Anencephaly develops in three phases. The first, cerebral dysraphia (encephaloschisis), is Cebocephaly. Indications of this condition have been found believed to arise as a failure of closure of the neural groove in an embryo attributed to stage 13 (Fig. 13–10). A graphic rostrally, an idea supported by many authors. Rupture of reconstruction was prepared, from which it could be seen the already closed neural tube cannot be entirely excluded that the notochord did not reach the adenohypophysis, as in some instances. Cerebral dysraphia arises early, proba- normally it would. A convergence of the nasal discs indi- bly as a mesenchymal defect, even as early as stages 8 or 9, cated a narrow median region of the head. The nasal sep- i.e., before fusion of the neural folds begins, because ele- tum would not develop, and the single nasal cavity would vation of the folds depends on the production of sufficient possess a single nostril. Cebocephaly arises earlier than mesenchyme. arhinencephaly, in which the brain is almost normal ex- Fusion of the neural folds commences during stage 10, cept for absence of the olfactory bulbs. It has been found when production of neural crest is only starting. The gan- experimentally in the mouse that in cebocephaly little or glia of the cranial nerves, derived largely from neural crest, no tissue from the medial nasal processes is involved in the are only minimally affected in anencephaly. A reduction in development of the nose, lips, and palate. The single nostril the size of the ganglia, however, as well as an incomplete in cebocephaly ends blindly, and the eyes are closely set. chondrocranium, would point to defective distribution of The brain is holoprosencephalic in type and the forebrain the cephalic mesenchyme, caused probably by a derange- septum is absent or reduced. The corpora striata are not ment of the mesencephalic neural crest in stages 10 and 11. separated from each other. Moreover, stage 10 is characterized by the first appearance Arhinencephaly. This term sensu stricto refers to of the optic primordium, and, rarely, anencephaly may be absence of the olfactory bulbs and tracts, irrespective combined with anophthalmia. Usually, however, the eyes of associations with other developmental malformations, are very well developed in anencephaly, indicating that such as holoprosencephaly, which is commonly combined development of the diencephalon at first proceeds nor- with arhinencephaly. Isolated arhinencephaly would be ex- mally, although later it degenerates. pected to arise at the time when the nasal discs should begin It would be extremely difficult to detect a pure cerebral to form: thickenings normally appear at stage 11, and a dysraphia at stage 11, because it is only during that stage nasal field is outlined at stage 12 (Bossy, 1980). This timing, that the rostral neuropore normally closes. Nevertheless, however, depends on the unproven assumption that the an example of complete cerebrospinal dysraphia at stage 11, olfactory bulb is induced by the olfactory nerve. Holopros- presumably the forerunner of craniorhachischisis totalis, encephaly and arhinencephaly may develop independently has been described in detail (Dekaban, 1963; Dekaban and of synophthalmia, probably at about stage 11, or perhaps Bartelmez, 1964). even 10. Although they are commonly linked, holoprosen- Cerebral dysraphia has been described in detail in a cephaly and arhinencephaly can also arise independently twin embryo of stage 13, and reconstructions are avail- of each other. Siebert et al. (1990) studied 103 cases of able (Muller ¨ and O’Rahilly, 1984). The neural tube was this condition and found that arhinencephaly is extremely open over part of the midbrain and forebrain, although heterogeneous both clinically and pathologically. the situs neuroporicus (at the locus of the future com- Cerebellar agenesis, although rarely total, could arise missural plate) was closed. Hence, in future anencephaly, as early as stage 13, or even in stage 12. The first part of fusion at the “terminal lip” of the rostral neuropore to form the cerebellum to develop is material for the hemispheres, the embryonic lamina terminalis (Figs. 11–7A and 13–9) whereas the primordium of the vermis becomes defined may not be affected. It is possible that a causal relation- only at stages 18 and 19. ship exists between neural tube defects and monozygotic Abducent-facial palsy (Mobius¨ sequence) presents as twinning. a nonspecific, commonly bilateral, mask-like facies. The Communication between the amniotic fluid and the nuclei of cranial nerves 6 and 7 are usually degener- ependymal (future cerebrospinal) fluid is normally elimi- ated, but they may be absent. Most of the motor nuclei nated by stage 13 because of neuroporal closure, so that of the cranial nerves begin to develop at about stage 13. α-fetoprotein no longer diffuses into the amniotic cavity, Other cranial nerves may be involved in the sequence, P1: JYS JWDD017-13 JWDD017-ORahilly April 17, 2006 12:56 Char Count= 0

MISCELLANEOUS ANOMALIES 83

A Figure 13–9. Comparison of normal and deﬁcient Somites 13 closure. (A) The normal sequence of closure of the rostral 14 neuropore involves (1) a caudorostral fusion of the neural folds at the dorsal lip and (2) a fusion at the terminal lip 17 proceeding towards the neuropore. (B) In an embryo of Dorsal lip stage 13 believed to be incipiently anencephalic, the M fusion of the neural folds is at a standstill. The open region indicates where fusion should have taken place Di.2 during stage 11. Fusion at the terminal lip, however, has 19 occurred. Di.1

Somites 20 13 17 19 Terminal lip

Ot. 8, 7 M 5 O p e Di. n

and limb defects are frequent. Some of the variable fea- and vertical eye movements could be produced by distur- tures (e.g., micrognathia and microglossia) are proba- bance of the interstitial nucleus (Crawford et al., 1991). bly secondary. Moreover, some instances of the sequence That nucleus appears in stage 13 at the ventral tran- are considered either to be caused by involvement of sitional area between diencephalon and mesencephalon peripheral nerves or as a myopathy. Abnormal torsional (Fig. 14–5). P1: JYS JWDD017-13 JWDD017-ORahilly April 17, 2006 12:56 Char Count= 0

84 Chapter 13: THE CLOSED NEURAL TUBE AND THE FIRST APPEARANCE OF THE CEREBELLUM

Figure 13–10. Development of cebocephaly. (A) Schematic A representation of the change in position of the nasal plates at stages 11 11–13 and 14–17, and also a combined view of stages 11–17. 14 13 Modiﬁed from Muller ¨ and O’Rahilly (2004c, Cells Tissues Organs) by 17 permission of S. Karger AG, Basel. (B) An abnormal embryo of stage 13 in which the nasal plates remained as a single structure at stage 12 12 instead of migrating bilaterally. This condition would lead to cebocephaly. (C) Two examples of cebocephaly drawn from photographs (in Siebert et al., 1990). None of the 43 holoprosencephalic embryos studied by Yamada et al. (2004) possessed olfactory structures.

Opt. D1 Neuropore Nasal plate

Phar. arch 1

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CHAPTER14 STAGE 14: THE FUTURE CEREBRAL HEMISPHERES

Approximately 5–7 mm in Greatest Length; Approximately 33 Postfertilizational Days

he future cerebral hemispheres (arrow) become future tentorium cerebelli. The pontine flexure appears. identifiable during stage 14 and are delimited The cerebellum is formed by the alar plate of the isth- Tfrom the telencephalon medium by the torus hemispher- mus as well as by that of rhombomere 1. Blood ves- icus internally and by the di-telencephalic sulcus exter- sels now penetrate the wall of the brain. Various bun- nally. Particularly advanced in the prosencephalon are dles (e.g., the medial and lateral longitudinal fasciculi, the hypothalamic, amygdaloid, hippocampal, and olfac- the common afferent tract) and a number of nuclei of tory regions. The synencephalon is identifiable. The mes- cranial nerves are present. All 16 neuromeres are now encephalic flexure is less marked and is occupied by the identifiable.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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86 Chapter 14: THE FUTURE CEREBRAL HEMISPHERES

Di. T

Figure 14–1. Right lateral view of the brain. The asterisk indicates the junction with the spinal cord. The future cerebral hemispheres begin to form during stage 14, but they were not evident in this embryo. The lens pit is present (Fig. 14–6). The synencephalon is recognizable. A minute, dorsal mesencephalic evagination (between M1 and M2) is frequently found: verg¨angliche epiphysen¨ahnliche Anlage des Mittelhirndaches (Hochstetter, 1919). The isthmus participates in the formation of the cerebellum. The hypoglossal roots and/or rootlets begin to unite usually into two trunks. The arteries to the head of this embryo were reconstructed by Padget (1948, Fig. 2), who showed that the carotico-basilar anastomoses are beginning to regress. P1: JYS JWDD017-14 JWDD017-ORahilly April 17, 2006 12:57 Char Count= 0

THE FUTURE CEREBRAL HEMISPHERES 87

Ventral thal. Dorsal thal. Medial eminence

Figure 14–2. Graphic reconstruction based on transverse sections to show a median view of the brain. The dividing line between the telencephalon medium and the future cerebral hemispheres is the torus hemisphericus, in the basal part of which the medial ventricular eminence (Fig 19–6) develops. Externally, the groove that accompanies the torus is the di-telencephalic sulcus. In the median plane, the borderline between diencephalon and telencephalon extends from the velum transversum to the preoptic recess. The velum transversum is a ridge in the roof of the prosencephalon, situated between D1 and the telencephalon medium. The telencephalon is surrounded by some mesenchyme, even ventrally. The prosencephalon occupies almost one-quarter of the length of the brain. Four areas are particularly advanced: (1) the hypothalamic region at the level of the chiasmatic plate as well as lateral to it [this is the area of the hypothalamic cell cord, from which the preoptico-hypothalamic tract arises (Fig. 14–3)]; (2) the amygdaloid region of the medial ventricular eminence; (3) the primordium of the hippocampus; and (4) the olfactory region. Topographically the hypothalamic cell cord corresponds to the “medial zone of the anterior hypothalamus,” which participates postnatally in the regulation of sexual comportment. The mesencephalic flexure has diminished to about 50◦, so that only a narrow space (the Mittelhirnpolster of Hochstetter) exists between the diencephalon and the rhombencephalon. The contained mesenchyme will form the tentorium cerebelli, the medial part of which now appears and is continuous with the cellular sheath of the notochord. A few extracerebral oculomotor and abducent fibers are present, and intracerebral trochlear fibers are developing. Blood vessels are much more numerous and, for the first time, penetrate the wall of the mesencephalon and rhombencephalon. The pontine flexure is beginning as a slight bulging of the ventral wall of the hindbrain. The cerebellum, which is the widest part of the brain, is formed by the alar plate of two neuromeres: the isthmus rostrally, and Rh.1 caudally. An intermediate layer is present in most of the cerebellum, and the future rhombic lip is discernible. The sclerotomes of the four occipital somites form two components near the base of rhombomere D. These will give rise to the basioccipital and exoccipital portions of the skull. The lower drawing shows the torus hemisphericus between the velum transversum and the preoptic recess. The diencephalon, which is thereby delineated from the telencephalon, possesses three elevations: the medial ventricular eminence, and the ventral and dorsal thalami. The entrance into the optic ventricle and the (dotted) outline of the optic cup are included. P1: JYS JWDD017-14 JWDD017-ORahilly April 17, 2006 12:57 Char Count= 0

88 Chapter 14: THE FUTURE CEREBRAL HEMISPHERES

Figure 14–3. Developing fasciculi and nerve exits. The outline of the right optic primordium is indicated by an interrupted line. The preopticohypothalamo-tegmental tract (black band indicated by a dagger) and the ventral longitudinal fasciculus are identifiable and are important in the transportation of monoamines from the locus caeruleus to the forebrain. The surface overlying the area of the future amygdaloid nuclei possesses tall horizontal cells of the Cajal–Retzius type. This is the first region where a primordial plexiform layer begins to develop. This is not surprising, because the site is adjacent to the diencephalon, and the only possible access for corticipetal fibers into the embryonic cerebral cortex is through the di-telencephalic sulcus (Mar´ın-Padilla, 1988a). The medial longitudinal fasciculus (thick black band) begins in the interstitial nucleus of the prerubral area (Fig. 14–5) and joins the ventral longitudinal fasciculus of the rhombencephalon. The lateral longitudinal fasciculus is indicated by a wide, stippled band. Dorsally, along the sulcus limitans, the common afferent tract (unshaded) contains sensory fibers from the cranial nerves. Present also are the beginnings of the habenulo-interpeduncular and medial tectobulbar tracts, and the mesencephalic tract of the trigeminal nerve. The exits of cranial nerves 3, 6, and 12 are ventral, whereas those of the others are along the sulcus limitans, where all afferent fibers enter.

1 23

B Figure 14–4. The telencephalon, showing the development of the future cerebral hemispheres in (1) right lateral, (2) median, and (3) head-on views: (A)no indication of cerebral hemispheres is seen; (B) hemispheric evagination has begun; (C) the future hemispheres are evident (C belongs to stage 15). In C column 2, the telencephalon is shown in yellow, and the entrance to the left optic stalk in black. In column 3, the telencephalic portion of the third ventricle is delineated between the lateral ventricles. P1: JYS JWDD017-14 JWDD017-ORahilly April 17, 2006 12:57 Char Count= 0

THE FUTURE CEREBRAL HEMISPHERES 89

The levels of the sections in Figures 14–5 and 14–6 are shown in the key. The bars represent 0.1 mm.

M1 Sulcus limitans

Primary Interstitial meninx nucleus

Di.

A-H

Figure 14–5. Section through the midbrain and hypothalamus. The interstitial nucleus is discernible at the ventral transitional area between diencephalon and mesencephalon. The adenohypophysial pouch is at all times closely related to the diencephalic ﬂoor. The mesenchyme adjacent to the brain is becoming looser: this is the primary meninx. From Bartelmez and Dekaban (1962).

Fig. 14 Ð 56

Syn.

Di.

Lens pit

Figure 14–6. Section through the optic stalks and optic cups. The optic ventricle still communicates with the interval between the retinal layers (where so-called detachment of the retina can occur). From Bartelmez and Dekaban (1962). P1: JYS JWDD017-14 JWDD017-ORahilly April 17, 2006 12:57 Char Count= 0

90 Chapter 14: THE FUTURE CEREBRAL HEMISPHERES

1 2

3 4 5

6 7

Syn.

Caudal par.

Rostral par.

Fig. 14 Ð 6

Figure 14–7. The neuromeres at stage 14 as shown in graphic reconstructions. The distinction that can now be made between the rostral and caudal parts of the parencephalon completes the series of 16 neuromeres. The initial appearance of the neuromeres is summarized in Table 10–1. The rostral parencephalon contains the opening of the optic ventricle on each side and is associated with the infundibular region and the ventral thalamus, whereas the caudal parencephalon presents the dorsal thalamus and the mamillary region. (A) Longitudinal section of the brain stem at the level indicated in the key. The mesencephalon is joined to the rhombomeres by the isthmus. Bar: 0.25 mm. (B) Section through the forebrain along the line B. The nasal discs and their neural crest are visible on each side. In the key drawing the asterisks denote the sulcus medius, which separates the dorsal (d) from the ventral (v) thalamus. The hypothalamic cell cord (stippled) indicates longitudinal differentiation in the diencephalon even before the hypothalamic sulcus appears at the next stage. (C) Section through the forebrain along the line C. The four compartments separated by horizontal lines are synencephalon, caudal parencephalon, rostral parencephalon, and D1 (immediately above the chiasmatic plate). The sulcus medius is marked by an arrowhead. Portions of the optic stalk and optic cup are visible on the right-hand side of the photomicrograph. Bar: 0.25 mm. P1: JYS JWDD017-14 JWDD017-ORahilly April 17, 2006 12:57 Char Count= 0

‘‘Optic EYE Figure 14–8. Comparison of the wall of the developing ventricle’’ forebrain and that of its derivative, the optic cup, at about 1 4 /2 weeks. The cavities (future third ventricle and BRAIN temporary optic ventricle) are continuous (Fig. 14–6). The corresponding layers are as follows: a a. Adjacent to the cavities is a terminal bar net, known in b c the retina as the external limiting membrane (ELM). d b. Germinal or proliferative cells, adjacent to the ventricle. e c. Mantle layer. Ventricle d. Marginal layer. e. The basement membrane is the external limiting membrane of the brain. In the eye, however, because of the invagination that forms the optic cup, it is the internal a b Retinal limiting membrane (ILM) of the retina. c fissure d e

BRAIN RETINA a Terminal bars ELM

b Germinal or Proliferative ventricular Layers Layers

c Mantle Mantle

d Marginal Marginal

e ELM ILM

Stage

12, 13

Common 15 efferent

Somatic efferent

Somatic afferent & Visceral 18 afferent

Visceral efferent

Sulcus limitans

G S S A Figure 14–9. The original position of the somatic G V G efferent nuclei in a ventrolateral cell column and of the A S G G, general V visceral efferent nuclei in a ventromedial column was S, special A V illustrated and clariﬁed previously (O’Rahilly et al., V E S 1984). It is not generally appreciated that the position E E changes considerably during development (Windle, 1970; Muller ¨ and O’Rahilly, 1990c, Table 2).

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92 Chapter 14: THE FUTURE CEREBRAL HEMISPHERES

Rh.2

Figure 14–10. Section through the trigeminal ganglion. Nerve fibers from the ganglion enter the rhombencephalic wall and form the common afferent tract. It is maintained that the motor fibers of the pharyngeal nerves leave the even-numbered rhombomeres, in which case (in the mouse) the trigeminal fibers that arise in the motor nuclei of Rh.2 and Rh.3 emerge from rhombomere 2.

Fig. 14 Ð 11 10

Figure 14–11. Section through hypoglossal rootlets, which emerge from the still laterally placed hypoglossal nucleus and traverse the clear marginal layer of the rhombencephalic wall.

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CHAPTER15 STAGE 15: LONGITUDINAL ZONING IN THE DIENCEPHALON

Approximately 7–9 mm in Greatest Length; Approximately 35 Postfertilizational Days

he brain presents five major subdivisions at five does not arise in the forebrain. The cerebellum is derived weeks (Table 15–1). The neuromeres of the fore- from both the isthmus and rhombomere 1. Most cranial Tbrain are still recognizable. Each cerebral hemisphere is nerves are present. Axodendritic synapses have been delimited externally by the di-telencephalic sulcus and inter- tected in the cervical region of the spinal cord, followed nally by the torus hemisphericus. The medial ventricular by axosomatic synapses early in the fetal period (Okado, eminence of the basal nuclei has appeared in the previous 1981). The vertebrae are now first clearly defined. The ta- stage and it is diencephalic. The lateral ventricular emi- pered caudal end of the trunk is not a “tail.” nence, which now appears, is telencephalic (Fig. 19–6). The amygdaloid region will be derived mainly from the medial eminence. The wall of the diencephalon presents five longi- Important tudinal zones: epithalamus, dorsal thalamus, ventral thala- By this stage all five major subdivisions of the brain are mus, subthalamus, and hypothalamus. The primordium of present: myelencephalon, metencephalon, mesenceph- the epiphysis cerebri is beginning. The sulcus limitans ends alon, diencephalon, and telencephalon (the future cere- rostrally at the midbrain (Ml) and is not continuous with bral hemispheres as well as the telencephalon medium). the hypothalamic sulcus. Hence the alar/basal distinction

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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94 Chapter 15: LONGITUDINAL ZONING IN THE DIENCEPHALON

Cerebellum Figure 15–1. Right lateral view of the brain. The asterisk indicates the Isthmus junction with the spinal cord. The cerebral hemisphere is demarcated End. div 4 from the diencephalon by the di-telencephalic sulcus. The lens vesicle Ot. and the optic cup with its retinal 11 5 (“choroid”) ﬁssure are shown 3 (Fig. 15–7). Still funnel-shaped, the 9 isthmus blends at its wider end with 8,7 the cerebellar region and narrows 12 towards M2. 10 Ch. Syn.

Hem.

Di.

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LONGITUDINAL ZONING IN THE DIENCEPHALON 95

Figure 15–2. Graphic reconstruction prepared from transverse sections to show a median view of the brain. The asterisk indicates the junction with the spinal cord. The cerebral hemisphere is limited from the diencephalon by an internal crest, the torus hemisphericus (Fig. 15–4), which begins at the velum transversum and ends as a basal thickening in the medial ventricular eminence (Table 15–2). In the development of the basal nuclei (Fig. 19–6), the lateral ventricular eminence, which is telencephalic, has appeared (Fig. 15–2, inset). The medial eminence, however, is entirely diencephalic, although it has been misinterpreted by others as the lateral eminence. The chiasmatic plate is well deﬁned and is limited by preoptic and postoptic recesses. The infundibular recess is appearing adjacent to the adenohypophysial pouch. The caudal part of the diencephalon (formerly D2) is the synencephalon, which will give rise to the prerubrum and the pretectum. At this level, the epiphysis cerebri begins as a thickening, but a recess is not yet present. A characteristic feature of this stage is the appearance of longitudinal zones in the diencephalon (Fig. 15–4 and Table 18–1). For example, the hypothalamic sulcus delineates the hypothalamus from the thalamus. In addition, the hypothalamus comprises subthalamus and hypothalamus sensu stricto (separated by a faint sulcus); the thalamus consists of epithalamus, dorsal thalamus, and ventral thalamus (Table 18–1). The dorsal and ventral thalami are incompletely separated in more advanced embryos by the beginning formation of the zona limitans intrathalamica, which is marked on the interior relief by the marginal ridge. Blood vessels begin to penetrate the wall of the diencephalon. The midbrain consists of two neuromeres: M1 and M2. The sulcus limitans ends at the rostral limit of M1. M2 is joined to the hindbrain by the isthmus. The supramamillary commissure is marked by a dagger. In the hindbrain, the cerebellar plate is distinct and extends over two rhombomeres: the isthmus and Rh. 1. The roof of the isthmus forms the superior medullary velum. The locus caeruleus is indicated (Fig. 15–10). The notochord is partly surrounded by sclerotomic material that represents the future basioccipital component of the skull. The inset drawing below left shows the contiguity of the torus hemisphericus and the medial ventricular eminence. The lateral eminence is visible in the lateral wall of the (left) cerebral hemisphere. The boundaries between the major divisions of the brain are listed in Table 15–2. P1: JYS JWDD017-15 JWDD017-ORahilly June 13, 2006 13:15 Char Count= 0

96 Chapter 15: LONGITUDINAL ZONING IN THE DIENCEPHALON

Figure 15–3. Median section of the brain. The mesencephalic ﬂexure is now extremely acute.

Chiasma

Commissural plate

Lateral ventricle Fig. 15 Ð 4 Torus hemisphericus

Hypothalamic sulcus

Subthalamus Hypothalamus

Isthmus

Figure 15–4. Section through the forebrain and isthmus rhombencephali. The hippocampal thickening is distinct on each side of the lamina terminalis. P1: JYS JWDD017-15 JWDD017-ORahilly June 13, 2006 13:15 Char Count= 0

LONGITUDINAL ZONING IN THE DIENCEPHALON 97

TABLE 15–1. The Sequence of Appearance of Key Features of the Brain, Including the Main Divisions and Subdivisions

Stage 9 10 11 12 13 14 15

Flexures Mesencephalic Pontine

Neuropores Rostral Caudal closes closes

Telencephalon 1 medium or Future impar cerebral hemispheres

Prosencephalon Diencephalon 2 Neural folds Mesencephalon 3 Isthmus rhomb.

Cerebellar 4 primordium Metencephalon

Rhombencephalon 5 Myelencephalon

TABLE 15–2. Boundaries Between the Main Subdivisions of the Brain

Division of Brain Limit at Roof Limit at Floor

Telencephalon medium Velum transversum Preoptic recess Diencephalon Between posterior commissure and Caudal supramamillary commissure commissure of superior colliculi Mesencephalon Rostral commissure Rostral to nuclei of trochlear nerves of trochlear nerves Rhombencephalon End of hypoglossal rhombomere (Rh.D) Spinal cord P1: JYS JWDD017-15 JWDD017-ORahilly June 13, 2006 13:15 Char Count= 0

Med. forebrain bundle

Figure 15–5. A number of tracts have appeared in the following order: the lateral longitudinal fasciculus, the spinal tract of the trigeminal nerve (which is a component of the common afferent tract), the medial longitudinal fasciculus, the mesencephalic tract of the trigeminal nerve, and the mamillotegmental tract (dagger). Fibers of the preoptico-hypothalamic tract are present, and precursor ﬁbers of the habenulo- interpedunclar and hypothalamo-thalamic tracts are forming. Fibers of the decussation of the superior colliculi are the precursors of the tectobulbar tract. Fibers to the amygdaloid part of the medial ventricular eminence (future striatosubthalamic tract) constitute a portion of the medial prosencephalic fasciculus. The shifting of the amygdaloid area into a clearly telencephalic position is comparable to the relocation of the globus pallidus from the diencephalon into the corpus striatum.

Figure 15–6. Right lateral view showing some peripheral nerves. All cranial nerves are present except 1, 2, and 8c. (The optic nerve is represented merely by the optic stalk until nerve fibers appear at stage 18.) The least advanced is the abducent, which is found in only one-third of embryos of this stage. Intramural trochlear fibers are indicated by two rows of dots. The vestibular nerve possesses sensory fibers that join the common afferent tract. The hypoglossal nerve has many connections with cervical nerves 1 to 3. The various ganglia of the cranial nerves are identifiable. Pax, En, and Wnt genes are involved in the patterning of the mesencephalon and metencephalon (Song et al., 1996), and the mes- rhombencephalic boundary shows Pax-5 gene expression (Gérard et al., 1995).

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LONGITUDINAL ZONING IN THE DIENCEPHALON 99

Nasal pit

Fig. 15 Ð 7 V3

Sulcus limitans

V4 Cerebellum

Figure 15–7. Section through the diencephalon and rhombencephalon showing the optic cup and the cerebellar plate on each side. The lens vesicles are closed from the surface. The optic stalk on the right-hand side of the photomicrograph shows the continuity between the third ventricle and the temporary optic ventricle.

AB C

Torus Lat. hemisphericus Isthmus ventricle

M2 Rh. V3

∗ Tel. D1

Figure 15–8. Sagittal sections in lateromedial sequence. The cellular strands in the lower left-hand corner of A are neural crest (asterisk in key).

Figures 15–7, 15–9, and 15–10. These photomicrographs are from the same embryo and their planes of section are shown on the next page. Bars: 0.15 mm. P1: JYS JWDD017-15 JWDD017-ORahilly June 13, 2006 13:15 Char Count= 0

100 Chapter 15: LONGITUDINAL ZONING IN THE DIENCEPHALON

Figure 15–9. Section through the hypothalamus and adenohypophysial pouch, showing a part of the optic chiasma.

Sulcus limitans Fig. 15 Ð 9 10

Locus caeruleus

Figure 15–10. Section through the cerebellar region at Rh.1 showing the locus caeruleus. The cells of the future locus caeruleus are present early (stage 13) and are situated in the intermediate layer of rhombomeres 1 and 2, ventral to the sulcus limitans. Later (at about stages 19 and 20), brightly ﬂuorescent processes have been traced into the telencephalic wall (Zecevic and Verney, 1995), and dopaminergic and adrenergic ﬁbers reach the tectum. P1: JYS JWDD017-15 JWDD017-ORahilly June 13, 2006 13:15 Char Count= 0

LONGITUDINAL ZONING IN THE DIENCEPHALON 101

Figure 15–11. Reconstructions of the A B Cbl rhombencephalon and isthmus rhombencephali. (A) Right lateral view to clarify (arrow) view D. (B) A block showing the isthmus and aqueduct seen from the caudal aspect (“from behind”). Rhombomere Aq. 1 is separated from rhombomere 2 by a ridge. The interrupted vertical lines between Rh. reconstructions C and D indicate the 1 caudorostral extent of the block. (C) The 2 ventricular surface of the left half of the brain. The roof of the isthmus represents the future superior medullary velum. Rh. 1 to 5 are clearly delineated by crests; Rh. 7 and 8 have to be distinguished by their C relationship to cranial nerves 9, 10, and 12 Cer. respectively. (D) The internal surface of the rhombencephalon ventral to the horizontal lines in A and C. The trigeminal ganglion is Is. related mainly to Rh.2, the facial (geniculate) to Rh.4, the otic vesicle to Rh.5 and 6, the superior glossopharyngeal Rh. 8 7 1 6 ganglion to Rh.6, and the superior vagal 2 ganglion to Rh.7. Bar, 0.2 mm. 5 4 3

4 3 2 5 1 Is. 7 6 M

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102 Chapter 15: LONGITUDINAL ZONING IN THE DIENCEPHALON

A D

Hydrocephaly

"Beaking" of inf. colliculi

Level of foramen magnum Herniated vermis

Descent of medulla

Figure 15–12. The pontine ﬂexure, barely discernible at (A) stage 15, becomes progressively accentuated at (B, C) stages 16 and 18 and at (D) 33 mm. Its failure to develop (A ) is one of several characteristic features of the (Cleveland–) Arnold–Chiari malformation.

NEUROTERATOLOGY: failure of the pontine flexure (stage 14) to form is believed ARNOLD–CHIARI to be an important factor in the abnormal elongation of MALFORMATION the hindbrain, but attempts to formulate a unified theory have been singularly unconvincing. The time of origin of Arnold-Chiari Malformation (Chiari Type 2). This ob- the condition lies in the embryonic period proper, perhaps scure condition was first described by Cleland in 1883. between 3 and 5 weeks. An example at about stage 16 has Hypoplasia of the tentorium cerebelli is found, and hy- been described (Ruano Gil, 1965). Irregularity of the fu- 1 drocephaly and myelomeningocele are usual but not ture vertebral column noted in vivo by ultrasound at 7 2 invariable accompaniments. Many features are probably postfertilizational weeks was followed at 10 weeks by signs secondary rather than primary (Gardner et al., 1975). A of the Arnold–Chiari malformation (Blaas et al., 2000a). P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

CHAPTER16 STAGE 16: EVAGINATION OF THE NEUROHYPOPHYSIS

Approximately 8–11 mm in Greatest Length; Approximately 37–39 Postfertilizational Days

he presence of the hippocampal thickening and vestibulocerebellar. The cochlear nerve has suddenly ap- various histological features makes possible a dis- peared. Asymmetry of the cerebral hemispheres was found Ttinction among the main, future cortical areas: archipal- in one embryo. Embryonic movements can be detected ul- lium, paleopallium, and neopallium. The most advanced trasonically at 5–6 weeks. differentiation is in the cortex of the future temporal pole Cerebral Asymmetry. A slight asymmetry of the left at the periphery of the amygdaloid area, in which the pri- and right cerebral hemispheres is well documented in the mordial plexiform layer can be discerned. Olfactory ﬁbers adult and dates back to at least the fetal period (Bossy et al., enter the wall of the brain at the site of the future olfac- 1976; Sun et al., 2005). It is entirely possible, if not indeed tory bulb, and the future olfactory tubercle is detectable. likely, that the asymmetry begins during the embryonic pe- The olfactory tubercle is the earliest component of the riod proper, perhaps even as early as stage 16. Hence some prosencephalic septum to appear. The marginal ridge sep- of the problems in lateralization discussed by Geschwind arates the dorsal from the ventral thalamus. The neurohy- and Galaburda (1985) may have a very early origin. pophysial outgrowth is now becoming distinct. A number Table 16–1 is useful in interpreting the important vas- of important pathways are beginning, e.g., olfactory and cular studies of Padget (1948, 1957).

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104 Chapter 16: EVAGINATION OF THE NEUROHYPOPHYSIS

Di.

T a

b c

Figure 16–1. Right lateral view of the brain. The asterisk indicates the junction with the spinal cord. The inset includes an end-on view showing the cerebellar plates, mesencephalon, epiphysis cerebri, diencephalon and optic cups, and cerebral hemispheres. In one embryo the cerebral hemispheres were strikingly asymmetrical, the left hemisphere being smaller than the right (as conﬁrmed by a Born reconstruction). Such an early cerebral asymmetry does not seem to have been recorded previously. In the eye, the retinal (so-called choroid) ﬁssure closes during stages 16 and 17. The polygonal outline of the (future iridial) rim of the optic cup is characteristic. Photomicrographs of the embryonic eye at each stage have been published (O’Rahilly, 1966). A comparison of the wall of the neural tube and that of the optic cup is shown in Figure 14–8. In addition, the main events of optic development have been summarized (O’Rahilly, 1983b). The right-hand key drawing shows (a) the sulcus limitans, (b) the hypothalamic sulcus, and (c) the marginal ridge. P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

EVAGINATION OF THE NEUROHYPOPHYSIS 105

Figure 16–2. Graphic reconstruction prepared from transverse sections to show a median view of the brain. The outgrowth of the infundibulum is now becoming marked; i.e., the evagination of the neurohypophysis is becoming distinct (Table 17–2). The rhombencephalon has become ﬂatter and broader, and the isthmus, which has become clearer, now shows an enlargement ventrally. The change in shape of the isthmus was appreciated by Hochstetter (1919), who described this region as funnel-shaped (at stage 15). The pontine ﬂexure is deeper. The rhombomeres are no longer clearly visible on the external surface. Amoeboid cells that may be precursors of microglial cells have been detected histochemically in the cerebral wall at about stage 16 (Fujimoto et al., 1989). Furthermore, glial cells can be distinguished immunologically from neurons at about this time. P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

106 Chapter 16: EVAGINATION OF THE NEUROHYPOPHYSIS

Syn.

Figures 16–3 and 16–4. Cranial nerves and tracts. The cochlear nerve appears suddenly, and all the cranial nerves are now visible. The hypoglossal nerve, which now reaches the apex of the tongue, is joined by fibers of cervical nerves 2 and 3, presumably the precursors of the ansa cervicalis and its roots (O’Rahilly and Muller, ¨ 1984b). Most motor nuclei of the cranial nerves have developed during stages 12 to 14. An examination of first-class material shows that it is not possible to distinguish the nucleus ambiguus at stage 16 or earlier, as has been claimed (Brown, 1990). Fibers ascending to the cerebellum are situated mainly along the sulcus limitans and are not clearly seen to penetrate that organ. Vestibulocerebellar and trigeminocerebellar fibers proceed towards the basal part of the cerebellar plate. The diencephalic subthalamic nucleus is present and includes fibers proceeding to the supramamillary commissure. The preoptico-hypothalamotegmental tract is marked by a dagger (Fig. 16–4). P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

EVAGINATION OF THE NEUROHYPOPHYSIS 107

Figure 16–5. Arterial development and the tentorium cerebelli. The cellular sheath of the notochord, which is anchored to the adenohypophysis (Fig. 15–9), is continuous with the medial part of the future tentorium cerebelli. The space between the hypothalamus and the rhombencephalon becomes increasingly compressed, resulting in a mesenchymal condensation (the Mittelhirnpolster of Hochstetter) between the diencephalic floor and the basilar artery. The notochord lies either ventral to or, in the more advanced embryos, within the notochordal cellular sheath. The latter and the sclerotomic material will form the basioccipital part of the skull. Most of the components of the future circulus arteriosus (of Willis) are now present: the basilar and the paired posterior communicating arteries, as well as the internal carotid vessels on both sides. An anterior communicating artery has not yet developed but will do so during stage 19 (Padget, 1948, Fig. 7b). The posterior communicating represents the original caudal division of the internal carotid artery (Fig. 21–23). The adult stem of origin of the posterior cerebral is at first the distal end of the original posterior communicating artery (Padget, 1948). Penetrating capillaries can be observed in most parts of the surface of the brain, except in the future archipallial and neopallial components of the telencephalon. They enter as deeply as the ventricular layer. The posterior communicating artery, a very important embryonic vessel that develops from stages 14 to 16, was also reconstructed by Padget (1948, Fig. 4). The posterior communicating is the vessel through which the internal carotid artery supplies the embryonic hindbrain. Although present and illustrated, the posterior cerebral artery was not named in Padget’s figure. P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

108 Chapter 16: EVAGINATION OF THE NEUROHYPOPHYSIS

Archi- pallium

Paleo- pallium

Figure 16–6. (A) lateral, (B) dorsal, (C) medial, and (D) ventral views of the telencephalon. The archipallium (stippled), paleopallium (horizontal lines), and neopallium (unshaded) are distinguishable on the basis of histological differences. The archistriatum (amygdaloid nuclei, Fig. 19–6) is indicated by cross-hatching, and the paleostriatum by interrupted horizontal lines at the interior surface in C. This is the area to which the globus pallidus externus moves during stages 22 and 23 (Figs. 23–17 and 23–25). The most advanced differentiation is in the future temporal pole (gamma) at the periphery of the amygdaloid nuclei. Here presumed Cajal–Retzius cells and fibers were already present in stage 15. These horizontally arranged cells in the “marginal” (Fig. 21–7) layer are more developed than the cells of the ventricular layer (Fig. 17–11). The “marginal” layer in this region constitutes the primordial plexiform layer, the “pallial Anlage,” which is believed to be functional by stage 20 (Mar´ın-Padilla and Mar´ın-Padilla, 1982). Olfactory fibers enter the wall of the brain at the site of the future olfactory bulb, and cellular islands indicate the future olfactory tubercle. Up to stage 16 the amygdaloid region, which is derived almost exclusively from the medial ventricular eminence, is recognizable by the advanced differentiation of its primordial plexiform layer. Neurogenesis in the amygdaloid complex of the rhesus monkey begins at a comparable time, and the cells have been considered to be the earliest postmitotic neurons in the telencephalon. Whatever the pros and cons of the tripartite brain hypothesis (so-called reptilian, paleomammalian, and neomammalian regions), scant support for it is apparent in human embryology, any more than for the outmoded “biogenetic law” of “recapitulation.” It would be very difficult (with present methods) to attempt to distinguish archi-, paleo-, and neopallial regions before histological differentiation has begun. The recorded appearance of synapses in the neopallium at stage 17 and later, however, serves to emphasize that that region is clearly more advanced than either the hippocampus or the olfactory bulb at the same stage. In other words, there seems to be no evidence that the development of the (human) brain follows a phylogenetic pattern from archi- to paleo- to neocortical structures. P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

EVAGINATION OF THE NEUROHYPOPHYSIS 109

Figures 16–7A to 16–7F. Six sections F E D C B A of the brain. From Bartelmez and Dekaban (1962).

ABC Hem. L.t. Olf. Hypothal Med. em. cord

Di.

Spinal Rh.8 cord

Hyp.-th. Marginal D E sulcus F Figure 16–7. (A) The olfactory ridge area and the lamina terminalis. Thal.d. (B) The medial ventricular Ep. eminence forms the basal part of Thal.v. the torus hemisphericus. (C) The Di. optic stalk and the hypothalamic cell cord of the two sides of the brain. (D) Section at the level of the adenohypophysis. (E) The 5 A.-H. 5 dorsal and ventral thalami, and the hypothalamic sulcus. Both V4 ventral and dorsal thalami possess Ot. V4 a thick ventricular layer and a 10 beginning intermediate layer. (F) Section at the level of the 11 epiphysis cerebri (pineal body, Rh. Table 17–1). The marginal ridge Rh. Rh. (future zona limitans intrathalamica) can be discerned and separates the ventral from the doral thalamus. P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

110 Chapter 16: EVAGINATION OF THE NEUROHYPOPHYSIS

Fig.16 Ð 8, 10 911

Di.

A.-H.

Int. carotid a. Figure 16–9. Some two sections more deeply, the surface of the cerebral hemisphere presents widely dispersed cells, indicating pro- Figure 16–8. Cerebral hemisphere showing the loose distribution gressive differentiation. Bar: 0.2 mm. of the superﬁcial cells at the periphery. Up to and including stage The cell columns of the ventricular layer of the diencephalon in 16 the neocortical part of the cerebral hemispheres is avascular Figures 16–9 and 16–10 are high and are penetrated by blood vessels. (Larroche and Jardin, 1985), although it is already surrounded by The cells of the intermediate layer are not as tightly packed as in the a prominent “perineural” vascular process (Streeter, 1919; Padget, telencephalic area shown in Figure 16–11, and this is a clear differ- 1948; Mar´ın-Padilla, 1978, 1988a,b). Bar: 0.2 mm. ence. Peripheral to the intermediate layer, nerve ﬁbers and scattered cells give an impression of a primordial plexiform layer.

Hyp.-th. sulcus

Hipp.

Figure 16–11. The hippocampal area, characterized by a marginal layer and a discrete ventricular thickening. Bar: 0.1 mm.

Figure 16–10. The subthalamus, ventral to (below) the hypothalamic sulcus, showing ﬁbers in the marginal layer and capillaries that have penetrated the cerebral wall. Such diencephalic blood vessels are present in most embryos of this stage. Bar: 0.1 mm. P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

EVAGINATION OF THE NEUROHYPOPHYSIS 111

Is. Figure 16–12. Three-dimensional representation of the rhombencephalon and part of the mesencephalon. The Cel. orientation of views B and C is shown A S.I. in the key drawing. (A) The left half seen from the median plane. M2 Intramural ﬁbers of the trochlear nerve are indicated by two, closely set interrupted lines which run in the M1 rostralmost part of the isthmic segment 8 inside a ventricular crest. (B) Block 7 6 2 5 4 3 with the roof of the mesencephalon removed, so that part of the ﬂoor of the isthmic segment becomes visible. At the left, the cerebellum (mostly Rh. 1) Ot. is seen to be much wider than the mesencephalon. (C) Block showing the ventral part of the rhombencephalon, B which is composed of rhombomeres 2 to 8.

Cel. M2

Is.

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112 Chapter 16: EVAGINATION OF THE NEUROHYPOPHYSIS

A Figure 16–13. The arterial system at about 4 to 5 postfertilizational weeks. The internal carotid artery is shown in black, and the basilar by horizontal hatching. These four drawings are simpliﬁed versions of the graphic reconstructions made by Padget (1948), whose work should be studied for further details. The venous system at stages 14 and 16 has been illustrated by Padget (1957, Figs. 2 and 3). (A) Lateral view at stage 13. The longitudinal artery (which is present bilaterally) 2 3 is connected to the internal carotid (black) by 1 4 temporary trigeminal, otic, and hypoglossal arteries TA (green). Aortic arches 1 to 4 are proceeding from the truncus arteriosus (TA). (B) Stage 13. The bilateral longitudinal arteries will unite to constitute the basilar. (C) Stage 14. The posterior communicating artery can be identiﬁed and at this time is the major supply of carotid blood to the hindbrain. Anastomotic channels unite the two longitudinal arteries, thereby initiating the formation of the basilar artery. Aortic arch 2 supplies the hyoid artery, which in turn will give rise to the stapedial artery. The interrupted lines indicate the caroticobasilar anastomosis. (D) Stage 16. The two Posterior communicating longitudinal vessels have now united to form the basilar artery, and the vertebral arteries are evident. The BC D posterior cerebral arteries (yellow) have begun their development.

Longitudinal

TABLE 16–1. Relationship Between Padget’s Vascular Phases and Carnegie Stages

Arterial Phases Venous Phases Carnegie Stages

—1 13 1 — 13–14 2214 — 3 15–16 3—16 4—17 — 4 17–18 5 — 18–19 —5 19 6 6 20–21 7 7 40 mm GL — 7a 60–80 mm GL P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

NEUROTERATOLOGY 113

NEUROTERATOLOGY: from rhombencephalic neural crest are smaller in holo- HOLOPROSENCEPHALY prosencephaly. Many basal areas of the forebrain that become distinct in stage 14 are absent in holoprosencephaly, Holoprosencephaly is a term used for a graded series of e.g., the olfactory region (paleocortex), the optic stalks, cerebral and facial anomalies that range from cyclopia to and the neurohypophysial area. Hence, holoprosencephaly the almost normal. The “entire prosencephalon remains is more than a mere failure to “diverticulate” into cere- holospheric rather than becoming hemispheric” (DeMyer, bral hemispheres. In those rare instances where holopros- 1987); i.e., the prosencephalon remains as a whole, a sin- encephaly is found independently of synophthalmia and gle, more or less undifferentiated sphere, incompletely cleft arhinencephaly, the origin is possibly at a later time, but into complex halves. In the telencephalon the future sep- nervertheless not later than stage 13 or 14. Such condi- tal area and the commissural plate (future anterior com- tions, although variable in their manifestation, would arise missure and corpus callosum) are missing, and the te- during the first 4 or 5 weeks (Fig. 16–14E, F). lencephalic portion of the corpus striatum is not formed Holoprosencephaly is more than 60 times more fre- (Muller ¨ and O’Rahilly, 1989c). At the diencephalic level, quent prenatally than in live births. Examples from stages disturbances are less evident, except at the level of the op- 13–23 have been described (Yamada et al., 2004). The con- tic primordia. The adenohypophysis may be absent or may dition may be autosomal dominant, autosomal recessive, merely become detached. Its absence may perhaps be re- or X-linked recessive, and about half of affected newborns lated to a disturbance of the prechordal plate. have chromosomal disorders (chiefly chromosome 13, 18, It is possible that holoprosencephaly involves a fun- or 21; deletions in chromosome 7 may be implicated). As- damental event, such as induction, and has an early ori- sociation with trisomy 13 and triploidy may also occur. gin (probably in stage 8). Absence of the rostral part of Holoprosencephaly is commonly graded into (1) alo- the notochord (with consequent cranial defects) could re- bar (a holotelencephalon that lacks division into hemi- sult from faulty interaction with the prechordal plate. At spheres; it can be detected ultrasonically by the demon- stage 8 a mesenchymal disturbance could already be active. stration of a single ventricle), (2) semilobar (incomplete Faulty development of the paraxial mesenchyme from the cerebral hemispheres), and (3) lobar (well-formed cerebral primitive streak or node could interfere with the eleva- hemispheres and longitudinal fissure). Alobar holoprosen- tion of the neural folds. Defective prechordal mesenchyme cephaly has been visualized in vivo by 3D ultrasound at 1 may fail to produce the normal facial structures and to 7 2 postfertilizational weeks (Blaas et al., 2000b). The clin- induce adequate morphogenesis of optic primordia and ical manifestations of holoprosencephaly, together with a of the brain. In stage 10 production of the neural crest survey of holoprosencephalic syndromes and an atlas of 35 is beginning. The ganglia of the cranial nerves derived cases, can be found in a useful book by Siebert et al. (1990). P1: JYS JWDD017-16 JWDD017-ORahilly June 13, 2006 10:34 Char Count= 0

114 Chapter 16: EVAGINATION OF THE NEUROHYPOPHYSIS

A B Figure 16–14. Holoprosencephaly. (A) and (B) The normal telencephalon and diencephalon at 5 weeks (stage 16). (C–F) The development of holoprosencephaly. (D) A ventral view in which shading indicates the basal part of the brain that is missing. (E) and (F) Dorsal views that show a single telencephalic ventricle. In E the optic cups are partially separated, whereas F has only a single optic cup. (G) Alobar holoprosencephaly in an infant Telencephalon presenting cebocephaly, slight Diencephalon hypotelorism, and median cleft lip and Medial ventricular palate. (H) Dorsal view of another example eminence of alobar prosencephaly after removal of the scalp and skull. The single D EF telencephalic ventricle is evident. A to F are based on personal reconstructions, G and H on photographs in Siebert et al. (1990) and in DeMyer (1975), respectively.

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CHAPTER17 STAGE 17: THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI

Approximately 11–14 mm in Greatest Length; Approximately 40 Postfertilizational Days

The first dopamine-producing areas are present. The first indication of a septal nucleus is recognizable. The hemi- ostral and caudodorsal growth of the cerebral spheric stalk unites the cerebral hemispheres with the ven- hemispheres results in deepening of the longi- tral thalamus and with the diencephalic part of the me- Rtudinal fissure, in which the vessels of the future choroid dial ventricular eminence. The di-mesencephalic boundary plexus develop. The olfactory bulb and tubercle become passes between the posterior commissure and the commis- outlined. The amygdaloid area, which is related to the me- sure of the superior colliculi (Table 15–2). Gustatory fibers dial ventricular eminence, contains three to four nuclei. are beginning to separate from the common afferent tract.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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116 Chapter 17: THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI

Figure 17–1. The various parts of the brain are clearly visible not only in reconstructions but even through the translucent tissues of the intact embryo. The pontine ﬂexure is now deeper, and the interval between the hypothalamus and the rhombencephalon has become narrow. The future frontal and temporal poles are marked α and γ in the key drawing of Figure 2. A three-dimensional reconstruction, prepared ultrasonically, of the ventricles in vivo in an embryo of 13 mm is illustrated by Blaas et al. (1995b). P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI 117

Figure 17–2. Solid (Born) reconstruction and key. The growth of the cerebral hemispheres initiates the appearance of the longitudinal ﬁssure. The telencephalon begins to overlap the diencephalon.

Figure 17–3. Lateral view (reversed) of the brain. The cerebellar plate is as wide as the combined width of the two cerebral hemispheres (Fig. 17–2). The inferior cerebellar peduncle is present already, the superior is distinguishable at the next stage, and the middle peduncle develops during the fetal period. The posterolateral ﬁssure delimits the external cerebellar swelling. Included in this ﬁgure are the oculomotor and trochlear nerves, the trigeminal ganglion, the three divisions of the trigeminal nerve, and the optic cup. Drawn by Mary M. Cope from a reconstruction. P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

118 Chapter 17: THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI

Figure 17–4. Graphic reconstruction prepared from transverse sections to show a median view of the brain. The asterisk indicates the junction with the spinal cord. (A) The sulcus limitans (a), the hypothalamic sulcus (b), and the marginal ridge (c). The sulcus limitans separates the alar and basal laminae of the rhombencephalon and mesencephalon. However, it does not continue into the diencephalon. The hypothalamic sulcus of the diencephalon separates the thalamus sensu lato from the hypothalamus sensu lato (Table 18–1). (B) The medial surface of each cerebral hemisphere has greatly increased and a hemispheric stalk can be identified. This is the junctional area between the telencephalon and the diencephalon. Shown here are the boundaries between the different parts of the brain, the newly developed recesses (arrows), the commissures, the sulci, and the entrance into the optic ventricle (black dot in the diencephalon). Four small arrows indicate the isthmic, supramamillary, inframamillary, and infundibular recesses. The boundaries are summarized in Table 15–2. The posterior commissure has suddenly appeared and consists of two subcommissures: the posterior commissure sensu stricto with fibers of the medial longitudinal bundle, and the commissure of the superior colliculi. Other commissures are the supraoptic in the caudal part of the chiasmatic plate, the supramamillary (dagger), and the commissure of the oculomotor nerves. The ventral commissure of the rhombencephalon, which consists of fibers that cross throughout the length of the floor-plate, has not been indicated here. The commissural plate itself does not yet contain crossing fibers. In the inset, features of the medial aspect of the lateral wall of the left cerebral hemisphere have been superimposed on the median reconstruction. The interventricular foramen is surrounded by the hippocampal area of the telencephalon and by the medial ventricular eminence of the diencephalon, as well as by the ventral thalamus. The medial eminence is invading telencephalic territory and is penetrated by blood vessels. The lateral ventricular eminence (Fig. 19–6) is visible in the left hemispheric wall. The internal cerebellar swelling lies between the sulcus limitans and the rhombic lip. Reconstructions from a different embryo were published by Hines (1922). P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

Sulcus limitans

A B

Ep. AH Di. Sclerotomes

Tel.

Velum transversum

Figure 17–5. Median section. All mesenchymal components of the head have increased greatly. Many skeletal elements can already be reconstructed: the stapes, the styloid process, the cartilage (Meckel’s) of pharyngeal arch 1, the thyroid laminae, and the cricoid cartilage. The primordia of the so-called hypophysial cartilages (trabeculae; polar cartilages) are present in the area of the future hypophysial fossa. The brain sits on a firm basal condensation of mesenchyme, which, in its rostral part, represents the future nasal septum. This restrains the growth of the cerebral hemispheres in a basal direction. Bar: 1 mm. The mesenchyme is beginning to form the future dural limiting layer, especially in basal areas, and, beginning at the rostral tip of the notochord, it continues to spread between the diencephalon and the rhombencephalon, i.e., at the site of the mesencephalic flexure. The condensed mesenchyme at the flexure is the primordium of the tentorium cerebelli, which is compressed between the basilar artery and the hypothalamus (Fig. 16–5). The dural limiting layer already contains openings (pori durales) for cranial nerves 3, 4, 5, and 12. The presence of the dural limiting layer between the pia mater and the skeletogenous sheath initiates the formation of the subarachnoid space. The space clearly begins its development before the presence of choroid plexuses. The roof of the fourth ventricle is very thin. Two areas are beginning to become the areae membranaceae rostralis et caudalis. They are formed by flattened ependymal cells, and their position is indicated by two arrows. Such areas (in the adult mouse) are thought to permit the passage of cerebrospinal fluid containing macromolecules, by way of interependymal cellular clefts. The “ependymal fluid” within the ventricles is believed to be produced by the lining cells that will develop later into ependymal and choroid plexus cells. Already in the previous stage, the vertebral arteries join the basilar, and an anastomosis is present between the basilar and the internal carotid arteries (Fig. 16–13D). An anterior choroid artery is now developing and was reconstructed by Padget (1948, Fig. 5). The main cerebral arteries are now well established. The caudal part of the spinal cord, which forms by secondary neurulation, reaches the caudal tip of the body. The definitive number of somites (usually 39 pairs: O’Rahilly and Muller, ¨ 2003) seems to be present at this and the next stage. The normal regression of the caudalmost part of the spinal cord may begin at approximately this time. The key shows the position of the sulcus limitans and the alar and basal laminae (cf Fig. 21–8). The neurohypophysis (characterized by folded walls) and the infundibular recess are present in all embryos of this stage. Cartilage appears in occipital sclerotomes 1–4, and the hypoglossal foramen has formed in sclerotome 4. The sclerotomic mass is shown in the key.

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120 Chapter 17: THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI

Figure 17–6. Six features and six recesses. A 1. Hypophysis (A) The six features that are developing here become more distinct later (Fig. 24–32) but maintain their sequence even in the adult. 2. Chiasmatic plate (B) Six named, ventricular recesses, one in the midbrain and ﬁve in the forebrain, can be 3. Emb. lamina identiﬁed. terminalis 4, 5. Commissural plate 6. Epiphysis

B RECESSES

Isthmic

Supramamillary Inframamillary

Infundibular Postoptic

Preoptic

Figure 17–7. The epiphysis is detectable already in stage 16 as an evagination of the synencephalic roof of the diencephalon. In stage 17 mitotic ﬁgures of the ventricular layer become numerous and an intermediate layer forms, which is the precursor of the future Vorderlappen. P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI 121

TABLE 17–1. Development of the Epiphysis Cerebri

Stadium of Carnegie Stage Figures in Features Turkewitsch (1933) O’Rahilly,1983 this Book

Site of future epiphysis may be distinguishable 15 19–16(I) Epiphysis detectable in diencephalic roof I 16 Cellular migration in an external direction begins II 17 19–16(II) Continuing cellular migration forms a Vorderlappen with “follicles” III 18 19–16(III) The Vorderlappen shows a characteristic step and wedge appearance. IV 19 19–16(IV) The epiphysis is limited caudally by the posterior commissure. One 19–17 ventricular recess. The habenular commissure appears, and the epiphysis is wedged V 23 19–16(V) between the habenular and posterior commissures Two ventricular recesses VI 23 23–3 Hinterlappen, “ducts,” etc. VI Fetal period 19–16(VI)

TABLE 17–2. Development and Components of the Hypophysis Cerebri

The adenohypophysial (A–H) and the neurohypophysial (N–H) primordia (upper left-hand corner) are in contact from their ﬁrst appearance. Hence the adenohypophysial pouch and the neurohypophysial evagination are also in contact and result in the adult pituitary gland (rectangle). The terminology in the adult is that of Rioch, Wislocki, and O’Leary, Res. Publ. Ass. Nerv. Ment. Dis. 20:3. 1940. The variously deﬁned terms “anterior” and “posterior” lobes are best avoided. P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

Figure 17–8. Medial view of the brain. In the forebrain, the hypothalamic region can be seen above; below it, from left to right, the elevations of the dorsal thalamus, ventral thalamus, and medial ventricular eminence are visible (cf. Fig. 17–4). Drawn by James F. Didusch from a reconstruction.

Basilar a.

NH Brain

AH Notochord

Ch. Pharynx Tongue

Figure 17–9. The hypophysis in median section. The elongated adenohypophysial pouch is in contact with the folded wall of the infundibulum.

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THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI 123

Med. forebrain bundle funiculus

Figure 17–10. The cranial nerves and tracts. All cranial nerves have been present since the previous stage. The last of the regular cranial nerves to appear are the abducent and the cochlear, at stage 16. The olfactory fibers, however, become clear in the present stage. Two bundles of nerve fibers, a lateral and a medial, can be distinguished, and at the site of their entrance into the hemispheres, the olfactory bulb will develop in the next stage. The hypoglossal nerve emerges from the occipital sclerotomic mass as either one (as seen here) or two trunks. The ventral ramus of the first cervical nerve joins the hypoglossal. Cervical nerves 1 and 2 unite to form the inferior root of the ansa cervicalis, and the loop is completed by the superior root, which descends from the hypoglossal nerve. Ganglia are indicated by small circles. Many tracts have appeared during the previous week (from stage 14 onwards). The order of their appearance as determined from graphic reconstructions is: lateral longitudinal fasciculus, common afferent tract, medial longitudinal fasciculus, dorsal funiculus, preopticohypotha- lamotegmental tract, mesencephalic tract of the trigeminal nerve, medial prosencephalic fasciculus, medial tectobulbar tract, and mamillotegmental and habenulo-interpeduncular tracts. The medial prosencephalic fasciculus (medial forebrain bundle) contains mainly ascending fibers that terminate in the amygdaloid and preoptic regions. The habenulo-interpeduncular tract (fasciculus retroflexus) delineates the synencephalon rostrally. Some of the nuclei and areas of loose intermediate layer are indicated by stippling. The term “nucleus” refers here to zones of lower cellular density and slightly larger cellular size. The amygdaloid nuclei form the most histologically advanced area of the cerebral hemispheres. The amygdaloid region is related to the medial ventricular eminence (Fig. 19–6). The subthalamic nucleus, red nucleus, interstitial nucleus, nucleus of the posterior commissure, and nucleus of the mesencephalic tract of the trigeminal nerve, and the locus caeruleus (asterisk) are recognizable. The cells of the locus caeruleus occupy the isthmus and rhombomere 1. Its tall cells, twice the size of ordinary neurons, lie at the innermost aspect of the intermediate layer, ventral to the sulcus limitans. The interstitial nucleus is indicated by a dagger. The gustatory fibers begin to separate from the common afferent tract as the tractus solitarius. The tectal area of the mesencephalon, shown in stippling, has developed an intermediate layer. In the cerebellum, cells of the rhombic lip participate in the formation of the dentate and isthmic nuclei, and later (stage 23) in the development of the external germinal layer. P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

124 Chapter 17: THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI

Figure 17–11. Photomicrograph showing the periphery of the amygdaloid area (the cortex of the future temporal pole), which contains multiple tall cells with long ﬁbers; rostral is to the left-hand side of the page. The neurons for the amygdaloid complex belong to the earliest postmitotic neurons. An initial burst of cell formation for the septal nuclei occurs at this time. Bar: 0.1 mm. P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI 125

Figure 17–12. Relationship of the olfactory A bulb to other parts of the developing limbic 1 system at approximately 6 /2–7 weeks. (A) Three-dimensional right lateral view of the Hippocampus amygdaloid complex, hippocampal primordium, septal area, and olfactory bulb of right and left sides. The amygdaloid complex is CAUDAL ROSTRAL at the future temporal pole of the cerebral hemisphere. (B) Schematic representation of the right amygdaloid complex, seen from the direction of the arrow in (A), with four main Amygdaloid nuclei nuclei. Two chief ﬁber connections exist: (1) Olfactory n. between olfactory bulb via olfactory tubercle to the medial nucleus and (2) between olfactory bulb and the basolateral and anterior nuclei. Septum Lat. striae The arrows at the right indicate a lateral to medial (∗) and a dorsal to ventral (†) “rotation” during the fetal period. (C) A posterosuperior Median B view of the adult amygdaloid nuclei showing plane that the deﬁnitive arrangement differs from the embryonic (After Neuwenhuys et al., cited in Benninghoff’s Anatomie). From Muller ¨ and O’Rahilly (2006) by permission of the Journal of Anatomy. Medial Anterior Baso- lateral Med. & lat. Cortical striae Olfactory tubercle

Ant. commissure

Thalamus

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126 Chapter 17: THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI

TABLE 17–3. Monoaminergic Centers

Stage Cells and Nuclei Fascicles

15 TH-IR cella Medial forebrain bundle (Fig. 15–5) from Locus caeruleus (A6, Fig. 15–2, 15–10) locus caeruleus rostrally Ventral tegmental area (A9, 10, Figs. 17–13, 20–11) Preoptico-hypothalamic tract (Fig. 15–5) 16 Mesencephalic tegmentum (Figs. 17–13, 20–12) 17 3–4 amygdaloid nuclei (Fig. 17–12) Medial forebrain bundle (Figs. 17–10, 17–13) Noradrenergic cells in locus caeruleus TH-IR-reaction of ﬁbers of medial forebrain TH-IR neurons in A8, A9, and A10 and along bundle from basal mesencephalon to vomeronasal organ amygdaloid regionb Elongated band of TH-IR cells from nasal sac to septuma,b Olfactory bulb (Figs. 17–10, 17–13) 18 4 amygdaloid nuclei (Fig. 18–5) 19 4 amygdaloid nuclei (Figs. 19–8, 19–9) 20 Interpeduncular nucleus (Figs. 17–13, 20–9) Nuclei solitarius and ambiguus (Fig. 20–19) Before or at 23 TH-IR penetrate telencephalic wall and [lateral] ventricular eminence Fibers in subplate, but not in cortical platea,b

a Verney et al. (1996). bZecevic and Verney (1995).

A6 A, Central nucleus of amygdaloid A8, Retrorubral cells ∗ A2 body A4 A2, Nucleus solitarius A9, Substantia nigra A4, Cells along superior cerebellar A10, Ventral Inter- peduncular peduncle tegmental area nucleus A5, Area near facial nucleus A15, External layer of olfactory bulb A6, Locus caeruleus A10

A15

Figure 17–13. Monoaminergic centers that are present in stage 17 and later. Those in stage 17 or even earlier (marked in purple) are locus caeruleus (A6), ventral tegmental area (A 10), and amygdaloid body (A). The tracts (orange) related to these centers and also present in stage 17 are the preoptico-hypothalamic tract (dagger) and the medial forebrain bundle. Centers that arise later include the nucleus solitarius (A2), the area along the superior cerebellar peduncle (A4), the area near the facial nucleus (A5), and the external layer of the olfactory bulb (A15). P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI 127

Fig. 17 Ð 15 14

Figure 17–15. The second section shows the interventricular foramina, which begin to be apparent at about this time. They become relatively narrower as the medial surface of each cerebral hemisphere develops and as the medial ventricular eminence grows.

Figs. 17 Ð 18 17 16

Figure 17–14. The rostralmost section shows only the paired cerebral hemispheres and the telencephalon medium between them. A slight swelling represents the lateral ventricular eminence. The longitudinal cerebral ﬁssure is ﬁlled with loose mesenchyme. Here, and elsewhere in the mesenchyme adjacent to the brain, thin-walled blood vessels are numerous, and the anterior choroid artery has appeared. The continuity between the nostril and the nasal sac is visible at the left side. The two nasal sacs are separated by dense mesenchyme that represents the future nasal septum. . Key for Figures 17–16 to 17–18 on page 128. P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

128 Chapter 17: THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI

Figure 17–16. The diencephalon is visible and the dorsal thalamus can be distinguished from the ventral. Di. The two are separated by the marginal ridge (zona Th.d. Dural limitans intrathalamica of Kuhlenbeck) and are limiting delineated towards the hypothalamus sensu lato by the Marg. ridge layer hypothalamic sulcus (Table 18–1). The ventral thalamus Subarachnoid (which possesses an intermediate layer) is more Hemisphere Th.v. space advanced than the dorsal thalamus. (In the mouse, the zona limitans intrathalamica has been found to be Hyp.-th. clearly delineated by gene expression.) The optic cup is sulcus surrounded by condensed material that represents the primordia of the orbital muscles. The retinal (“choroid”) fissure of the optic cup is closing. Its continuation on the Opt. stalk optic stalk, however, is still open and allows the ingrowth of optic fibers, which begin to develop in this stage. A hyaloid vessel can be seen in the optic stalk. The part of the hemisphere shown contains the amygdaloid area. This figure closely resembles illustrations in various articles (Sidman and Rakic, 1982, Fig. 1–41) and textbooks in which the interpretation is incorrect: a section that includes all five parts of the diencephalon as well as the eyes cannot also pass through the mesencephalon.

Sulc. lim. Tectum Di.

Marg. 3 ridge

Hyp.th. sulcus

Tentorium N.-H. Rh.2 Rh.3 Ggl Rh.4 5 A.-H.

Ot.

Figure 17–18. The sulcus limitans in the mesencephalon separates the tectum from the tegmentum. The area of the oculomotor nucleus Figure 17–17. The neurohypophysis and the adenohypophysis are belongs to M2 (future inferior collicular region). Rhombomeres can in close apposition, as they are from the beginning of their develop- still be recognized by ventricular grooves. Thinnings appear in the ment, although this is frequently not appreciated. The primordium wall of the otic vesicle; the thicker areas represent the future semi- of the tentorium is attached at the surface of the adenohypophysis. circular ducts. P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI 129

A Figure 17–19. The primordial plexiform layer. (A) The earliest afferent (probably p catecholamine) fibers in the human embryo can be detected in the primordial plexiform layer of the future temporal cortex at 6 weeks (stage 17). This is the cortex overlying the primordium of the amygdaloid region. Catecholamine fibers may perhaps participate in early synaptogenesis in the subplate of the human embryo (Larroche, i 1981). Axodendritic and axosomatic synapses have been found in the cerebral hemispheres before the appearance of the cortical plate (Choi, 1988). Abbreviations: v, ventricular layer; i, intermediate layer; p, primordial plexiform layer with large neurons. Bar: 20 μm. (B) Epon section (1 μm) of the telencephalic wall of an unstaged human embryo of 6 weeks. The primordial plexiform layer contains scattered Cajal–Retzius cells. The pia mater is visible at the top of the v photomicrograph. ×128. (C) Higher-power view of the primordial plexiform layer showing Cajal–Retzius (CR) cells. A glial barrier (the glia limitans, GL) is formed by cell processes at the pial (PM) surface. The glial barrier and the basement membrane are thought to be critical to the migration and final positioning of the neurons and to the differentiation of the laminar cortical pattern BCwithin the developing neopallium (Choi, 1994). ×697. (D) Another higher-power view PM showing Cajal–Retzius cells with ovoid GL nuclei, prominent nucleoli, and abundant p cytoplasm. A mitotic figure is evident in the C. R. Cells lower left-hand corner. ×697. B, C, and D are reproduced by courtesy of Ben H. Choi, M.D., MZ Ph.D., University of California, Irvine.

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130 Chapter 17: THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI

Figure 17–20. Median reconstructions at A (A) stage 15, (B) stage 16, and (C) stage 17. A′ The now small opening to the optic ventricle is indicated in solid black. The solid horizontal line in A refers to a section that would include all ﬁve longitudinal zones of D2 (Table 18–1). Asterisks in A-C denote the sulcus medius. A-C are key drawings to show the limits of the neuromeres; Dl and Ml are stippled. Tracts shown by interrupted Ep. lines are in A the habenulo-interpeducular tract, in B the tract of the posterior commissure, in C from top to bottom the tract of the posterior commissure, the habenulo-interpeduncular tract, and the tract of the zona limitans intrathalamica. y, commissure of the superior colliculi; z, posterior commissure sensu stricto. Bars: A, 0.2 mm; B, 0.22 mm; C, 0.4 mm. From Muller ¨ and O’Rahilly (1997b, Cells Thalamus (dorsal & ventral) Tissues Organs) by permission of S. Karger Medial eminence AG, Basel. Lateral eminence

B′

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THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI 131

A M2

Syn.

Zona limitans Lateral intrathalamica ventricle

Hippocampus

CB A C

V3 Optic stalk

V3 Olfactory bulb

Olf. n.

Figure 17–21. Important neuromeres in lateral to medial sagittal sections (cf. Fig. 17–20). The blood vessels, which appear here in white, penetrate the ventricular layer. (A) The cavities of the synencephalon and of the two mesencephalic neuromeres are visible. (B) and (C) More medially, the third ventricle (V3) and its connections to the optic stalk and to the lateral ventricle become evident. P1: JYS JWDD017-17 JWDD017-ORahilly June 13, 2006 13:20 Char Count= 0

132 Chapter 17: THE FUTURE OLFACTORY BULBS AND THE FIRST AMYGDALOID NUCLEI

NEUROTERATOLOGY later than that of the Arnold–Chiari malformation, perhaps 6 to 8 weeks. Dandy–Walker Syndrome. This ill-understood com- Diagnostic studies and clinical experiences can be plex includes dysgenesis of the vermis, cystic dilatation of found in a treatise by Raimondi et al. (1984). the fourth ventricle, a high tentorium, and hydrocephaly. It Dysgenesis of the Optic Nerve. The optic nerves is different from the Arnold–Chiari malformation (Gardner are elaborations of the optic stalks and their persistence et al., 1975). Lack of patency of one or more of the apertures depends on the ingrowth of optic nerve ﬁbers. In the in the roof of the fourth ventricle is frequent. A number absence of such an ingrowth (e.g., because of premature of features are probably secondary rather than primary. closure of the ﬁssure in the stalk), the optic nerve does not Maldevelopment of the ventricular roof (the rostral mem- develop. branous area) is believed to be an important factor in the Neuronal Ectopia. Disruption of the pia–glial barrier development of the abnormality. The time of origin of the may lead to the migration of neurons and glial cells into condition is probably in the embryonic period proper, likely the subarachnoid space (Choi, 1987). P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

CHAPTER18 STAGE 18: THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES, AND THE DENTATE NUCLEUS

Approximately 13–17 mm in Greatest Length; Approximately 42 Postfertilizational Days

he head is now more compact and the cerebral do not yet enter the chiasmatic plate. The red nucleus hemispheres are slightly flattened in the future is present and the substantia nigra is beginning to de- Tinsular region. The olfactory bulb and tubercle are sepa- velop. The external cerebellar swellings represent the floc- rated by a sulcus. The C-shaped hippocampus, accompa- culi. The internal cerebellar swellings contain the den- nied by the area dentata, reaches the olfactory region. The tate nuclei. The inferior cerebellar peduncles reach the lateral ventricular eminence of the future corpus striatum region of these nuclei. The primary sensory nuclei of the (Fig. 19–6) is distinct. Four amygdaloid nuclei are present rhombencephalon are now present. Choroid plexuses de- in the region of the medial ventricular eminence, so that velop in the lateral as well as in the fourth ventricle, so that the archistriatum is now identifiable. The interventricu- the production of cerebrospinal fluid sensu strico can now lar foramina are relatively narrower. The prosencephalic begin. The vomeronasal organ, nerve, and ganglion have septum is recognizable. Optic fibers form, although they appeared. At least two semicircular ducts are isolated.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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134 Chapter 18: THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES

Di.

Figure 18–1. Right lateral view of the brain. The cerebral hemispheres are slightly flattened in the area overlying the corpus striatum, i.e., in the future insular region. Frontal and temporal poles are indicated in the key by α and γ , respectively. The optic cups are assuming a more ventral position. The pontine flexure is deep, in association with shortening of the head. The bilateral cerebellar swellings (ausserer¨ Kleinhirnwulst of Hochstetter, 1929) represent the flocculi, which are delineated by the posterolateral fissure. The rhombic lip is part of the external cerebellar swelling and is characterized by “nonsurface mitotic” figures, which are found also in the otic region, where the rhombic lip seems to participate in the formation of the cochlear nuclei. The ventral outpocketing of the isthmus was named Isthmushöcker and Tuberculum interpedunculare (dagger) by Hochstetter (1919). It is identified also in the key to Figure 17–2. It serves as an important landmark for the localization of the interpeduncular nucleus, because dopaminergic cells develop rostral to this ventral projection. The semicircular ducts are becoming isolated one from another, and at least two are distinct, which is typical for this stage. The main events in the development of the ear have been summarized elsewhere (O’Rahilly, 1983b). The inset includes an end-on view showing the cerebellar plate, mesencephalon, epiphysis cerebri, diencephalon, and cerebral hemispheres. The cerebellar plate is still slightly wider than the combined cerebral hemispheres. The posterolateral or dorsolateral fissure (Larsell, 1947) or sulcus transitorius (Hochstetter, 1929) is marking off the rhombencephalic lip, including the anlage of the flocculus (Larsell, 1947), whereas according to Hochstetter this area represents the external cerebellar swelling and is more than the primordium of the flocculus. Comparison between Hochstetter’s figures and the reconstructions of the present authors would suggest that only the most lateral part of the external cerebellar bulge is the primodium of the flocculus, and that it probably corresponds to the Randstreifen, which gives rise also to the nodule and to the inferior medullary velum. P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

a (a) Sulcus limitans (b) Hypothalamic sulcus b (c) Marginal ridge

Figure 18–2. Graphic reconstruction prepared from transverse sections to show a median view of the brain. The asterisk indicates the junction with the spinal cord. The olfactory bulb is separated from the olfactory tubercle by a groove, the sulcus circularis rhinencephali (Fig. 18–9). The bulb shows a recess, and the olfactory ventricle is forming. In the inset, the medial wall of the left hemisphere is shown as if transparent, so that the C-shaped hippocampus can be seen to reach the olfactory region. It is accompanied by a small rim of area dentata, adjacent to which the area epithelialis is visible. In the future corpus striatum, a groove (the “intereminential” sulcus) separates the medial from the lateral ventricular eminence. The interventricular foramina become relatively narrower, chiefly because of the enormous growth of the medial ventricular eminence. Each foramen is bounded rostroventrally by the commissural plate and the medial ventricular eminence (Fig. 19–6), and dorsocaudally by the ventral thalamus. The medial eminence continues to invade telencephalic territory, as seen rostral to the interrupted line that extends from the preoptic recess to the velum transversum. The prosencephalic (forebrain) septum is the area between the embryonic lamina terminalis and the olfactory bulb. It can be regarded as a junctional region where hippocampal, amygdaloid, and olfactory germinal matrices meet. What has been termed the septum verum (Andy and Stephan, 1968) is the basal part of the medial walls of the hemispheres. Hence it is formed when the hemispheres expand beyond the lamina terminalis, beginning at stage 17. The fibers of the supraoptic commissure, which are fine and pale, can readily be distinguished from the optic fibers, which appear coarse and black. Although optic fibers are present in about half the embryos of stage 18, they do not yet enter the chiasmatic plate. The adenohypophysial pouch is now closed off from the pharynx, with which it is connected by a solid epithelial cord. The caudodorsal part of the midbrain is wide, presaging the appearance of a cul-de-sac (hinterer Mittelhirnblindsack of Turkewitsch, 1935). The midventral proliferative area participates in the formation of the red nucleus and the substantia nigra. The latter has been stated to develop in the monkey at a time that would correspond to human stages 18–21. The internal cerebellar swelling of Rh.1 is more prominent than the tegmentum. It contains the dentate nucleus (reconstructed by O’Rahilly et al. 1988), the site of which is shown here by an interrupted line. Choroid folds are present bilaterally in the fourth ventricle of nearly half of the embryos, and their villi present cylindrical cells characterized by protrusions into the ventricular cavity. A photomicrograph of a median section has been published (Muller ¨ and O’Rahilly, 1990a, Fig. 1B).

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136 Chapter 18: THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES

Stage 12

17 14

15 18

Figure 18–3. Right lateral views of the brain from stage 12 to stage 18 showing the mesencephalic ﬂexure and the form of the mesencephalon. P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

C A

Figure 18–4. The cerebral hemispheres and relationships between the diencephalon and the telencephalon. The di-telencephalic border (arrowheads) is shown in (A)–(C). The orientation of the four views is summarized in the inset drawing. (A) Ventral view showing olfactory and optic areas. The adenohypophysis, neurohypophysis, nasal sacs, and medial and lateral ventricular eminences (interrupted lines) are projected onto the ventral surface, and the chiasmatic plate is marked. The supraoptic commissure is formed by ﬁbers of the preoptico-hypothalamic tract (dagger). (B) Dorsal view. Newly arisen nuclei in the dorsal thalamus are marked by asterisks. Medial and lateral ventricular eminences are indicated by interrupted lines. (C) Frontoventral view showing the relationship between the olfactory and amygdaloid areas. (This view is foreshortened in comparison with A because of its different angle of projection.) (D) Lateral view of the future temporal pole with the projected amygdaloid nuclei (hatched) of the right cerebral hemisphere.

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138 Chapter 18: THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES

Lat. em. C

Med. em.

Figure 18–5. The future amygdaloid complex indicates the developing temporal pole. Three blocks through the ventricular eminences are presented, as shown in the key (D). The di-telencephalic sulcus is marked by a long black arrow. The small arrow points to the hypothalamic sulcus. (A) The lateral ventricular eminence, which is visible adjacent to the roof of the interventricular foramen. (B) Four amygdaloid nuclei, which are arising almost entirely from the medial ventricular eminence. The nuclei present at this stage are (1) cortical, (2) medial, (3) anterior, and (4) basolateral. The medial ventricular eminences are clearly visible. Humphrey’s (1968) claim that the human amygdaloid complex is derived exclusively from the telencephalon is incorrect (Muller ¨ and O’Rahilly, 1989b, 2006). The lateral and particularly the medial eminence at stages 18–20 contain large cavities that were observed by earlier investigators. (C) The basal part of the cerebral hemispheres, showing the ventral thalami. The optic stalk enters at the rostral part of the chiasmatic plate. (D) The right cerebral hemisphere and the ventricular eminences are projected onto a median section. The medial eminence indicates the site of the future temporal pole. P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES 139

Figure 18–6. The di-telencephalic transition showing the zona limitans intrathalamica, ventral thalamus, subthalamus, and hypothalamus. Two amygdaloid nuclei (the medial, No. 2, and the basolateral, No. 4) are identifiable. The five subdivisions of the diencephalon (Table 18–1) are based on the comportment of their matrix zones, as elucidated by Kahle (1956), adopted by Richter (1965), and confirmed by Muller ¨ and O’Rahilly (1988c). The subdivision of dorsal and ventral thalami used by 2 Bartelmez and Dekaban (1962) and Kuhlenbeck (1978) is similar, although based on different grounds. The dorsal and ventral thalami are separated by the sulcus medius, 4 which is adjacent to the marginal ridge that overlies the zona limitans intrathalamica. This last is the precursor of the lamina medullaris externa. Hochstetter (1919) marked the marginal ridge by “Leiste” and generally by an asterisk. His S.M. (Sulcus Monroi, hypothalamic sulcus) has been incorrectly taken by many writers to be the sulcus medius.

In Figures 18–6 to 18–13 the bars represent 0.2 mm.

Figure 18–7. A section from the same embryo to show the interventricular foramen, the medial ventricular eminence, and the amygdaloid area. The lateral prosencephalic (forebrain) bundle is indicated by an arrowhead. The optic stalk and a portion of the eye are visible below. The ventricular eminences show a distinct subventricular layer. In addition to their separation by the sulcus medius, the ventral thalamus is distinguishable by its possession of a distinct intermediate layer, whereas the dorsal thalamus has only ventricular and marginal layers. Intramural capillaries penetrate the ventricular layers, but the vessels in the subarachnoid space are not yet distinguishable histologically as arteries and veins. P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

140 Chapter 18: THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES

Plexus fold Paraphysis

Figure 18–8. The rostral area showing the lateral ventricular emi- Figure 18–9. The olfactory bulbs, separated from the septal area nences, the paraphysis in the roof between the hemispheres, and be- by the sulcus circularis (arrowhead). The longitudinal fissure, filled ginning vacuoles in the subdural space. The roof of the telencephalon with mesenchyme, can be seen between the hemispheres below. medium and the lamina epithelialis of the lateral ventricle form a choroid fold that is lined by a relatively thick epithelial layer of four to five nuclear rows. The nasal sacs are evident, as well as related mesenchymal condensations, especially that of the nasal septum. The neocortical differentiation of an embryo of stage 18 was illustrated by Mar´ın-Padilla (1983, 1988a).

Olf. bulb

Olf. n.

Figure 18–10. The prosencephalic septum and the olfactory tuber- Figure 18–11. The cerebral hemispheres and the olfactory nerves. cles. The arrowheads point to cellular islands. The light area marked The arrowhead points to the intermediate layer along the lateral ven- by an asterisk is the olfactory nerve. tricular eminence, the primordium of the future caudate nucleus. The dark cells between the olfactory bulbs and the nasal sacs (visible also in Figs. 18–12 and 18–13) are neural crest and ganglionic cells. The olfactory bulb and nerve are indicated. P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES 141

Figure 18–12. The caudal part of the nasal sacs. The oronasal membrane (arrowhead) has almost regressed on the other side. Figure 18–13. The vomeronasal ganglion (v-n), the nerve ﬁbers of which begin in the wall of the vomeronasal organ, which appears bilaterally as an epithelial pocket in the nasal septum. Further details: M¨uller and O’Rahilly (2004c). The organ continues to enlarge during prenatal life, and measurements have been published (Smith et al., 1997). Its involution postnatally has been queried.

18 Ð 9

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142 Chapter 18: THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES

Figure 18–14. The epiphysis cerebri. A transverse section to show that the epiphysis now appears as a dorsal evagination of the synencephalon. One so-called follicle is visible. The adjacent part of the diencephalic roof is a portion of the habenular region. The epiphysis is now at Stadium III of Turkewitsch (1933). See Figure 19–16(III). ×214. P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES 143

Fig. 18 Ð 14

3rd ventricle N.-H.

Chiasma

e a ll u d A.-H. e m Basilar a. m u t p th Not. e 4 S vent.

Figure 18–15. The hypophysis cerebri. A sagittal section. The adenohypophysis and the neurohypophysis are in close apposition; mesenchyme has not yet inﬁltrated between them. In contrast, vascular mesenchyme has penetrated between the adenohypophysis and the hypothalamic ﬂoor. The folded wall of the neurohypophysis seems to be characteristic at this time. Various extensions of the lumen of the adenohypophysial pouch have been described (Conklin, 1968). P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

144 Chapter 18: THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES

AB Figure 18–16. The cerebellar plate at stage M 18. (A) Medial view of the right half of the brain, indicating the right part of the cerebellar plate 4 Int. shown in B. (B) Medial view, as seen from the cerebellar ventricular cavity, to show the internal swelling cerebellar swelling. The cerebellar primordium Alar is formed not only by rhombomere 1 but also by lamina a part of the isthmus. (C) Left lateral view of the Basal brain, indicating the portion shown lamina in D. (D) Left lateral view to show the external cerebellar swelling. Cranial nerve 8 is in close C D proximity and vestibular fibers from it already reach the flocculus. (E) A block of tissue shown Postero- in F and G has been removed from D. (F) The lateral posterolateral fissure delimits the rhombic lip fissure and the primordium of the flocculus from the remainder of the alar lamina. The fibers to and from the cerebellum are arranged in two strata, internal and external; the latter is the marginal layer. The fibers to the primordium of the F flocculus are mostly vestibulocerebellar (shown Int. fibers by small black arrows at the level of the external cerebellar swelling). (G) To clarify the two Sulcus sources of the cells that build up the cerebellum: limitans (1) radially migrating cells produced by the ventricular layer, and (2) tangentially migrating cells from the rhombic lip. The two streams intermigle. The open (white) arrow marks the direction of the afferent fibers to the cerebellum. Ext. fibers Posterolat. fissure

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THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES 145

int.

ext.

18 Ð 17

Figure 18–17. Transverse sections through the cerebellum. (A) A laterally situated band of cells that represents the region of the future flocculus. The internal cerebellar swelling (int.) faces the fourth ventricle. (B) The transitional region between the internal (above) and external (below) cerebellar swellings (ext.). Two streams of cellular migration can be recognized and are indicated by arrows in the upper inset drawing: (1) radially oriented cells produced in the ventricular layer form the main cellular mass, and (2) tangentially oriented cells produced by the rhombic lip form a peripheral band. A layer of nerve fibers is present internal to that band, and another external to it. Tracts present at stage 18 include the stria medullaris thalami, mamillothalamic tract, medial and lateral tectobulbar, dentatorubral, and the tractus solitarius. The inferior cerebellar peduncles have been reconstructed (O’Rahilly et al., 1988). They contain vestibulocerebellar and trigeminocerebellar fibers, and they reach the region of the dentate nuclei (Fig. 18–3). Collateral vestibular fibers run to the flocculus. The tracts mentioned will be illustrated with the next stage. P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

146 Chapter 18: THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES

Radial A Tangential Sulcus limitans Mixed 4th ventricle

2 2 3 Rhombic lip

1 Somatomotor nucleus Sensory nuclei

Corpus 4th ventricle Rhombic Raphe lip Sulcus limitans

External germinal B layer

Purkinje

Sulcus C limitans B Future aqueduct Ventral tegmental Tegmentum area Interpeduncular nucleus A Fibers Interpeduncular fossa

Figure 18–18. The sites of production and the migration of neurons in (A) the rhombencephalon, (B) the cerebellum, and (C) the mesencephalon. (A) Block from the hindbrain showing migration from the ﬂoor plate to the raphe (1), from the ventricular layer for the motor and sensory (e.g., vestibular) nuclei (2), and from the rhombic lip, (e.g., for the cochlear nuclei (3)). The sensory areas are lateral to the sulcus limitans. (B) Cerebellar migration from both the ventricular layer and the rhombic lip for the primordium of the dentate nucleus (stage 21). Cells from the ventricular layer give rise also to the piriform (Purkinje) cells, and those from the rhombic lip form the external germinal (or external granular) layer (stage 23). (C) Migration in the mesencephalic tegmentum from the ventricular layer, producing ﬁrst the interpeduncular nucleus and later the ventral tegmental area. (D) The plane of the sections. P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES 147

Sup. salivatory nucleus

Red 8v 3 nucleus AE7i 7m

Interpeduncular nucleus Vestibular nuclear zone 6 Intermediate layer 7 BF

4 Dorsal & ventral cochlear nuclei

12 M.I.f. 9s C Mes. 9m tr. 5 Nucleus Visceral ambiguus 5s efferent Tractus solitarius 5s 5m L.I.f. H

D 12 10s 10m 5m

5s Nucleus ambiguus

Figure 18–19. The nuclei of the cranial nerves. The visceral efferent, ventromedial cell column and the nuclei derived from it are in mauve. The somatic efferent nuclei and the reticular formation are in orange. The afferent nuclei are in blue. Comments on the original site of the nuclei and their migration were included in the legend of Figure 14–9. (A) The oculomotor nucleus lies lateral to the midventral proliferative area and the interpeduncular nucleus. The material of the interpeduncular nucleus has been identifiable since stage 15. (B) The trochlear nucleus in the isthmus has a more medial position than the oculomotor nucleus. (C) and (D) The trigeminal area is continuous with the cerebellar plate. An afferent trigeminal nucleus has appeared. (E) The dorsal nucleus of the trapezoid body or superior olivary nucleus (dagger) is lateral to the reticular formation. The medial cell column for the facial nerve is still voluminous. Only a few fibers of the genu cross the rostral part of the abducent nucleus. (F) Fibers of the cochlear nerve with the basal and dorsal cochlear nuclei. Also recognizable is the vestibular zone with fibers to the medial longitudinal fasciculus. The nuclei of the abducent (6) and (in G and H) hypoglossal (12) nerves are in a similar position, but are not continuous. (G) The glossopharyngeal nerve with its motor and sensory components, and the cell mass derived from the rhombic lip. (H) The nucleus ambiguus of the vagus. Abbreviations: m and s (after the numeral of a cranial nerve) motor and sensory components, respectively. The levels of A to H are indicated in the key drawing on page 148. P1: JYS JWDD017-18 JWDD017-ORahilly June 13, 2006 13:23 Char Count= 0

148 Chapter 18: THE FUTURE CORPUS STRIATUM, THE INFERIOR CEREBELLAR PEDUNCLES

Sulcus limitans

Somatic & visceral afferent Visceral efferent Somatic efferent

H G

E, F C D B

Figure 18–19. (Continued )

TABLE 18–1. Longitudinal Zones of the Diencephalon

Zone Fig.a Sulcus

Di-telencephalic sulcus 1. Epithalamus 2. Dorsal thalamus 16–7E 17–15 18–6 Thalamus 17–16 Sulcus medius, marginal ridge, 18–6 zona limitans intrathalamica 18–7 3. Ventral thalamus 16–7E 18–6 Hypothalamic sulcus 4. Subthalamus 18–6 Faint, unnamed sulcus Hypothalamus sensu lato 5. Hypothalamus sensu stricto 18–6

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CHAPTER19 STAGE 19: THE CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS

Approximately 16–18 mm in Greatest Length; Approximately 44 Postfertilizational Days

aution needs to be exercised in assigning an beginning to form. Electrical activity can be detected in embryo to stages 19–23, and details of inter- the brain stem at about stages 18 and 19 (Borkowski and Cnal structure are particularly important here. The embryo Bernstine, 1955). Three semicircular ducts are isolated. (which is human since the time of fertilization) now has a The basicranium comprises occipital and sphenoidal parts. recognizably human face (Padget, 1957). The olfactory nerve, bulb, and tubercle are well- Precision developed. The nucleus accumbens appears. The cerebral hemispheres have grown rostrally, so that the prosen- Basal nuclei is the correct term, not basal ganglia, be- cephalic septum has become larger. A paraphysis may be cause, by definition, ganglia are found only in the pe- present and is telencephalic. Optic fibers arrive in the chi- ripheral nervous system. asmatic plate. The globus pallidus externus has developed in the diencephalon. The dorsal and ventral thalami are demarcated by the marginal ridge, and the dorsal thalamus shows an intermediate layer. The habenular region Important and its connections are well formed. Many bundles are The isthmus contains the trochlear decussation and its identifiable, including the thalamostriatal and the stria alar lamina contributes to the cerebellum and the ros- medullaris thalami. The fourth ventricle possesses lat- tral medullary velum. Its site in the adult is indicated eral recesses and a choroid fold. Cerebellar connections by the trochlear nerves. are increasing. The medial accessory olivary nucleus is

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150 Chapter 19: CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS

Figure 19–1. An embryo of stage 19 surrounded by the intact amnion (limiting the amniotic cavity) and the bisected leafy mass of the chorion (limiting the extra-embryonic coelom). The fourth ventricle is clearly visible “behind” the cerebellar plate. The umbilical vesicle appears as a small sphere at the lower right-hand corner. Villous stems are visible in the future chorion frondosum. Photography by Mr. Chester F. Reather. P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS 151

Figure 19–2. A lateral view of the brain. An occipital pole (β in the key drawing) can be clearly identified for the first time. The olfactory bulb and tubercle are visible. All cranial nerves are present, although the V4 well-developed olfactory nerve (Figs. 19–12 and 19–14) Int. & ext. is not shown here. The roof of the fourth ventricle is cerebellum indicated by an interrupted line. The cerebellar plate is “vertical” and at almost a right angle to the longitudinal axis of the rest of the rhombencephalon. The inset (end-on view) demonstrates that the cerebellar plates are still wide and that their width equals that of the cerebral hemispheres. It is of interest to mention that the insular region was identified by Rager (1972, Fig. 7) in an intact embryo of 17 mm. Partly from a drawing by Mary M. Cope (Gilbert, 1957). 12 5 9

11 10

Di.

g b

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152 Chapter 19: CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS

a (a) Sulcus limitans (b) Hypothalamic sulcus b (c) Marginal ridge

Figure 19–3. Graphic reconstruction prepared from transverse sections to show a median view of the brain. The asterisk indicates the junction with the spinal cord. Clearly the cerebral hemispheres have grown rostrally, and hence the prosencephalic septum (inset) has increased in size. The nuclei in the septum will be discussed with the next stage. The interventricular foramen is narrow and is bounded mainly by the ventral thalamus (dorsally), the medial ventricular eminence (ventrally), and the hippocampal region (rostrally). Some embryos possess a paraphysis, which opens into the telencephalic part of the third ventricle. The choroid plexus becomes visible by ultrasonography in vivo at 7 postovulatory (9 postmenstrual) weeks. P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS 153

Figure 19–4. Median section of the brain and the related cartilaginous skeleton. The chiasmatic and commissural plates are important landmarks. The choroid fold of the fourth ventricle is evident, and the subdural mesenchyme is a fluid-filled meshwork. Among the injected arteries, the basilar is especially well visible. Fine vessels can be seen in the area of the future falx cerebri. The dorsal funiculus appears as a thick bundle in the spinal cord. The median raphe (His, 1890), known as the septum medullae rhombencephali, consists of sagittally arranged fibers derived from the embryonic floor plate and representing the adult floor plate (Sidman and Rakic, 1982). In the photomicrograph, it is clearly visible above the basilar artery. The basicranium (reconstructed by O’Rahilly and Muller, ¨ 1984b) now consists of an occipital part (developed from sclerotomes 1–4) and a sphenoidal part, which has grown rostrally to reach the adenohypophysis. Although not visible here, the orbital wing of the sphenoid (mainly the postoptic root) is forming.

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Figure 19–3. (Continued ) The di-telencephalic borderline is indicated by an interrupted line between the velum transversum and the preoptic sulcus. The first optic fibers arrive in the chiasmatic plate but do not yet cross to the opposite side. The commissure shown is formed by supraoptic fibers. The epiphysis cerebri is adjacent to the posterior commissure and contains several follicles. At stages 19–21 it corresponds in general to Stadium IV of Turkewitsch (1933), as pointed out by O’Rahilly (1968). The globus pallidus externus has developed in the subthalamus. The dorsal and ventral thalami are well-separated from each other by the marginal ridge associated with the sulcus medius at the ventricular side and with the zona limitans intrathalamica (Fig. 18–6). The dorsal thalamus possesses an intermediate layer. The epithalamus is well-delimited, and its habenular nucleus (Fig. 19–13) has sent fibers (the habenulo-interpeduncular tract) to the midbrain since stage 17. The fibers arriving in the habenular area constitute the stria medullaris thalami, and arise mostly in the nucleus ovalis of the diencephalon (Figs. 19–9 and 19–23). Medial and lateral ventricular eminences, seen partly by transparency, are shown in the inset. The isthmic groove between the mesencephalon and the cerebellum is indicated by a short arrow. The lateral recess and choroid fold of the fourth ventricle are shown. The floor of the rhombencephalon is thickened, and this will become more pronounced with the addition of further fibers in subsequent stages. The medial accessory olivary nucleus (Fig. 19–4) is beginning to form in between the roots of the hypoglossal nerve, and its site is indicated schematically by a projection onto the median plane. The lemniscal decussation is visible. The characteristic hairpin bend of the mesencephalic flexure is formed by the metencephalon and the diencephalon, and indicates the site of the future pontine and interpeduncular cisterns of the subarachnoid space. The apex of the flexure marks the exit of the oculomotor nerves. The pontine flexure is eliminated later, so that the medulla and pons are in a straight line postnatally. P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

154 Chapter 19: CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS

Figure 19–5. Section through the neural tube, clariﬁed in the key below the photomicrograph. The three zones of the neural tube are identiﬁed. A spinal ganglion is visible at the left (medial to the neural arch). The key at the left shows the formation of a spinal nerve. An atlas of the developing spinal cord is available (Bayer and Altman, 2003).

Ventricular Intermediate Marginal

Spinal ganglion Dorsal A root Dura Ventral Sulcus root limitans Dorsal Neural B ramus arch

Spinal n. Ventral Dura ramus Sympathetic ganglion

Ramus Notochord communicans

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CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS 155

Figure 19–6. Scheme of the basal nuclei showing the development of their diencephalic and telencephalic components. Stages of appearance are also included. Late in the embryonic period, the amygdaloid complex as well as the globus pallidus externus will occupy telencephalic territory. Whether the amygdaloid complex and the claustrum should be included with the other basal nuclei is doubtful. The basal nuclei are best deﬁned as the basal structures affected pathologically in so-called extrapyramidal motor diseases. P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

Figure 19–7. Reconstruction of the developing basal nuclei (transitional between stages 18 and 19). (A) Medial view of the right half of the forebrain, in which the medial wall of the right cerebral hemisphere is shown as if transparent. The region of the amygdaloid nuclei is projected as an oval. (B) Dorsal view of the cerebral hemispheres, with the right hemisphere opened to illustrate its basal aspect from the interior. The medial ventricular eminence has almost completely invaded telencephalic territory (cf. Fig. 19–3). The lateral eminence represents the main primordium of the future corpus striatum (Fig. 19–6). From O’Rahilly, Muller, ¨ Hutchins, and Moore (1988). The medial ventricular eminence has been found in the rat to resemble the globus pallidus histochemically far more than it does the lateral eminence, and it is connected to the dopamine pathway that leads from the ventral tegmental region of the midbrain to the forebrain. The nucleus accumbens develops as a separate entity far earlier than in rodents, and projects as a thickening into the ventricular cavity. It was shown by Hewitt (1958, Fig. 3) in an early human fetus, where it appeared as the elevation known as the “paraterminal body.” It is regarded by various authors as a ventromedial extension of the caudato-putamen complex. Its superﬁcial component includes the nucleus of the diagonal band (Kuhlenbeck, 1973). The nucleus accumbens has been shown in the human to contain dopamine, and it resembles the caudato-putamen complex in its histochemical development (Brana et al., 1995).

TABLE 19–1. Comparison of Medial and Lateral Ventricular Eminences

Medial Ventricular Eminence Lateral Ventricular Eminence (Archistriatum) (Neostriatum)

Medial eminence of diencephalic origin gives rise to most of Neocortical GABA-expressing interneurons are believed to the early amygdaloid nuclei (medial, anterior, basolateral, be derived (in the mouse) from the lateral eminence and part of lateral) Lateral eminence invaded by the cortical nucleus of the amygdaloid body in and after stage 19. Medial eminence with scant striatum-like tissue. Neurochem- Lateral eminence characterized by striatum-like tissue, which ical resemblance to globus pallidus is acetylcholinesterase-positive and dopamine-receptive Short proliferative phase Long proliferative phase

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Thal. d. Figures 19–8 to 19–10 show neocortical areas and choroid plexuses. The bars represent 0.1 mm. The inset drawings on this page show Thal. v the amygdaloid nuclei.

Figure 19–8. Sagittal section showing cerebral hemisphere, choroid plexus (rectangle), medial prosencephalic (forebrain) bundle (arrowhead), and dorsal and ventral thalami. Connections between the amygdaloid nuclei in the medial eminence and the diencephalon belong mostly to the medial Medial prosencephalic bundle, which is the main Medial Anterior amygdaloid pathway for longitudinal connections in forebrain Baso- nuclei the hypothalamus (Fig. 19–23). The bundle lateral lateral ventricle is invaded by the choroid Diagonal fold, which, thicker than that of the (septal fourth ventricle, consists of a nucleus) multilayered epithelium and a mesenchymal core with thin-walled blood vessels.

Thal. d.

Med. em.

Olf. bulb & tub.

Figure 19–9. Another section, to show the olfactory bulb and tubercle, and the medial ventricular eminence. The stria medullaris thalami (arrowhead at right) arises in the diencephalon from the nucleus taeniae or ovalis (Fig. 19–22), although minor contributions come from the lateral prosencephalic bundle. The choroid ﬁssure is visible (arrowhead at left).

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158 Chapter 19: CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS

Figure 19–10. Still another section, to show the medial ventricular eminence and the ventral thalamus. Preoptico-hypothalamic (lower Thal. v arrowhead) and mamillotegmental (upper arrowhead) tracts are identiﬁable.

Med. em.

Figure 19–11. Transverse section through part of one of the nasal sacs. The (blue) basement membrane is interrupted where emigrating crest cells leave the nasal epithelium. P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS 159

A Figure 19–12. Olfactory and vomeronasal nerves Olfactory bulb in lateral to medial silver-impregnated sagittal sections. (A) The olfactory ﬁbers accompanied by olfactory ensheathing cells enter the olfactory bulb and form the external ﬁbrous layer of the bulb. At the “pole” the intermediate layer of the bulb consists of only one lamina of tangentially arranged cells. (B) The vomeronasal nerve enters the olfactory bulb above the olfactory nerve (which differs in rodents). The area between the olfactory bulb and the medial ventricular eminence is the Ventricular forebrain septum. From Muller ¨ and O’Rahilly (2004c, Cells Tissues Organs) by permission of S. Karger AG, Basel.

"Pole" Intermediate

Olf. n.

B Med. eminence O l f a c t.

b u l b

V.n.n.

Olf. n.

Stria medullaris thalami

Habenulo-interpeduncular tract Lateral habenular nucleus Figure 19–13. The lateral habenular nucleus in a sagittal section, an example of a far-advanced epithalamic area. The arriving ﬁbers are of the stria medullaris thalami, the leaving ﬁbers form the habenulo-interpeduncular tract (Fig. 19–23). P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

160 Chapter 19: CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS

Olf. ventricle

N. M terminalis

×4

Isthmic nucleus

Figure 19–14. Relationships of olfactory tubercle and bulb, showing the entry of the nervus terminalis into the olfactory tubercle, and of the olfactory nerve fibers into the olfactory bulb. The olfactory ventricle is evident. Both tubercle and bulb possess an intermediate layer, and multiple nerve fibers are present in the tubercle. The sulcus circularis is marked by an arrowhead. The neural crest of earlier stages had developed into vomeronasal and terminal ganglia, but only after a certain degree of development of the central structures (tubercle and bulb). Both ganglia are medial, but the terminalis is more rostral, although its nerve fibers enter the brain caudal to the sulcus circularis. The ganglion of the nervus terminalis, although not yet found in the previous stage, is almost constantly present in stage 19. The fibers of the nervus terminalis appear later than the ganglion, as described Figure 19–15. The isthmic nucleus and the commissure of the in a fetus of 38 mm by Pearson (1941). trochlear nerves. The level of this coronal section is shown in the key drawing. The bilateral isthmic nuclei are ventrolateral and rostral to the trochlear decussation (X4). Details have been provided by O’Rahilly et al. (1988). P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS 161

Figure 19–16. The development of the epiphysis cerebri. Based on Turkewitsch (1933), whose stadia are given Roman numerals. See Table 17–1. I 0.1 mm

A, Vorderlappen P, Hinterlappen

A Posterior commissure

III A

Habenular commissure

Intermediate P zone

Commissures VI

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162 Chapter 19: CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS

Figure 19–17. A sagittal section to show the epiphysis, which is now a rostrally directed outgrowth of the roof of the synencephalon (Fig. 19–16D). This is the Vorderlappen of Stadium IV of Turkewitsch (1933). It projects towards the left side of the photomicrograph and forms a characteristic “step” (Stufe). Two so-called follicles are visible, as observed also by Hochstetter (1923). The site of the epiphysial evagination is marked by the pineal recess. Bar: 0.05 mm.

Infundibulum Infundibular recess NEUROHYPOPHYSIS

Optic chiasma Median eminence Infundibular stem ADENOHYPOPHYSIS Infundibular process Pars (neural lobe) tuberalis Pars intermedia

Pars distalis

ANTERIOR POSTERIOR

Figure 19–18. The terminology of the hypophysis cerebri based on Rioch et al. (1940). Cf. Table 17–2. P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS 163

A B Infundibular notch

Pars distalis

Solid stem Pharyngeal Pharynx hypophysis

C D 3rd ventricle Chiasma

Basi-

cranium Pharynx Stem

Tongue

E F Pars Pars tuberalis intermedia Basi- cranium

Dorsum Pars sellae distalis

Hypophysial fossa

Pharyngeal hypophysis

Figure 19–19. Development of the hypophysis as seen in median sections. (A), (C), and (D) The adenohypophysial stalk is closed and is embedded in the developing sphenoid cartilage. The attachment of the stalk to the roof of the pharynx constitutes the pharyngeal hypophysis. The wall of the neurohypophysis is characteristically folded. (B) The adenohypophysial pouch seen from in front. (E) At stage 23. The remains of the stalk are shown by an interrupted line. (F) At 60 mm. The greater part of the organ lies in the hypophysial fossa of the (still cartilaginous) sphenoid bone. The (white) cleft represents the cavity of the original adenohypophysial pouch. P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

164 Chapter 19: CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS

Mes. tract of 5

Inf. cerebellar peduncle

Figure 19–20. The area of the pontine flexure with cranial nerves 5, 7, 8, 9, and 10, silver-impregnated. Many tracts are identifiable, e.g., the mesencephalic tract of the trigeminal nerve, the trigeminospinal tract, and the tractus solitarius. Among the cerebellar connections are found the inferior cerebellar peduncle (vestibulocerebellar and trigeminocerebellar fibers) and even components of the superior peduncle (dentatorubral fibers, which pass lateral to the nucleus isthmi). The porus duralis of the trigeminal nerve is visible. The internal carotid artery, sectioned below the trigeminal ganglion, is filled with blood and possesses a thick arterial wall. Bar: 0.2 mm. From Muller ¨ and O’Rahilly (1990a). In monkeys at a comparable stage, cerebellar neuronal production is at a peak. Two migratory waves participate in the formation of the cerebellum: from the rhombic lip, the migrating cells being at the surface, to which their nuclei are parallel; and from the ventricular layer, the cells lying at a right angle to the surface of the cerebellum. The cells of the two migrations become partly mixed, as is true in the dentate nucleus. Parasympathetic ganglia appear in the head between stages 15 and 19 (Wo´zniak and O’Rahilly, 1980). P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS 165

Inferior cerebellar peduncle

6 7 8v 8c

Cochlear nerve 8v 6

Trigeminospinal tract

Figure 19–21. The cochlear nerve and nuclei. The cochlear nerve has a spiral pattern like a rope from stage 19 onwards. It pierces a dense mass of cells (the ventral cochlear nucleus), where it enters the rhombencephalon. Both cochlear nuclei are lateral to the inferior cerebellar peduncle, whereas the vestibular nuclei are medial. An asterisk indicates the tractus solitarius in the key. Bar: 0.1 mm. P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

166 Chapter 19: CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS

Fig. 19Ð24

Figures 19–22 and 19–23. Tracts of the forebrain in a median and a right lateral view, respectively. Some of the nuclei are shown as stippled areas, and superficially situated tracts are also stippled. New tracts in stage 19 include the thalamostriatal tract (Stammbundel ¨ of His or lateral prosencephalic fasciculus), around which the internal capsule continues to develop (but does not yet reach the pallium) (Fig. 19–24), the stria medullaris thalami, the fibers of the zona intrathalamica, and the amygdalo-habenular tract. The tract of the zona limitans intrathalamica later becomes the lamina medullaris externa. The sequence of appearance of the tracts is given in Appendix 4. The fibers of the catecholamine neurons seem to penetrate no further than the ventricular eminences (Zecevic and Verney, 1995). At about this stage it has been found in the rat that septohippocampal projections reach the hippocampus, and that they are preceded by hippocamposeptal projections. P1: FAW/FAW P2: FAW JWDD017-19 JWDD017-ORahilly June 13, 2006 13:25 Char Count= 0

CHOROID PLEXUS OF THE FOURTH VENTRICLE AND THE MEDIAL ACCESSORY OLIVARY NUCLEUS 167

Di. Tel.

Dorsal thalamus Striothalamic fibers Lat. forebrain bundle Med. ventricular eminence Lat. ventricular eminence Hypothalamic sulcus

Figure 19–24. Beginning development of the internal capsule. Thalamostriatal fibers end abruptly in the medial ventricular eminence (cf. Fig. 5 in Richter, 1965), after having changed their direction at the ditelencephalic boundary (hemispheric stalk), where the fibers contribute to the lateral forebrain bundle (Stammbundel ¨ of His, 1904). Corticothalamic fibers appear in stage 21 (Meyer et al., 2000). Their outgrowth (in the mouse) is influenced by Pax 6-positive cells at the corticostriatal boundary. Gene mutations (Pax 6 Sey/sey, Gbxc-2, f.ws.) cause defects of the internal capsule (Table 2 in Molnár and Butler, 2002). The level of this section is indicated in Figure 19–23. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

CHAPTER20 STAGE 20: THE CHOROID PLEXUS OF THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES, AND THE INTERPEDUNCULAR AND SEPTAL NUCLEI

Approximately 18–22 mm in Greatest Length; Approximately 47 Postfertilizational Days

he globus pallidus externus is distinct in the sub- choroid plexuses of the lateral ventricles at stage 20 are at thalamic area. The optic commissure is present, the “club-shaped” phase. Cuneate and gracile decussating Tand crossing fibers begin to form in the future habenu- fibers are present. Histological differences are now appar- lar commissure. The medial septal nucleus and the nu- ent between perimural arteries and veins (although not in cleus of the diagonal band are differentiating, and fiber the intramural vessels until trimester 2). connections with the hippocampus and the medial pros- Catecholaminergic cell groups have been detected at encephalic fasciculus are present. Important fiber connec- as early as 5 weeks in the rhombencephalon and mesen- tions of the olfactory system are now identifiable: from the cephalon, and at 6 weeks in the hypothalamus (Verney olfactory bulb to the olfactory tubercle, to the septal nu- et al., 1991). See also Figure 17–13 and Table 17–3. A band clei, to the amygdaloid nuclei and via the stria medullaris of densely packed cells that corresponds to the primordium thalami to the habenular nuclei; then from there via the of the dopaminergic substantia nigra and ventral tegmen- habenulo-interpeduncular tract to the interpeduncular tal region has been recorded at 7 weeks (Verney et al., 1991). nucleus. Connections exist also from the mesencephalic Nigrostriatal fibers develop at this time and extend initially tegmentum via the medial prosencephalic fasciculus to the to the subventricular zone of the lateral ventricular emi- amygdaloid and septal nuclei and olfactory tubercle. The nence (Freeman et al., 1995).

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170 Chapter 20: THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES

Figure 20–1. Right lateral view of the brain. The frontal, occipital, and temporal poles are indicated (by α, β, γ ). The tuberculum interpedunculare (of Hochstetter), which faces the mamillary region, is particularly evident in this embryo (dagger). The roof of the fourth ventricle leaves a part of the cerebellum free (ausserer¨ Kleinhirnwulst of Hochstetter, 1929). The ventricular cavity between the internal cerebellar swelling and the caudal part of the rhombencephalon has become very narrow. The cranial nerves have been cut short. A mesencephalic Blindsack (the site of the future inferior colliculus) is visible on each side of the mesencephalon and almost touches the cerebellum. In a dorsal view in the left-hand inset, the cerebellar hemispheres are seen to be separated from each other. Dorsally, the left and right halves of the cerebellum are joined only in the area of the rostral (superior) medullary velum. The right-hand inset is an end-on view showing the cerebral hemispheres, part of the diencephalon with the epiphysis, and the mesencephalon. The neocortical development of an embryo belonging to stage 20 was illustrated by Mar´ın-Padilla (1983, 1988a). At this stage the intrinsic vascularization of the neocortex begins. “It evolves from perforating capillaries of the pia-vascular plexus, and progressively advances in ventro–dorso–lateral and antero–posterior [rostrocaudal] gradients, paralleling the differentiation and maturation of the neocortex” (Mar´ın-Padilla, 1988a). The intraneural vascular territories of the cerebral cortex M in the embryo and in the adult are quite similar. Both are characterized by a short-link anastomotic network of intracortical capillaries established between adjacent perforating vessels (Mar´ın-Padilla, 1988b). Certain portions of the primordial plexiform layer are considered to be functionally active in the Di. embryo by this stage (Mar´ın-Padilla and Mar´ın-Padilla, 1982). Is has been found in the cat that corticipetal and some corticofugal ﬁbers are present prior to the appearance of the T cortical plate. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

Cerebellar hemisphere Plexus fold Isthmic groove X4

Lemniscal decussation

Globus pallidus Post. ext. X N.-H. Ep.

Supraoptic X Habenular X Ch.

Comm. Marginal l.-v.f. ridge

Olfactory buld

0.4

(a) Sulcus a limitans (b) Hypothalamic sulcus b (c) Marginal c ridge

Figure 20–2. Graphic reconstruction prepared from coronal sections to show a median view of the brain. The asterisk indicates the junction with the spinal cord. The choroid plexuses of the lateral ventricles at stage 20 are at the “club-shaped” phase described by Shuangshoti and Netsky (1966). In the diencephalon, the position of the marginal ridge no longer corresponds to that of earlier stages. A ventral shift has occurred, whereby the dorsal thalamus has become larger towards the interventricular foramen. The earliest part of the globus pallidus, the globus pallidus externus, appears at the surface of the subthalamus in this and in the previous stage. Subsequently it moves into the hemispheric stalk. The optic chiasma lies rostroventral to the decussating fibers of the preoptico-hypothalamotegmental tract, and these form the supraoptic commissure. In most embryos of this stage, the epiphysis cerebri is immediately rostral to the posterior commissure. The caudal shift is probably caused by a growth gradient. It is likely that the habenular commissure, containing a few fibers, is present in most embryos of this stage. The habenulo- interpeduncular tract is no longer at the surface but runs between the ventricular and intermediate layers of the diencephalon and arrives in the mesencephalon lateral to the interpeduncular nucleus (Fig. 20–12). The commissural fibers of the oculomotor nerves (dagger) are joined by the crossing fibers of the dentatorubral tract. This is the beginning of the decussation of the superior cerebellar peduncles. The basal plate of the rhombencephalon has increased greatly in thickness, especially in its caudal part. The lateral portions of the rhombencephalon are depressed in the region of the pontine flexure and hence are not visible in this view. The cerebellar hemispheres are conspicuous. The villi of the choroid plexus of the fourth ventricle extend from the choroid fold into the wall of the lateral recesses. The septum medullare (median raphe of His, 1890) begins at the isthmic recess. It is derived from the rhombencephalic floor plate and is important in the production of neurotransmitters. Cuneate and gracile decussating fibers are present at the transition from rhombencephalon to spinal cord.

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172 Chapter 20: THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES

Figure 20–3. Sections through the prosencephalon. (A) A portion of the wall of the brain from the rectangle indicated in B. The ventricular layer gives origin to the ventricular ependyma (that lining the ventricle) and to the choroidal ependyma (of the choroid plexus), and the two are continuous with each other. The choroid plexus consists of choroidal ependyma and tela choroidea; the latter is a vascularized pia mater. (B) Transverse section showing that the interventricular foramina are now narrow. The choroid plexus extends into the lateral ventricle on each side, and its line of invagination is the choroid ﬁssure. The ependyma of the plexus is continuous with the medial wall of the lateral ventricle. (C) An enlargement of a portion of the choroid plexus at stage 19 from the rectangle indicated in B. The epithelium is the choroidal ependyma, the layers of which enclose the vascular pia mater known as the tela choroidea. Bar: 0.05 mm. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES 173

Dural limiting layer Pia Hippocampal Primordial primordium plexiform layer Ventricular Area layer epithelialis Choroid plexus

Lat. ventricular eminence Roof Choroid rd of 3 fissure Subventricular ventricle layer

Med. ventricular eminence Lat. forebrain Subarachnoid bundle space

Figure 20–4. An oblique section through one cerebral hemisphere. The third and lateral ventricles are united by the interventricular foramen. The line of invagination of the prominent choroid plexus into the lateral ventricle is the choroid ﬁsssure. Noteworthy is the absence of the corpus callosum, which has not yet developed. The asterisks are placed on artifactual spaces. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

174 Chapter 20: THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES

Figure 20–5. Section through the nasal epithelium, from which crest cells form cords that enter the mesenchyme and proceed towards the basal forebrain.

3 2 4

Figure 20–6. Telencephalic migration. Radial migration (1) to the cortex, (2) and (3) to the amygdaloid nuclei. Tangential migration (4) and (5) to the cortex. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

Motor end Figure 20–7. A portion of the wall of the neural tube Axon plate showing the main cells. (A) The germinal or ventricular Oligodendrocyte Myelin sheath cells in the ventricular or matrix zone (1) give rise to (a) immature and eventually mature neurons, (b) Neural crest Neurilemma glioblasts (precursors of astrocytes, oligodendrocytes, and radial cells, which are essential for radial migration; Monocyte Node Fields and Stevens-Graham,´ 2002), and (c) Oligodendro- ependymoblasts, which develop into ependymal and 3 cyte choroid plexus cells. According to an alternative theory, Neuron neurons and glioblasts arise from different cells in the Microglia ventricular zone. Moreover, it is now maintained that Immature glial cells can give rise to neurons. Above, an axon is neurons Astro- shown surrounded by a neurilemmal sheath consisting A cyte Radial B of neurilemmal cells (derived from neural crest). 1,

2 glial choroidea ventricular zone; 2, intermediate layer; 3, marginal layer. Tela Glioblast cell Choroid plexus Pia mater (B) The choroid plexus consists of choroidal ependyma and a vascular pia termed the tela choroidea (cf Fig. B.v. B.v. 20–3A, C). ependyma Choroidal

1 Ependymo- Ependymal Choroid Germinal or blast cell plexus ventricular cells cell VENTRICLE

Stage 15

Figures 20–8 to 20–12 show the development of the interpeduncular nucleus from 5 to 7 weeks. This nucleus is important for neural grafts as a possible treatment for Parkinson disease (Freeman et al., 1991; Freed et al., 1992). The bars represent 0.1 mm. M2 Di.

Figure 20–8. At stage 15 a ventral proliferative area of the mesencephalon, between the right and left oculomotor nuclei, is already visible (arrowheads).

Figure 20–9. At stage 16 the loose material between the oculomotor nuclei has increased to several rows of cells.

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176 Chapter 20: THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES

Figure 20–10. At stage 17 transverse ﬁbers ventral to the proliferative area represent the commissure of the oculomotor nerves.

20 Ð 12

20 Ð 11

Figure 20–11. At stage 20 the fibers passing through the tegmentum of the mesencephalon have increased to such an extent that the cerebral peduncles and the interpeduncular groove have begun to appear. The interpeduncular nucleus is visible, and the nucleus niger is lateral to it. The neurons of the substantia nigra are believed to be generated (in the rat) in the region of the isthmus rhombencephali. Transverse fibers, which are beginning to penetrate the loose cellular sheath, probably are rubrocerebellar fibers belonging to the superior cerebellar peduncles (Cooper, 1946a). The oculomotor nuclei are visible. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES 177

Figure 20–12. At stage 21 Stage 21 habenulo-interpeduncular fibers are seen to arrive in the lateral part of the interpeduncular nucleus. The substantia nigra is lateral to those fibers. The commissure of the superior colliculi is visible dorsally in the roof. Mesencephalic dopaminergic neurons have been detected at approximately this stage (Freeman et al., 1991). The red nucleus, which is already distinguishable at stage 17, is lateral and slightly dorsal to the oculomotor nucleus. The ventral tegmental region is dorsal to the interpeduncular nucleus, and its fibers ascend in the medial forebrain bundle. Mesencephalic dopaminergic neurons, especially of the ventral tegmental area, project to the ventral striatum (Vernier et al., 2004).

Figure 20–13. A graphic reconstruction and two transverse sections. The medial septal nucleus is near the hippocampus and includes two separate portions, X and Y. The nucleus of the diagonal band is ventrocaudal and occupies the middle third of the septum. Nerve fibers are present between the nucleus and the hippocampus. The nucleus of the diagonal band is identified by its projecting fibers (b) to the hippocampus. The caudalmost part of this area, however, is less clear. In the monkey (studied by thymidine marking), the production of cells of the septal nuclei (medial and nucleus of the diagonal band) is almost simultaneous with that of the nucleus basalis (of Meynert). This would correspond approximately to Carnegie stage 14, followed by a second wave between stages 18 and 22. The three functional cholinergic groups of the basal forebrain (medial septal, nucleus of the diagonal band, and nucleus basalis) “are the most outstanding sets of neurons regulating cortical functions. Each group specifically ends in a part of the cortex,” and their number and function are “statistically diminished in AD {Alzheimer disease} patients” (Toledano, 1992). P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

178 Chapter 20: THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES

Intermediate layer Septal nucleus

Figure 20–14. A graphic reconstruction of the medial septal nucleus, which consists of one separate mass in this embryo. Two additional ﬁber bundles are shown: a, between the olfactory bulb and the medial septal nucleus, and b, between the rostral and caudal septal areas.

Figures 20–13 to 20–17 show the nuclei of the prosencephalic septum. The septal nuclei are cellular agglomera- tions at the periphery of the intermediate layer. The cholin- Figure 20–15. Detail of the septal area of the right hemisphere in ergic neurons of the nuclei at the base of the forebrain a coronal section. The cellular agglomeration at the periphery of the are believed to be important in the degenerative processes intermediate layer of the medial wall of the telencephalon represents leading to Alzheimer disease. Septo-hippocampal cholin- the primordium of a septal nucleus. ergic ﬁbers reach their target (in the rat) at what would correspond to stage 19. Figures 20–15 to 20–17. Sections at the levels in- The basal part of the medial telencephalic wall (the dicated in the key on the next page. The bars represent septum verum) forms as the cerebral hemispheres expand 0.1 mm. beyond the lamina terminalis, and it extends between the commissural plate and the olfactory bulb. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES 179

20 Ð 15, Commissural 17 plate 16

Figure 20–16. A more rostral section showing the right and left sides of the septal area. The connection is the commissural plate, which at this time consists mainly of ventricular layer. The cellular agglomeration in the septal area is evident.

Olfactory bulb Olfactory nerve fiber layer

Figure 20–17. A coronal section at the level of the olfactory bulbs. Fibers from the developing external ﬁbrous layer of the olfactory bulb ascend (arrowheads) to the medial septal nucleus. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

180 Chapter 20: THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES

Figure 20–18. A coronal section through the rhombencephalon in the region of the facial nucleus. The septum medullae, which is derived from the floor plate, is present in the epinotochordal region and extends as far rostrally as the diencephalon (to the boundary between caudal and rostral parencephalon). The septum is a specialized grid formed by intersecting sagittal and transverse fibers, between which are migrating cells from the floor plate. These cells form the raphe nuclei, which, because of their neurotransmitters, are essential for the development of the brain. Moreover, they are related to the locus caeruleus, the substantia nigra, the red nucleus, and (after stage 20) to the cortical plate. Bar: 0.1 mm. At their first appearance the visceromotor nuclei are ventromedial in position (Fig. 14–9). Subsequently, the neurons of cranial nerves 5 and 9–11 migrate laterally. The facial nucleus, however, remains medially and is now also dorsal in position. Migration of the facial neurons laterally and rostrally occurs relatively late (Windle, 1970): in the late embryonic or early fetal period. The facial nucleus becomes better defined at the beginning of the fetal period (Pearson, 1946; Jacobs, 1970). The migration of the facial nucleus and the unexpected course of its fibers around the abducent nucleus are an example of neurobiotaxis, a term introduced in 1907 by C. U. Ariëns Kappers (1932) for the retention of a neuron as close as practicable to its main source of stimulation, and the migration that may occur in the direction from which the greatest density of stimuli arises, achieved by elongation of the axon. The mechanism of this phenomenon remains obscure. Another example is provided by the nucleus ambiguus.

Floor plate

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THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES 181

Hypoglossal Somatic & visceral nucleus afferent

Visceral efferent

Somatic efferent

20 Ð 18

20 Ð 19

Med. accessory olivary nucleus 20 Ð 19 18

Dorsal efferent vagal nucleus

Nucleus intercalatus 12 Nucleus solitarius

Inferior cerebellar peduncle Med. Septum accessory medullae olivary Spino- nucleus thalamic tract

Figure 20–19. A coronal section of the rhombencephalon. The medial accessory olivary nucleus arises between the hypoglossal roots of the two sides. This nucleus is the first of five (Muller ¨ and O’Rahilly, 1990c) that will be present by the beginning of the fetal period (Fig. 24–4). The hypoglossal nucleus is visible dorsally. Migratory material has accumulated at the ventral surface of the section. It arises in the rhombic lip and was first described in the human embryo by Essick (1912). His term “olivo-arcuate migration” is unsatisfactory, however, because it has since been shown (in the monkey) that the olivary nuclei arise mainly from the ventricular layer. Tall cells present in the raphe are contacted by fibers from the nuclei of nearby cranial nerves, and are important in the production of neurotransmitters. Bar: 0.2 mm. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

182 Chapter 20: THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES

Cerebellum

Roof plate 4th ventricle

Alar lamina Basal lamina

Floor plate

Basilar a.

Figure 20–20. A transverse section through the hindbrain showing the internal cerebellar swellings. The alar and basal laminae, which are lateral and medial in this region, are separated from each other on their ventricular surface by the sulcus limitans. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES 183

A Middle Figure 20–21. The venous system of the head. (A) At stage 17 the tributaries of the plexus Primary capital v. primary capital vein are arranged as three Otic vesicle dural plexuses. The internal jugular vein has Caudal begun its development. (B) At stage 20. The plexus sigmoid sinus has begun to form. From now Rostral on the venous system of the head is plexus asymmetrical. From Streeter (1918). The venous system from stage 14 to 80 mm GL has been studied in detail by Padget (1957). Future jugular foramen Precardinal v.

B Tentorial plexus

Transverse sinus Sagittal plexus

Caudal plexus

Inf. cerebral v. Sup. petrosal sinus

Sigmoid part

Int. jugular Ophthalmic v. v.

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184 Chapter 20: THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES

Ventricular

Intermediate Zones Marginal

Spinal ganglion

Neural process

Leptomeninx Centrum Notochord

Figure 20–22. Section through the spinal cord and a centrum. The neural processes of the two sides do not yet meet each other dorsally, thereby constituting the normal spina bidﬁda occulta that is characteristic of the embryonic and early fetal periods. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

NEUROTERATOLOGY 185

NEUROTERATOLOGY SPINA be said to be present throughout the length of the verte- BIFIDA OCCULTA bral column. This is the condition at birth. Postnatally a radiologically detectable failure in the completion of one Spina bifida occulta is possible from the first sign of the or more neural arches may be merely a lack of ossification appearance of vertebrae at stage 15 until completion of the dorsomedially, especially in the lumbosacral region. This is neural arches early in fetal life (Fig. 20–22). It is important a normal finding in children of 2 years of age and in part of to keep in mind that before ossification of the spinous pro- the sacrum it persists in about one-fifth to one-quarter of cesses has taken place, a normal spina bifida occulta may adults. P1: FAW/FAW P2: FAW JWDD017-20 JWDD017-ORahilly April 17, 2006 15:49 Char Count= 0

186 Chapter 20: THE CHOROID PLEXUS THE LATERAL VENTRICLES, THE OPTIC AND HABENULAR COMMISSURES

TABLE 20–1. Features of the Longitudinal Zones of the Diencephalon: Details for the General Scheme Given in Table 18–1

Zone Feature Stage of Primordium Fig.

1. Epithalamus Habenular nucleus 15 19–13 Epiphysis 16 16–7F Posterior commissure 17 19–4 2. Dorsal thalamus Nucleus of posterior commissure 15 Lateral geniculate body (dorsal part) Fetal period Sulcus medius (marginal ridge) 15–16 16–7F 17–16 18–6 21–14 3. Ventral thalamus Lateral geniculate body (ventral part) 21 21–14 Hypothalamic sulcus 15 15–4 16–7E 17–16 4. Subthalamus Subthalamic nucleus 16 21–12 Globus pallidus externus 19–20 21–15 Globus pallidus internusa 21 21–14 Faint, unnamed sulcus 15 15–4 5. Hypothalamus sensu lato Chiasmatic plate 10 10–7 12–5 15–9 Hypothalamic cell cord 14 16–7C Preoptico-hypothalamotegmental tract 14 19–10 Interstitial nucleus 14 14–5 Medial ventricular eminence 14 16–7B Neurohypophysial diverticulum 15–16 17–17 21–15 Mamillary nuclei 15–16 21–11 22–9

This table provides details for the general scheme given in Table 18–1. The ﬁgure references are to photomicrographs. a Entopeduncular nucleus. P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

CHAPTER21 STAGE 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

Approximately 22–24 mm in Greatest Length; Approximately 50 Postfertilizational Days

n important feature is the appearance of the Precision cortical plate within the primordial plexiform Alayer, adjacent to the lateral ventricular eminence (the In the embryo the caudal border of the mesencephalon future corpus striatum). This makes it possible to distin- passes rostral to the isthmus. guish subpial and subplate layers, corresponding respectively to future layer 1 and the white matter of the neopal- Most telencephalic neurons arise in the ventricular lium. The lateral prosencephalic fasciculus (Stammbundel ¨ and subventricular layers. In addition, neocortical GABA- of His) is prominent and unites the telencephalon and the expressing interneurons are believed to be derived (in the diencephalon. Corticothalamic ﬁbers appear. Clinically im- mouse) from the lateral ventricular eminence. Indeed, in portant relays of the subthalamus are distinguishable: the the human (at 26 mm) GABA-positive cells have been found subthalamic nucleus proper, the entopeduncular nucleus dorsal and ventral to the developing cortical plate (Zecevic (future globus pallidus internus), and the globus pallidus and Verney, 1995). externus. The rostral surface of the cerebellar plate has developed a longitudinal elevation that contains the inferior Important cerebellar peduncle. A distinct feature of the cranial nerves from stage 21 onwards is the presence of multiple glial cells It should be stressed that, although the third ventri- (olfactory and optic nerves) and neurilemmal (Schwann) cle is mostly diencephalic, its preoptic portion is telen- cells between the ﬁbers. The nasal septum becomes car- cephalic. This rostral part is visible in Figure 21–3 below tilaginous. “Membrane” bones develop: the mandible and the interrupted line through the forebrain. the maxilla are always present.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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188 Chapter 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

Figure 21–1. An embryo attached to the placenta and showing the superﬁcial vascular plexus of the head. In the cord an umbilical vessel is visible, as are also coils of intestine belonging to the normal, temporary umbilical hernia.

Figure 21–2. Right lateral view of the brain with the membranous labyrinth added. A ﬂat surface marks the site of the future insula. Frontal, occipital, and temporal poles are distinguishable (α, β, γ ). The cerebral hemispheres overlap more Di. b than half of the surface of the diencephalon. The 1 isthmic groove has deepened. Between 6 and 7 2 g weeks the head rises in position. This is largely because at stage 21 the growth and expansion of the trunk are such that it could not remain in the position it occupied at stage 18 (although in both a stages it rests on the ventral wall of the trunk). A number of features typical of this stage were described by Hochstetter (1919, his embryos Ha3 and Peh4). P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES 189

Isthmic groove

Fig. 21 Ð

18 17

N.-H. Ep.

Supraoptic X Ch.

Comm. Habenular X l.-v.f. Olf. bulb

Paraphysis 0.3

b c

Figure 21–3. Graphic reconstruction from transverse sections to show a median view of the brain. The asterisk indicates the junction with the spinal cord. The pineal recess has formed. Ependymal cells over the posterior commissure form the subcommissural organ. The ﬂoor of the rhombencephalon is bent sharply, as described by Hochstetter (1919), and a transverse groove, the sulcus transversus rhombencephali, results. The isthmic recess (short arrow) is a guide to the interpeduncular nucleus. Interrupted lines delimit the rhombencephalon, mesencephalon, diencephalon, and telencephalon. Striatal arteries in this embryo were shown by Padget (1948, Fig. 21). As shown in the inset, the main internal grooves are (a) the sulcus limitans, (b) the hypothalamic sulcus, and (c) the marginal ridge. P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

190 Chapter 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

Figure 21–4. (A) The overlap between the left cerebral hemisphere and the left half of the diencephalon. The positions of the subthalamic nuclei (medial and lateral mamillary nuclei, subthalamic nucleus proper, entopeduncular nucleus which is the future globus pallidus internus, and the globus pallidus externus) are shown schematically. The ventral part of the lateral geniculate body has developed (Table 20–1). The hippocampus, area dentata, area epithelialis, and the choroid fissure are indicated on the medial wall of the left hemisphere, which is shown as if transparent. The hippocampus reaches almost as far as the temporal pole. The site of the future lamina affixa, which at this stage overlies the ventral thalamus, is marked by a dagger. The asterisk at the base of the telencephalon is at the site of a cistern. Parts not visible from the surface are shown by interrupted lines. The horizontal interrupted line delimits the diencephalon from the telencephalon. (B) Levels of Figures 21–11 to 21–17, which, because they are from a different embryo, do not necessarily show a perfect fit. Fig. 21 Ð

11 12

6, 15 17

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THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES 191

Figure 21–5. An almost median section. The olfactory and lateral ventricles are continuous. Choroid folds can be seen in the lateral and fourth ventricles. In the diencephalon, the zona limitans intrathalamica is distinguishable between the dark, dorsal area (dorsal thalamus) and the less dark, ventral area (ventral thalamus). The posterior commissure is partly diencephalic and partly mesencephalic (commissure of the superior colliculi). The interpeduncular nucleus is immediately rostral to the tuberculum interpedunculare of the isthmus, which segment includes also the trochlear commissure and the isthmic recess. In the cerebellum, the internal ﬁber layer is detectable. The sulcus transversus rhombencephali is produced by the sharp bend of the ﬂoor of the rhombencephalon. The inferior olivary nucleus is ventral in the rhombencephalon. The base of the chondrocranium shows the dorsum sellae and the hypophysial fossa (containing the hypophysis cerebri), and continues rostrally into the nasal septum. The dens of cervical vertebra 2 is evident. P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

192 Chapter 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

Figure 21–6. A portion of the right cerebral hemisphere adjacent to the diencephalon. The groove between the two (di-telencephalic sulcus) is filled with loose mesenchyme. The choroid plexus now presents stumpy villi limited by three to four rows of epithelial cells. The layer adjacent and ventral to the plexus is the future lamina affixa, which at this stage lies opposite the ventral thalamus. In the adjacent massa cellularis reuniens (Richter, 1965) cellular strands (asterisk below) possibly indicate migrating cells. A deep groove, the sulcus terminalis, is situated medial to the medial ventricular eminence. The germinal zone (matrix and subventricular layer) of the ventricular eminences is bordered immediately by the postmitotic layer, without an intervening intermediate zone. The cortical plate, which is typical of stage 21, has begun to form opposite the ventricular eminences. It was seen by Molliver et al. (1973). The transition from the hemisphere to the diencephalon is the hemispheric stalk, which contains a thick bundle of fibers, the lateral prosencephalic fasciculus (Stammbundel ¨ of His). The telencephalic area adjacent to it is the amygdaloid region. The diencephalic nucleus ventral to the lateral prosencephalic fasciculus is the globus pallidus externus. The hemispheric stalk seen in this figure is the original connection between the diencephalon and the telencephalon. It will become greatly enlarged by fibers and tracts, especially by the continuation of the internal capsule. The levels of Figures 21–6 to 21–10 Lamina affixa are shown in Figure 21–4B. The bars represent 0.1 mm.

Sulcus terminalis Medial ventricular Hemi- eminence spheric stalk

Cortical plate

Lateral prosencephalic fasciculus Globus pallidus externus

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THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES 193

Figure 21–7. Developmental comparison between the spinal cord and the brain wall as derivatives of the neural tube. The cortical plate develops within the primordial plexiform layer (preplate), so that it comes to lie between superﬁcial and deep laminae, namely layer 1 and the subplate of the neocortex. The stages illustrated are 11 for the neural tube, and 17 for the spinal cord. The neocortical blocks are (left) up to stage 20, and (right) from stage 21. P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

194 Chapter 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

A B Figure 21–8. A median view of the brain at stage 22 to show the termination of the alar and basal Sulcus limitans laminae, and that of the sulcus limitans in the brain. The chief interpretations of the ending of the BASAL ALAR sulcus limitans, as summarized by Richter (1965, Fig. 35), are as follows: (A) The supramamillary recess (Kingsbury; Schulte and Tilney; Kuhlenbeck). (B) The prechiasmatic recess (His; Johnston; Streeter). (C) Floor The interventricular foramen (Spatz; plate Kahle; Richter). Interpretation A is Ma. that supported by the present authors Hypothal. for the human embryo. (D) An sulcus enlargement of the commissural plate Ivf to show three subregions described in the rat: (a) the future anterior C Ch. commissure; (b ) the probable site of closure of the rostral neuropore; and (c) the future hippocampal commissure and the corpus callosum. With further development of these commissures, the embryonic lamina D terminalis becomes reduced to the NH adult type (Ad.), which extends from the caudal limit of the commissure to AH a¢ the optic chiasma. b¢ Ch. c¢ Ad. P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES 195

Subpial layer Cortical plate Subplate Intermediate layer Ventricular & subventricular layers

Figure 21–9. The cortical plate is visible within the cell-poor primordial plexiform layer at the periphery of the ventricular eminences. The plate separates the former primordial plexiform layer into the subpial layer, which is future layer 1, and the subplate (Fig. 21–7). The subplate contains thalamocortical fibers that arrived in the primordial plexiform layer already at the previous stage. Penetration of the cortical plate by monoamine fibers occurs at the end of trimester 1 (Verney et al., 1993). It is to be noted that the subpial layer and the subplate appear during the embryonic period and not, as has been claimed (Kostović and Rakic, 1990), in the middle third of prenatal life. Transient fibers in the subplate are illustrated in Figure 23–22. Glial production begins from stem cells in the subventricular layer. From Muller ¨ and O’Rahilly (1990b). P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

196 Chapter 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

Lat. em. Figure 21–10. An overall view of the Cortical septal area showing the nucleus of the plate diagonal band. The prosencephalic septum is closely related to the hippocampal region, which lies dorsomedially. A faint groove separates the lateral and medial ventricular eminences. The cortical plate of the Med. em neocortex is contiguous to the piriform Lat. olf. cortex. Lateral olfactory ﬁbers are fibers visible. The loose tissue surrounding Piriform the base of the telencephalon is a basal Nucleus of cistern (asterisk in key on next page.) diagonal band cortex P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES 197

21 Ð 11 12 V3 13

Mam. recess

Habenulo- V3 inter- Subthalamic Basilar a. peduncular nucleus tract Figure 21–12. Section through the mamillary recess showing the migratory stream from the mamillary area to the subthalamic nucleus. The ﬁbers, which are from the mamillotegmental tract, arise in the lateral, as well as the medial, mamillary nucleus.

Mamillo- thalamic tract

Mamillary area V3

Figure 21–11. The di-mesencephalic transition showing the mamillary area with its budding surface (“leicht höckerige Oberfläche,” Hochstetter, 1919; “mamelones de crecimiento,” Orts Llorca, 1977). The buds are indicated by arrows. The habenulo- interpeduncular tract runs between the ventricular and intermediate layers, and this part of the section is the caudal area of the diencephalon. Ventrally, its median cellular material seems to be a Figure 21–13. The mamillothalamic tract runs from the lateral continuation of the interpeduncular nucleus of the midbrain. Large mamillary nucleus to the thalamus. The nucleus appears on each meshes occur in the subdural space and are generally near the cere- side as a dark, basal area. bral wall, whereas smaller meshes are found near the skeletogenous layer.

The levels of Figures 21–11 to 21–13 are shown also in Figure 21–4B. The bars represent 0.2 mm. P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

198 Chapter 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

Figure 21–14. The ventral part of the lateral geniculate body at the level of the sulcus medius, and the entopeduncular nucleus of the subthalamus. The entopeduncular nucleus (globus pallidus internus) is at ﬁrst at a more caudal level than the globus pallidus externus. 21 Ð 14 15

Lat. geniculate body

Marginal ridge

Zona limitans intrathalamica

Sulcus medius Thal. v.

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Medial Figure 21–15. Fibers of the optic tract, the ventricular globus pallidus externus, and the lateral eminence prosencephalic bundle (Stammbundel ¨ of His). The cellular bridge between the medial ventricular eminence and the thalamus (cf. Fig. 21–6) is important in the formation of the pulvinar during the fetal period (Rakic and Sidman, 1969). The Thalamus central part of the neurohypophysis is visible ventralis between the lateral parts of the adenohypophysis.

Hypothalamic sulcus Lat. pros. Subthalamus fasc.

Globus pallidus ext.

Optic tract Hypothalamus

N.-H.

A.-H.

21 Ð 17 16

Lat. pros. fasciculus Di-telencephalic sulcus Figure 21–16. The globus pallidus externus in a more rostral area. The lateral prosencephalic bundle is surrounded by Globus pallidus ext. ﬁbers of the fasciculus lenticularis (arrowhead).

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200 Chapter 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

21 Ð 19 20

Hipp.

Roof of V3

Area dentata

Corpus Wall of Area cerebelli lat. recess Stria epithelialis medullaris thalami Sulcus limitans Figure 21–17. The hippocampus and adjacent areas. The root of the choroid plexus continues into the area epithelialis. From there, the following zones can be traced upwards: area dentata, hippocampus and subiculum, and mesocortex. In the hippocampus, marginal and pyramidal cells can already be distinguished (Muller ¨ and O’Rahilly, 1990b). The telencephalon is separated from the diencephalon by loose mesenchyme. The stria medullaris thalami and the folded roof Intermediate of the third ventricle are visible. layer

Figure 21–19. General view of the cerebellum at the level shown above. Choroid villi are present in the choroid fold and in the wall of the lateral recess of the fourth ventricle. The internal cerebellar swelling, which is lateral to the sulcus limitans, consists mainly of cellular columns of the ventricular layer. A lighter area represents the intermediate layer, followed by the internal ﬁber layer. The dark area near the lower part of the section is the primordium of the dentate nucleus (between arrowheads). The external ﬁber layer is entirely at the periphery. Bar: 0.2 mm.

Figure 21–18. Schematic representation of the development of the tentorium cerebelli at stage 21. The medial part is shown by hatching, the lateral parts by black arrows. P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES 201

Ventricular layer Sulcus limitans ∗

Rhombic Dent. lip

Flocculus

Dentate Int. fiber Flocculus nucleus layer

Figure 21–20. The internal cerebellar swellings. The vertical columns of the ventricular layer are distinct. Numerous blood vessels penetrate almost as far as the ventricular surface. The rhombic lip has no marginal layer. Bar: 0.2 mm. Above, in the schematic interpretation of the section the open arrow indicates the ascending ﬁbers of the inferior cerebellar peduncle, the black arrows the direction of the migrating cells. Asterisk, intermediate layer. P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

202 Chapter 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

Stage 15 Figure 21–21. Right lateral views to show the 1 1 13 ventricular cavities at approximately 4 /2–7 /2 weeks. The ventricles at stage 23 are illustrated in Figure 23–27. Growth of the medial and lateral ventricular eminences transforms the formerly hemispherical lateral ventricle into a C-shaped cavity, which is continuous rostrally with the olfactory ventricle. The ﬁrst indication of anterior and inferior horns can be seen in stage 21 in the lateral ventricle (O’Rahilly and Muller, ¨ 1990).

17 21

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THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES 203

A B

C D

AICA

Figure 21–22. The arterial system at about 6 to 7 postfertilizational weeks. The internal carotid artery is shown in black, and the basilar by horizontal hatching. (A) and (B) The arteries at stage 17. New vessels that can now be identiﬁed include the anterior and middle cerebral (AC, MC), and the anterior and posterior choroid arteries. The vertebral artery is formed by anastomoses between the cervical segmental arteries. (C) and (D) The arteries at stage 21 showing the anterior, middle, and posterior cerebral vessels. The anterior communicating artery is present, so that the circulus arteriosus is now complete. The choroid plexuses of the lateral and fourth ventricles are included. These drawings are based on graphic reconstructions made by Padget (1948), whose work should be studied for further details. The venous system at stages 18, 19, 20, and 21 has been illustrated by Padget (1957, Figs. 6, 9, 11, and 10). The arterial system at the end of the embryonic period is shown in Figures 23–33 and 23–34. Abbreviations: AC, anterior cerebral; AICA, anterior inferior cerebellar artery; DA, ductus arteriosus; MC, middle cerebral; PC, posterior cerebral; P.co., posterior communicating; PICA, posterior inferior cerebellar artery; PT, pulmonary trunk. P1: FAW/FAW P2: FAW JWDD017-21 JWDD017-ORahilly June 13, 2006 13:29 Char Count= 0

204 Chapter 21: THE FIRST APPEARANCE OF THE CORTICAL PLATE IN THE CEREBRAL HEMISPHERES

4 weeks 5 67 9 Stages 10 11 12 13 14 15 16 17 18 19 20 21

Inter- Post. spinal segmental Vertebral Longitudinal Ant. spinal PICA neural Basilar Labyrinthine Sup. AICA Trigeminal cerebellar CAROTICO- Otic BASILAR ANASTOMOSIS regresses Aortic arch Hypoglossal 1 2 3 Ext. carotid

Hyoid Stapedial

Post. choroid c Post. communicating Int. Post. cerebral CIRCULUS carotid ARTERIOSUS Middle cerebral r Olfactory Ant. cerebral Ant. communicating

Ant. choroid Hyaloid Ophthalmic New ophthalmic

Development of circulus arteriosus

Stage 19 Stage 21

Figure 21–23. Above, summary of the arterial development. c, caudal division; r, rostral division. Below, the completion of the circuit by the formation of the anterior communicating artery. P1: FAW/FAW P2: FAW JWDD017-22 JWDD017-ORahilly June 13, 2006 13:52 Char Count= 0

CHAPTER22 STAGE 22: THE INTERNAL CAPSULE AND THE OLFACTORY BULBS

Approximately 23–28 mm in Greatest Length; Approximately 52 Postfertilizational Days

he internal capsule and its connections to the Important neopallium are now present and are as fol- Tlows: (1) to the epithalamus, (2) to the dorsal thalamus, Contrary to the opinion of certain authors in the past and (3) to the mesencephalon. The claustrum develops, (including His), what appears to be a fusion between the and a clear developmental relationship exists between cerebral hemisphere and the diencephalon is a thicken- it and the intermediate layer of the olfactory bulb. The ing of the thalamic wall at the di-telencephalic sulcus globus pallidus externus moves towards a telencephalic as the internal capsular ﬁbers begin to pass through it. position. This was appreciated by Hochstetter (1929) and Sharp (1959), as well as by Bartelmez (cited by Padget, 1957).

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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206 Chapter 22: THE INTERNAL CAPSULE AND THE OLFACTORY BULBS

Figure 22–1. Right lateral view of the brain in a Born reconstruction. The midbrain is at the summit. The temporal and frontal poles of the cerebral hemisphere are evident.

Figure 22–2. Right lateral view of the brain. The cerebral hemispheres cover about three-quarters of the diencephalon. The three poles (α, β, γ ) are distinguishable. The mesencephalon is “ballooning out” (Bartelmez and Dekaban, 1962), sits on top of the brain, and is higher than the cerebellar plates. Its M delineation, therefore, is easier than in earlier stages. The inferior colliculus forms a slight bulge on top of the Blindsack. The isthmus is markedly narrow. The posterolateral ﬁssure, b Di. which delineates the future ﬂocculus, has g become a sharp boundary. The cerebellar plates are no longer as wide as the cerebral hemispheres (see inset). A reconstruction of the cranial nerves a T is available (Muller ¨ and O’Rahilly, 1991, Fig. 4). P1: FAW/FAW P2: FAW JWDD017-22 JWDD017-ORahilly June 13, 2006 13:52 Char Count= 0

THE INTERNAL CAPSULE AND THE OLFACTORY BULBS 207

b c (a) Sulcus limitans (b) Hypothalamic sulcus (c) Marginal ridge

Figure 22–3. Graphic reconstruction prepared from transverse sections to show a median view of the brain. The asterisk indicates the junction with the spinal cord. The internal relief is shown, and the structures of the medial wall of the left hemisphere are projected as interrupted lines: the caudal extent of the cerebral hemispheres, the area dentata, and the hippocampus. The hippocampus extends between the occipital pole and the prosencephalic septum. The marginal ridge separates the diencephalon into halves: the dorsal thalamus on one side, and the ventral thalamus, subthalamus, and hypothalamus on the other. The pineal recess (arrow at right) is still undivided. The isthmic groove (upper arrow) and the isthmic recess (lower arrow) are also marked. The commissural plate has become thicker. No fusion takes place during the embryonic period proper between the cerebral hemispheres, as was clearly understood and stated by Hochstetter (1919).1 The approximate levels of Figures 22–7 to 22–12 are indicated, although the ﬁt does not correspond completely, because these are from different embryos. (For example, in Figure 22–7 the interpeduncular fossa is slightly more dorsal than in Figure 22–3.) A three-dimensional reconstruction, prepared ultrasonically, of the ventricles in vivo in an embryo of 24 mm is illustrated by Blaas et al. (1995b).

1“Nicht der kleinste Umstand aber deutet darauf hin, dass die zu beobachtende Dickenzunahme etwa auf eine Verwachsung der unmittel- bar an die Kommissurenplatte anschliessenden Abschnitte der medialen Hemisphärenwände zuruckzuf ¨ uhren ¨ wäre” (p. 109). See also definition of Massa commissuralis in the Glossary. P1: FAW/FAW P2: FAW JWDD017-22 JWDD017-ORahilly June 13, 2006 13:52 Char Count= 0

208 Chapter 22: THE INTERNAL CAPSULE AND THE OLFACTORY BULBS

Figure 22–4. Median view to show elements that are important in understanding the internal capsule. The lateral ventricular eminence, which gives rise to the future corpus striatum, is projected onto the medial surface to show its extent. The fibers of the lateral prosencephalic fasciculus (Stammbundel ¨ of His) arise in the neopallial wall and descend lateral to the lateral ventricular eminence. The fibers, having traversed the hemispheric stalk, ascend in the diencephalic wall and spread into, among other structures, the dorsal thalamus. All the features indicated are shown as if the prosencephalon were transparent. The stria terminalis “arising mainly in the amygdaloid complex” follows the curvature of the sulcus terminalis towards the interventricular foramen and here, near the anterior commissure, various components of the stria terminalis become separated (Kuhlenbeck, 1977). It has been found (in the hamster) that thalamocortical fibers (stage 21) are present before corticothalamic fibers become visible in the internal capsule.

Lateral forebrain bundle & internal capsule

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THE INTERNAL CAPSULE AND THE OLFACTORY BULBS 209

A C Nerves Vertebrae C1 C1 2 2 3 3 4 4 5 5 6

6 7

7 8

T1 T1

B NORMAL SPINA BIFIDA

Foramen Notochord transversarium

Figure 22–5. Development of the skull and vertebrae. (A) Left lateral view of a reconstruction of the brain and chondrocranium. The asterisk indicates the junction with the spinal cord. The basal portions of the skull are present in cartilage. The basolateral and lateral walls are still far from complete, but the following are discernible: the greater and lesser wings of the sphenoid; the otic capsule; and the parietal plate, which is not yet fused with the plate of the other side. Hence the foramen magnum has not yet developed. The chondrocranium of stage 22 is compared with that of stage 23 in Figure 23–8. (B) The temporary, normal spina biﬁda. Cf. Fig. 20–22. (C) Relationship of spinal nerves to vertebrae. Cervical nerve 1 emerges below the skull (otherwise it would be a cranial nerve!) and above the atlas. Cervical nerves 2 to 7, therefore, leave the vertebral canal above the correspondingly numbered vertebrae. Cranial nerve 8 emerges below cervical vertebra 7 and above thoracic vertebra 1. All the remaining spinal nerves leave below the correspondingly numbered vertebrae. P1: FAW/FAW P2: FAW JWDD017-22 JWDD017-ORahilly June 13, 2006 13:52 Char Count= 0

210 Chapter 22: THE INTERNAL CAPSULE AND THE OLFACTORY BULBS

Stria medullaris B thalami

Lateral eminence Medial eminence Internal capsule Stria terminalis

Figure 22–6. A schematic representation of the development of the internal capsule based on reconstructions. (A) Dorsal view of the opened right hemisphere showing the internal capsule in relation to the lateral ventricular eminence. Neopallial fibers (between the black arrowheads), which are an essential component of the definitive internal capsule, are shown on their way from the neopallium, lateral to the ventricular eminence and running to the lateral prosencephalic fasciculus (cf. Fig. 22–11). The first fibers can be traced to an area comparable to the later postcentral gyrus. The lateral ventricular eminence has grown more rapidly than the medial, which is adjacent to the hemispheric stalk. A faint groove called the intereminential sulcus by the present writers is distinguishable between the eminences. The neurons for the neostriatum arise during stages 21–23, as has been shown in rhesus. It has been found that the histochemical development of the nucleus accumbens resembles that of the lateral ventricular eminence. (B) A right lateral view showing the internal capsule in more detail. The neopallial fibers (black arrowheads) between the primordia of the future caudate nucleus medially, and the putamen laterally, accumulate in the thick lateral prosencephalic fasciculus (Stammbundel ¨ of His) before entering the diencephalon. Finally they continue in three main groups: epithalamic, thalamic, and mesencephalic (white arrows). The main bundle is arched over by the stria terminalis, which is composed chiefly of fibers that can be traced to the medial part of the amygdaloid nuclei. (C) Also a right lateral view: the cortical plate at stage 22 (stippled area) extends over half the surface of the neopallium, and its increase from stage 22 to stage 23 is shown. P1: FAW/FAW P2: FAW JWDD017-22 JWDD017-ORahilly June 13, 2006 13:52 Char Count= 0

THE INTERNAL CAPSULE AND THE OLFACTORY BULBS 211

22 Ð 7, 8

Lat. eminence Ivf

Hippocampus V3

Tegmental fibers Med. longutidinal fasciculus

Inf. colliculus

Figure 22–7. The lateral ventricular eminence, hippocampus, and choroid plexus are visible. The folded roof of the diencephalon is adjacent to the stria medullaris thalami on each side. The dorsal thalami appear dark. The mesencephalic ventricle (future aqueduct) and its prolongation into the right inferior colliculus are evident. The ﬁber masses in the tegmentum are increasing. The medial longitudinal fasciculus is visible on each side. Dorsal to the main mesencephalic ventricle, the white lines are ﬁbers leading to the trochlear decussation.

Figures 22–7 to 22–11. The levels of these sections 22–9 and of Figure 22–11 were selected by Bartelmez and are indicated also in Figure 22–3. The left side is cut at a Dekaban (1962), who completed their study with stage 22. deeper level than the right. The sections of Figures 22–7 to The bars represent 1 mm.

Insula Lat. & med. em.

Sulcus terminalis Hypo- Inf. horn thalamic Figure 22–8. The cortical plate is evident on each side sulcus and is mostly opposite the ventricular eminences at the site of the future insula. A faint groove can be seen between the medial and lateral eminences. The sulcus terminalis is medial, towards the diencephalon. The inferior horn of the left lateral ventricle is evident. The diencephalic area dorsal to the hypothalamic sulcus is mainly ventral thalamus. In the isthmus, the tegmentum is ﬁlled with ﬁbers, including the medial longitudinal fasciculus. A cerebellar plate is visible to the left of the isthmus. P1: FAW/FAW P2: FAW JWDD017-22 JWDD017-ORahilly June 13, 2006 13:52 Char Count= 0

212 Chapter 22: THE INTERNAL CAPSULE AND THE OLFACTORY BULBS

22 Ð 9, 10

TEL.

Lat. Sulcus prosenc. terminalis fasciculus DI.

Tentorium

Mamillary area

Internal cerebellar swelling

Figure 22–9. This section, at the level of the interventricular foramina, shows the lateral prosencephalic fasciculus (Stammbundel ¨ of His) on the left side. The sulcus terminalis is the internal boundary between telencephalon and diencephalon. The mamillary region and the mamillothalamic tract are visible. The internal cerebellar swellings almost ﬁll the fourth ventricle. The ﬁbers penetrating it (on the left side) belong mainly to the inferior cerebellar peduncle. The lateral portions of the tentorium cerebelli are evident here as well as in the other sections.

Cortico- thalamic fibers

Inf. cerebellar peduncle Tentorium Figure 22–10. At the right, ﬁbers can be seen Flocculus arising in the neopallium and running towards the Stammbundel ¨ , which is visible at the di-telence-phalic borderline (hemispheric stalk). The stalk lies between the sulcus terminalis on the ventricular and the di-telencephalic sulcus on the external surface. The mamillary region still shows. At the rostral surface of the left cerebellar plate, the lighter triangular area is the inferior cerebellar peduncle. To its left is the ﬂocculus, and to its right is the area of the dentate nucleus. P1: FAW/FAW P2: FAW JWDD017-22 JWDD017-ORahilly June 13, 2006 13:52 Char Count= 0

THE INTERNAL CAPSULE AND THE OLFACTORY BULBS 213

Figure 22–11. The entire extent of the 22 Ð 11 internal capsule is visible in the right hemisphere. Some villi are present in the thin wall of the lateral recess of the Olfactory fourth ventricle. Although skeletal bulb 22 Ð 12 Migrating elements are not encountered as far cells dorsally as this level, the skeletogenous layer is clearly delimited (cf. Fig. 22-14B).

Lateral eminence

MEDIAL VIEW RIGHT LATERAL VIEW

Int. capsule

Lat. prosenc. fasciculus

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214 Chapter 22: THE INTERNAL CAPSULE AND THE OLFACTORY BULBS

Cortical Figure 22–12. The primordium of the plate claustrum develops as a condensed stream of neurons that extends from the area caudal to the olfactory bulb and along the lateral ventricular eminence to the future insular region (right-hand inset on previous page). Later in trimester 1, cells of the Lat. subventricular layer of the olfactory bulb will em form the subpial granular layer. Bar: 0.2 mm.

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THE INTERNAL CAPSULE AND THE OLFACTORY BULBS 215

Figure 22–13. The choroid A folds of the fourth ventricle as seen in a coronal section through the rhombencephalon. The first inset drawing on the next page V4 Internal indicates the field shown in A. cerebellar The second illustrates the swelling migration pathways in the rhombencephalon: (1) from the rhombic lip along the external surface of the brain stem, and (2) from the entire ventricular layer into the alar and basal laminae. V4 (A) The ependyma of the lateral recess presents small villi, whereas the choroid folds more medially show large villi. The rhombic lip is well developed but differs in shape depending on the stage and the precise region (e.g., Fig. 21–20). In addition to the median sulcus, the sulcus limitans is distinguishable on each side. The tractus solitarius (asterisk) is visible inside the alar lamina. Dark areas on both sides of the median raphe are the B rostral parts of the inferior olivary nuclei. ×36. (B) A view at higher power. Blood vessels have penetrated the choroid folds. The tall neurons of the hypoglossal nucleus are discernible medially, adjacent to the matrix of the basal × Ependyma lamina (dagger). 87. The choroid pleuxus of the Tela fourth ventricle, from its first choroidea appearance at stage 19, is more advanced than that of the telencephalon. Apertures in the † roof of the rhombencephalon are not yet present. The choroid plexus will undergo enlargement and differentiation, including the production of more villi and the appearance of two types of ependymal cells, dark and light (O’Rahilly and Muller, ¨ 1990). P1: FAW/FAW P2: FAW JWDD017-22 JWDD017-ORahilly June 13, 2006 13:52 Char Count= 0

216 Chapter 22: THE INTERNAL CAPSULE AND THE OLFACTORY BULBS

A Figure 22–13 (Continued ). The level of A and the areas A and B in the photomicrographs are indicated.

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A B

1 Figure 22–14. Schematic representation of the development of the cranial meninges. (A) At approximately 3 2 postfertilizational weeks, mesenchyme from various sources surrounds the brain, and blood vessels are present. The sources probably include prechordal plate, un- segmented paraxial mesenchyme, segmented paraxial (somitic) mesenchyme, ectomesenchyme (neural crest), and neurilemmal cells (neural crest). The pia mater develops between the blood vessels and the cerebral wall. A dense skeletogenous layer forms at the periphery and veins are situated on its internal aspect. As the meningeal vessels are transformed into arteries and veins, they become progressively isolated from the CSF compartment (Mar´ın-Padilla, 1988b). (B) Approximately 7 postfertilizational weeks. The dural limiting layer appears between the pia and the skeletogenous layer. Large meshes form in the future subarachnoid space, smaller meshes between the dural limiting and skeletogenous layers (in the pachymeninx). Cartilage and intramembranous bone are forming within the skeletogenous layer. The veins (dural sinuses) on the internal aspect of the skeletogenous layer are now intradural in position. The leptomeningeal cells establish perivascular spaces around the arachnoidal and pial vessels, and these drain into the perivascular lymphatic system of the extracranial vasculature (Mar´ın-Padilla, 1988b). (C) Scheme of the meninges in the adult. So-called subdural hemorrhage is within the dural border layer and hence is intradural. Based largely on Schachenmayr and Friede (1978) and Alcolado et al. (1988). The development of the cranial meninges was investigated by Hochstetter (1939) among others, and the complicated origin of these membranes from several sources (including the prechordal plate, parachordal mesoderm, and neural crest) was studied by O’Rahilly and Muller ¨ (1986). The loose mesenchyme around most of the brain at stage 13 (Fig. 13–5) is termed the primary meninx. At stage 17 the dural limiting layer begins to form basally (Fig. 17–5) and the skeletogenous layer of the head soon becomes visible (Fig. 22–14). At stage 23 the pachymeninx and the leptomeninx are distinguishable in the head (Fig. 23–9). The spinal meninges have been investigated particularly by Hochstetter (1934) and Sensenig (1951). The future pia mater, derived from neural crest cells, can be detected at stage 11 and, at stage 15, the primary meninx is represented by a loose zone between the vertebral primordia and the neural tube. At stage 18 the mesenchyme adjacent to the vertebrae becomes condensed as the dural lamella. At stage 23 the dura lines the vertebral canal completely and the future subarachnoid space is becoming cell-free. The arachnoid, however, does not appear until either trimester 3 or postnatally, although a much earlier artifact has frequently been mistaken for it. P1: FAW/FAW P2: FAW JWDD017-22 JWDD017-ORahilly June 13, 2006 13:52 Char Count= 0

218 Chapter 22: THE INTERNAL CAPSULE AND THE OLFACTORY BULBS

NEUROTERATOLOGY: neuronal migration. The responsible genes are located on EXENCEPHALY AND chromosome X, and a marked female preponderance is ANENCEPHALY noted (Barinaga, 1996). Anencephaly develops successively as (1) cerebral dys- Exencephaly. The second phase in the development raphia (see stages 11 and 13), (2) exencephaly (see stage 22; of anencephaly is the exposure of a highly developing a good example at 35 mm has been illustrated by Hunter, and well-differentiated brain during the embryonic period 1934), and (3) degeneration of the exposed brain through- proper. A number of examples are available in the litera- out the fetal period. Phase 3 is believed to be brought ture (Table 3 of Muller ¨ and O’Rahilly, 1991). The condition about by partial or complete exposure of the uncovered includes either cranioschisis or craniorhachischisis. An ex- brain to amniotic fluid for prolonged periods (Lemire et al., amination of anencephaly at stage 22 has shown that the 1978). This secondary degeneration of a well-developed brain attains a high degree of differentiation before disin- brain affects mainly those parts that are situated rostral tegration takes place during the fetal period (Muller ¨ and to the medulla oblongata. Interesting clinical studies of O’Rahilly, 1991). The skeletal covering, however, can be- anencephaly have been published by André-Thomas and come deviated very early, so that the typical features of an de Ajuriaguerra (1959). anencephalic skull can be present before the characteristics of an anencephalic brain. Moreover, even as early as Precision stage 22, variations in anencephaly are noteworthy. In their useful book on anencephaly, Lemire et al. Anencephaly refers to the condition, whereas the des- (1978) illustrate 56 instances of embryos/fetuses that range ignation anencephalus is restricted to an individually from 17 mm (22 mm when fresh) to 345 mm (360 mm when afflicted fetus or infant. fresh) in CR length. Lissencephaly. The abnormal cerebral cortex resembles that in reeler mice and is attributed to disturbed P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

CHAPTER23 STAGE 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Approximately 27–31 mm in Greatest Length; Approximately 56 Postfertilizational Days

he cortical plate covers almost the whole neopal- r Stage 23, 8 postfertilizational weeks, needs to be lial surface. The hippocampus has reached the stressed because this is the close of the embryonic temporal pole; its cells exhibit the largest intercellular dis- T period proper. tances in the entire brain. The insula appears as an indented r area. In the corpus striatum the primordia of the caudate The pyramidal decussation appears already during nucleus and the putamen are recognizable, and the globus the embryonic period. r pallidus externus has moved into a telencephalic position. The brain at stage 23 is far more advanced morpho- The anterior commissure begins to develop in the commis- logically than is generally appreciated, to such an sural plate, which has gained in thickness. It needs to be extent that functional considerations are impera- stressed that the telencephalon and the diencephalon are tive. r not fused. The optic tract reaches the ventral portion of The arrangement of the rhombencephalic nuclei the lateral geniculate body. The dorsal thalamus occupies and tracts at 8 weeks is very similar to that present approximately half of the medial diencephalic surface. In in the newborn. It is likely that the rapid growth addition to the ventricular layer, which is found in all parts of the rhombencephalon during the embryonic pe- of the brain, the rhombic lip has a germinative role. It pro- riod proper is associated with correspondingly early duces the external germinal layer of the cerebellum, which functional activity. has begun to spread over the rostral surface of the ﬂoccu- lus. The rhombic lip also gives off olivo-arcuate and pontine migratory sheets. The cerebellar commissures have Important appeared. Two cerebellar peduncles, the inferior and the superior, are well-developed. The term basal nuclei is best reserved for the basal structures affected pathologically in so-called extrapyramidal motor diseases, i.e., the corpus striatum, the subthalamic nucleus, and the substantia nigra (Fig. 19–6). The inclusion of the claustrum and the amygdaloid complex, however, has little to recommend it.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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220 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Figure 23–1. A right lateral view of the head accompanied by a reconstruction of the brain of an embryo of stage 23, modiﬁed from a drawing by Mary M. Cope (Gilbert, 1957). This stage was not included by Bartelmez and Dekaban (1962). The insula, previously recognizable by its ﬂat surface (stages 18–20), is now clearly indented. Almost the entire diencephalon is covered by the cerebral hemispheres, so that the epiphysis cerebri is no longer visible in this embryo, although it is in some others of the same stage. Contrary to the opinion of certain authors in the past, the telencephalon and the diencephalon are not fused: They are separated from each other by a thin sheet of mesenchyme. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 221

MES- BCENCEPHALIC

CERVICAL M

Di.

PONTINE

Figure 23–2. External features of the brain. (A) The interrupted circle around the drawing serves to emphasize that the brain is more compact than in the previous stage. This is related in part to the progression of such C-shaped features as the hippocampus, the corpora striata, and the entire cerebral hemispheres. The inset shows the topographical changes of the hemispheric poles from stage 18 (continuous line) to stage 23 (dotted line). (B) The three ﬂexures are arranged approximately in the form of the letter M. (C) In this embryo, in contrast to that shown in A, the roof of the diencephalon is still visible externally. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

222 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Figs 23 Ð 19

Figs 23 Ð 24

16, 17

a Post. X Post. lobe

Ant. lobe Ep. b Pineal c recesses

Habenular X

Figure 23–3. Graphic reconstruction prepared from transverse sections to show a median view of the brain in which the internal relief is based on an unpublished Perspektomat reconstruction. The asterisk indicates the junction with the spinal cord. The outline of the left hemisphere is continued as an interrupted line. Only small portions of the diencephalic surface remain uncovered by the hemispheres. The di-telencephalic sulcus is filled with mesenchyme (Figs. 23–19 and 23–24) and the only bridge is that present since the beginning, which is now termed the hemispheric stalk. The stalk contains fibers between the thalamus and the hemisphere, and these travel in the lateral prosencephalic fasciculus, as seen already in the previous stage (Fig. 22–6). Corticothalamic fibers arise in proximity to the future central sulcus, probably in the area that corresponds to the future precentral and/or postcentral gyrus. The commissural plate is very thick and, in some embryos, is approached by fibers of the anterior commissure. Lateral strands leading to the site of the commissure can be observed before crossing fibers are present. The choroid fissure is now longer. It and the hippocampus are shown as if the prosencephalon were transparent. The height of the diencephalon from the chiasmatic plate to the epiphysis is appreciable. The suprapineal recess has developed. The marginal ridge, which separates the dorsal from the ventral thalamus, ends at the level of the interventricular foramen. In this embryo the fibers of the posterior commissure are separated from those of the commissure of the superior colliculi, which latter has two portions. If not earlier, then at least at stage 23 it would seem to be legitimate to use the terms basal nuclei and corpus striatum, and their various components (Fig. 19–6) The internal ridge in the mesencephalon does not seem to indicate the border between neuromeres M1 and M2. The isthmic recess has become a shallow groove. Dopaminergic neurons are no longer produced in the ventrocaudal proliferative area of the mesencephalon, as they 1 1 were from 6 2 to 7 2 weeks (Freeman et al., 1991). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 223

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Figure 23–3. (Continued ) A commissure of considerable size situated adjacent to the isthmic recess seems to be the decussation of the superior cerebellar peduncles (Cooper, 1946a). The cerebellum is not visible in its whole extent because portions of it extend ventrally and laterally, and are hidden by the rhombencephalic tegmentum. The cerebellar commissures contain, from rostral to caudal: (1) decussating fibers of the mesencephalic trigeminal root, (2) decussating vestibulocerebellar fibers, and (3) fibers from the area that includes the dentate nucleus. These ontogenetic data have been partly described by other authors, although only commissure No. 3 seems to correspond with the adult condition. The region with the (cerebellar) commissures is covered by an external germinal layer and so should be regarded already as the primordium of the vermis. The decussation of the trochlear nerves is rostral to the cerebellar commissures. At the cerebrospinal junction two bundles are found: the fasciculus cuneatus (larger) and the fasciculus gracilis (smaller). They form the decussation of the medial lemnisci. More caudally, the pyramidal decussation is shown. The pyramidal tract and its decussation become definitive bundles only at this stage.

Olf. fibers Insula

Figure 23–4. The cranial nerves. (A) A basal view of the brain at stage 23 (Perspektomat reconstruction) showing most of the cranial nerves. The mesencephalon and nerves 3 and 4 are hidden. The combined cerebral hemispheres are now wider than the cerebellum. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

224 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Lat. olf. fibers

Figure 23–4. (Continued ) (B) Reconstruction of the cranial nerves in relationship to some of the “membrane” bones and to the surface of the head. The arrangement of the nerves is now very complex and resembles the adult pattern. The laryngeal nerves are a good example of this (Muller ¨ et al., 1981, 1985). Interestingly, small branches that are easily overlooked in the adult can readily be followed in embryos and fetuses. The recurrent branch of the trochlear nerve is a case in point. The skeletal surroundings of the nerves, however, are still in an unﬁnished state. The facial nerve, for example, is surrounded only by mesenchyme instead of bone, and neither the cribriform plate nor the foramen ovale has formed. All the cranial autonomic ganglia are present. The main divisions of the trigeminal nerve (5) are marked by superscripts 1, 2, and 3. The sheaths of cranial nerves 3, 4, and 5 are partly meningeal and partly peripheral in type (Kehrli et al., 1995). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 225

Figure 23–5. The medial aspect of the left cerebral hemisphere and the left half of the diencephalon are shown, including the lateral ventricular eminence, the stria terminalis (orange), and striatothalamic ﬁbers (mauve). The thick part of the commissural plate (cf. Fig. 23–3) has also been called massa commissuralis. It is penetrated later in trimester 1 by ﬁbers of the fornix. The central stem of the chondrocranium is shown by horizontal hatching. The levels of Figures 23–20 to 23–22 are indicated. A basal view of the brain at Figs 23 Ð stage 23 is shown in Figure 23–4A.

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226 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Figure 23–6A. A sagittal (almost median) section. The (left) cerebral hemisphere is seen to expand basally into the caudally directed olfactory bulb. The choroid plexus and the medial ventricular eminence are evident. The gray area caudal to the eminence is the striatothalamic radiation (lateral prosencephalic fasciculus). The hypophysis can be seen lying in the hypophysial fossa. Caudally in the mesencephalon, the (left) inferior colliculus contains a ventricular outpocketing. The skeletogenous layer of the head (Fig. 22–14B) and the subarachnoid space are recognizable. The amount of mesenchyme external to the skeletogenous layer is increasing. A reconstruction of the vertebral column of this embryo has been published (O’Rahilly, Muller, ¨ and Meyer, 1980, Fig. 3; O’Rahilly, Muller, ¨ and Meyer, 1983, Fig. 1). Some 33 cartilaginous vertebrae are arranged in a ﬂexed column approximately 20–23 mm in length. They do not yet show spinous processes, however, and hence a normal spina biﬁda occulta may be said to be present throughout the length of the column (O’Rahilly, Muller, ¨ and Meyer, 1980). A key (below) for the interpretation of the occipitocervical region seen in Figure 23–6A. Four occipital somites develop in the human and give rise to the basi-occipital portion of the skull; X, Y, and Z refer to the three components of the central pillar of the second cervical vertebra (the axis).

Occipital somites Somites

Basicranium & 3 cervical centra 4 3 Ð 5 5 Arch of atlas & tripartite pillar 6 of axis X 7 Y Occipital (1 Ð 4) 8 & cervical CV2 Z somites CV3 9

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THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 227

SOMITES/ SCLEROTOMES L A T. M E D. L A T. SCLERO- NEURAL PLEXUS CENTRA TOMES ARCHES SPINAL Basioccipital 1 1 GANGLIA & NERVES 2 Basi- 3 Ex- occ. 4 occ. 2 C1 X 5 1 C1 Variation Y 6 2 cervical Z 7 3 3 C3 8 4 12 5 9 4 10 6 H 7 brachial CN T1 8 5 T1 T1 X 1 T1 Y 6

intercostal nn. Z 7 CV 3 20

L1 subcostal n. L1 L1

lumbar Dense zones of sclerotomes 2 Ð 9 and corresponding L4 neural arches S1 S1 S1 Tripartite pillar of axis (X, Y, Z) 30 sacral Cervical centra 3 Ð 5

S4 Hypoglossal & cervical nerves 1 Ð 5 Co.1 coccygeal Co.1 Co. Figure 23–6C. The craniovertebral region based on the authors’ graphic reconstructions. The sclerotomes (on the left), and their derivatives and the perinotochordal components (to the right). The vertical arrows on segment 6 indicate the greater height of the neural arch of the axis. H, site of a hypochordal bow. Figure 23–6B. Scheme of the early development of the human ver- From Muller ¨ and O’Rahilly (2003b) by permission of the Journal tebral column and related nerves. X, Y, and Z refer to the three com- of Anatomy. ponents of the central pillar of the second cervical vertebra (the axis). Based on reconstructions by the authors. From Muller ¨ and O’Rahilly (1994) by permission of the Journal of Anatomy. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

228 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Figure 23–7. Left lateral view of the brain and skull. At this stage, as during the previous 5 weeks, the brain dominates the morphological appearance of the head. The chondrocranium is mainly a basal support for certain parts: the surface of the spheno-ethmoidal cartilage for the anterior part of the olfactory bulb; the sphenoid for the hypothalamus and the hypophysis. The mesencephalon and the cerebellum, however, lack such a basal cartilaginous support. The pons is buttressed mediobasally by the basisphenoid and laterobasally by the cochlear portion of the otic capsule. The portions of the eye and brain covered by skeletal elements are shown by interrupted lines. The protective covering of the superolateral surface of the cerebral hemispheres is beginning to be strengthened by the frontal bones. The lateral portions of the cerebellum and of the pons and medulla oblongata are encased by the parietal laminae and by the tectum posterius and pilae occipitales. The foramen magnum is very extensive, portions of the medulla oblongata being surrounded by mesenchyme only. The cartilages of the pharyngeal arches, including the ﬁrst (Meckel’s), are well developed: those for the auditory ossicles, styloid process, and hyoid and laryngeal cartilages (Muller, ¨ O’Rahilly, and Tucker, 1981). The neural arches of the vertebrae have not fused across the median plane. The normal spina biﬁda totalis characteristic of stage 23 has been studied in detail (O’Rahilly, Muller, ¨ and Meyer, 1980, 1983, 1990a,b). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 229

Figure 23–8. Dorsal (superior) schematic views of the chondrocranium at stages 22 and 23, drawn to the same scale. (A)The main components of the skull are listed on the left, the chief foramina and future canals on the right. At the junction of the basisphenoid, basioccipital, greater wing of the sphenoid, and petrous temporal, the carotid foramen is visible (in black). A superimposed outline (double line) of the chondrocranium at stage 23 aids in showing the considerable increase in size between A and B within 2 or 3 days. (B) The internal acoustic foramen (future meatus) is again evident in the petrous temporal, the jugular foramen is situated posteriorly, and the hypoglossal foramen lies close to the foramen magnum. The thick black, vertical line in both A and B is the notochord in transit from the dens to the cranial base. The main changes are the acquisition of the nasal capsule, the widening of the greater wings of the sphenoid (which support the cerebral hemispheres), and the formation of the parietal laminae (which include the foramen magnum). The occipital part of the brain sits in a skeletal bowl, from which, however, it is protected by ﬂuid-ﬁlled mesenchyme (as in the area between the rhombencephalon and the basicranium in Fig. 23–6). The inventory of the “membrane” bones is almost complete in some embryos of stage 23. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

230 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Dural limiting layer

Falx cerebri

Medial wall of right cerebral hemisphere

Figure 23–9. The dura mater, silver-impregnated. The falx cerebri is clearly formed from the skeletogenous layer, beginning at the level of the future crista galli. Most of the tissue between the cerebral hemispheres is still leptomeningeal, whereas the dural limiting layer is ﬁbrous. The primordium of the superior sagittal sinus is visible at the edge of the developing falx. The beginnings of the transverse and occipital sinuses are also present and are intradural. See key on next page. Bar: 0.2 mm. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 231

Skeletogenous layer Subarachnoid Dural limiting space layer Lateral forebrain Pia mater bundle Lateral eminence

Lateral Basi- 23 Ð 10 ventricle cranium

Skeletogenous layer Dural limiting layer Cistern

Figure 23–10. A coronal section showing a subarachnoid cistern (asterisk in key) situated between the olfactory bulb and the optic nerve. Most of the cisterns found in the adult are now present. Bar: 0.2 mm.

Figure 23–11. Right lateral reconstruction to show (stippled) the tentorium cerebelli. The medial part of the tentorium still extends from the sellar region to the mamillary area, but it is becoming thinner. It separates incompletely two future subarachnoid areas: (1) that of the telencephalon and diencephalon, and (2) that of the rhombencephalon, including the cerebellum. In this reconstruction only the lateral parts are represented: the 23 Ð 12 rostrolateral and the caudolateral, joined at the future tentorial notch, which is continuous with the medial part. Caudolateral part The development of the tentorium during the fetal period Rostrolateral part is complicated, but has been well schematized by Tentorial notch Markowski (1922) and measured by Klintworth (1967). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

232 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Cortical Figure 23–12. A section through the eyes, nasal plate cavity, and pharynx. The cortical plate extends even to the rostralmost levels. The primordium of the falx cerebri appears as a septum between the two olfactory bulbs. It extends from the skeletogenous layer towards and into the longitudinal ﬁssure. The closeness of the two cerebral hemispheres can be appreciated here and also in Figures 23–14 and 23–15. Olf. bulb Figures 23–12 and 23–14 to 23–19 are transverse sections that give an overall view of the cerebral hemispheres. The bars represent 1 mm.

Cervical vertebra

Fig. 23 Ð 13B

Retina Figure 23–13. The development of the eye. See Vitreous body also Figure 13–4. Pigmented The eye arises from (1) neural ectoderm (the layer retinal disc), (2) somatic ectoderm (the lens disc Cerebral and anterior epithelium of the cornea), (3) layer neural crest (probably the stroma and posterior Lens epithelium of the cornea, the sclera and choroid, and the ciliary muscle), and (4) mesoderm (the Conjunctival sclera and uvea). In contrast, the internal ear sac arises from somatic ectoderm, and the vestibular and cochlear ganglia mostly from neural crest. A The otic and epipharyngeal discs associated with ganglia of the cranial nerves were regarded by Streeter as islands of neural ectoderm (Table 7–1). (A) General view at 8 weeks (stage 23). At about 12 weeks the rim of the optic cup will differentiate into the ciliary region and the iris will begin to develop. The front part of the optic cup will then become the ciliary and iridial parts of the retina, to which other layers will be added externally. The slight separation between the pigment layer (No. 1) and the remaining layers (Nos. 2–10) of the retina seen here in a few places is the site of the former optic ventricle (Fig. 14–6) and shows where so-called detachment of (in reality a separation within) the retina would occur. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 233

B Permanent layers

1. Pigment layer 3. ELM

Developmental layers

External "neuroblastic"

Transient fiber

Internal "neuroblastic"

9. N. fiber layer 10. ILM

Figure 23–13. (Continued ) (B) The retina at 7 weeks (stage 20). Of the 10 layers that are characteristic later, layers 1, 3, 9, and 10 are present here. ×400. Of the direct derivatives of the neuroepithelium of the optic cup (Figs. 14–6 and, 15–8), the external “neuroblastic” layer will give rise to layers 4, 5, and 6 (external nuclear, external plexiform, and internal nuclear) and the transient ﬁber zone to layer 7 (internal plexiform), both “neuroblastic” layers will contribute to layer 8 (ganglion cells). (C) The retina at the end of trimester 2 (25 weeks). All 10 layers have been identiﬁable since approximately 15 weeks. For details of retinal development see Rhodes (1979). ELM, ILM, external and internal limiting membranes. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

234 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Hipp.

Nucleus accumbens

Basi- sphenoid Chiasma

Basi- occipital 23 Ð 15 14 & dens

Figure 23–14. A section along the base of the skull. The internal ear is shown on each side. A small, basal part of the diencephalon can be seen at the level of the tuberculum sellae. The optic chiasma and the third ventricle are visible. The mesenchyme surrounding the diencephalon and telencephalon basally is the meshwork of a basal cistern. The cerebral hemispheres contain the septal area with the nucleus accumbens, the hippocampus, and the lateral ventricular eminence, which last is the primordium of the caudate nucleus. Ontogenetically, the nucleus accumbens is more closely related to the corpus striatum than to the septal nuclei. In addition, its origin is possibly associated with the medial ventricular eminence (Sidman and Rakic, 1982). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 235

Lat. & med. eminences

Prosenceph. septum Sulcus terminalis V3 Chiasma

Malleus Incus Stapes

Occipital condyle

Int. carotid a.

V3 Ganglion 5 Di. Optic chiasma Otic capsule AH Figure 23–15. A section through the Basi- sphenoid hypophysial fossa, the adenohypophysis, and the optic chiasma. A small, basal part of the diencephalon and third ventricle is included. The prosencephalic septum is prominent. Nerve 7 The sulcus terminalis limits it laterally, Notochord towards the beginning of the medial ventricular eminence. At this level the lateral eminence is mainly caudate Hypoglossal Jugular nucleus. canal foramen The internal carotid artery traverses Dens the mesenchyme of the future cavernous sinus. Its histological structure already resembles that of the adult (Tobenas-Dujardin et al., 2005). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

236 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

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THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 237

Figure 23–16. A section through the insular region and the left interventricular foramen. The cortical plate, which first appeared at stage 21 in the insular region, is thickest there, partly because of the increase of the intercellular spaces. The internal capsule, putamen, and globus pallidus externus are visible. The gray band lateral to the putamen is the claustrum. The choroid plexus at this time has become lobular, the epithelium is low prismatic, and the gelatinous stroma resembles that in the umbilical cord (Ariëns Kappers, 1966). The insula becomes buried during the fetal period and will possess extensive connections, as well as numerous functions (Augustine, 1996). In the key drawing, arrows indicate the course of the internal capsule. Its fibers, mostly thalamocortical, become dispersed in the intermediate layer and the subplate of the neopallium. Some fibers may be corticothalamic, although it is doubtful that they reach the thalamus already. The developing corpus striatum is composed of several neurochemically defined populations, and neuropeptide genes are expressed during trimester 2 (Brana et al., 1995). Moreover, the subependymal germinal layer is voluminous at this time, whereas the matrix disappears near birth. Neuropeptide gene expression is already under dopamine control through innervation from the substantia nigra (Freeman et al., 1995). The density of dopaminergic innervation is greatest caudal to the genu of the corpus callosum (Verney et al., 1993). Most, if not all, striatal neurons bear dopamine receptors (Brana et al., 1996). In addition to the nigrostriatal influence, corticostriatal inputs are believed to be important.

Figure 23–17. The sulcus terminalis is the site of the future thalamostriate vein and is parallel to the stria terminalis, which is recognizable already at stage 22 (Fig. 22–6B). The order of structures, from medial to lateral, is (1) hippocampus (still prominent rostrally), (2) choroid fissure and plexus, (3) thalamus and lamina affixa, (4) sulcus terminalis, and (5) caudate nucleus. Arrows indicate the internal capsule (in orange-brown). Later in prenatal life the corpus callosum and the fornix become interposed between the rostral remains of the hippocampus and the choroid fissure. Then the order of structures is similar to that in the adult, as shown in the lower drawing: (1) indusium griseum and longitudinal striae (rostral remains of the hippocampus), (1a) corpus callosum and fornix, (2) choroid fissure and plexus, (3) thalamus and lamina affixa, (4) thalamostriate vein and stria terminalis (in the sulcus terminalis), and (5) caudate nucleus. The internal capsule (arrows) passes first between two telencephalic structures (finer stippling), the caudate nucleus and the putamen, and then between two diencephalic structures (coarser stippling), the thalamus and the globus pallidus. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

Dural limiting layer Leptomeninges Subpial Cortical Subplate Intermediate Subventricular & ventricular

Figure 23–18. The neopallial cortex showing cell bodies. Azan staining. Cf. silver impregnation in Figures 23–22 to 23–24, showing ﬁbers. The relatively loose subpial layer and subplate (derived from the primordial plexiform layer) are present before stage 21.

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THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 239

Thalamus dorsalis Hypo- thalamic sulcus Ext. germinal layer Flocculus

Internal cerebellar swelling

Rhombic lip

Dentate nucleus

Sulcus limitans

Fibers

Ventricular & intermediate layers

Figure 23–19. A section through the interpenduncular fossa, which appears in the middle of the photomicrograph. The dorsal thalamus, which has enlarged considerably, is evident at this level and is characterized by a dark (subventricular) layer and a clearer superficial (intermediate) layer. The matrix is still in its migrational period (Richter, 1965). Its ventricular zone is still thicker than that of the ventral thalamus. A mesenchymal sheet, the primary meninx, is noteworthy between the diencephalon and the cerebral hemispheres. The cerebellum has developed an external germinal layer, the extent of which has been reconstructed (Muller ¨ and O’Rahilly, 1990b, Fig. 2B; Müller and O’Rahilly, 1990c, Fig. 1A). The fibers in the cerebellum are mostly from the inferior cerebellar peduncle, rostral to which the dentate nucleus can be distinguished. (See also the scheme in Fig. 21–20.) A small rectangular section through the interpeduncular fossa, containing numerous small blood vessels, is visible below the third ventricle. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

240 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Figures 23–20 to 23–22 show sections through the frontal part of the neopallium of a silver-impregnated embryo. The levels are indicated in Figure 23–5. The bars represent 0.05 mm.

V Figure 23–20. A section through an e area in which a cortical plate has not yet n developed. The primordial plexiform layer t contains bipolar horizontal and other r Primordial i plexiform neurons. Radial ﬁbers can be seen c. layer between the vertically arranged cells of the ventricular layer. The cell columns & (“proliferative units” of Rakic) are deﬁned s by glial septa. The postmitotic cells u migrate towards the periphery, and the b bipolar radial glial cells are believed to v guide them. e n t r i c

Subpial layer

Cortical plate

Pia mater

Subplate Intermediate layer

Figure 23–21. An overall view of an area that shows the cortical plate, which is situated within the former cell-sparse primordial plexiform layer (Fig. 21–7). The plate now consists of five or more cellular rows that have migrated radially from the ventricular layer. The elements of the cortical unit and those of the proliferative unit form an ontogenetic column (Rakic). The following are present from the ventricular towards the pial surface: ventricular layer, intermediate layer, subplate, cortical plate, and subpial layer. Tangentially arranged nerve fibers are seen in the subpial layer, which is future cortical layer 1, and also between the cortical plate and the intermediate layer (shown also in Fig. 23–22). The latter fibers are specific thalamic afferents, which are transiently in the subplate before they invade the cortical plate. The early monoamine projection to the subplate that has been shown at about this time is believed to be permanent, although direct data in the human are lacking. Fibers from catecholamine neurons enter the intermediate layer (Zecevic and Verney, 1995). Nigrostriatal fibers arrive in the hemispheres at 8 weeks (Freeman et al., 1991). Other afferents are from the brain stem and the basal part of the prosencephalon. The labels for the different zones shown here are based on the fact that the layer internal to the cortical plate is rich in tangential fibers, but poor in cells, which is characteristic of the subplate. The space between the pia mater and the subpial layer is artifactual. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 241

Subpial layer

Cortical plate

Subplate

Figure 23–22. The peripheral part of Figure 23–21 [enlarged area, indicated by rectangle]. Numerous silver-impregnated, tangentially arranged neurites are evident within the subplate. On its ﬁrst appearance, a part of the cortical plate contains early-generated subplate cells. Later, those cells leave the cortical layer and come to reside in the subcortical layer. They may give off the descending axons that run in the intermediate zone and reach the internal capsule. Although formerly it was thought that only layers 2 to 5 develop from the cortical plate, it is now generally believed that layer 6 is also derived from the plate (Mrzijak et al., 1988). The ﬁrst synapses in the brain appear in the two parts of the former primordial plexiform layer in human embryos and fetuses. Already at stage 19, that layer contains horizontal cells corresponding to Cajal–Retzius cells (Larroche and Houcine, 1982), which form the earliest synapses in the neopallium of the human brain (Choi, 1988), probably at stage 17.

Figure 23–23. Formation of the cerebral cortex. (A) The ventricular zone or layer. (B) A marginal zone (green) is added. It is known as the primordial plexiform layer, because it contains long nerve ﬁbers that arrive early (stages 13–15) from the brain stem. Furthermore, it contains horizontal Cajal-Retzius cells, which are the earliest neurons to be derived from the ventricular layer. (C) An intermediate layer is added between the ventricular and primordial plexiform layers. It consists of cells that have migrated peripherally from the ventricular layer. (D) At stage 21 the cortical plate (blue) begins to form within the primordial plexiform layer. (D) Medial view of the left half of the brain at 8 weeks. (E) The deﬁnitive cerebral cortex of the adult consists typically of six layers. Layers 2–6 are derived from the cortical plate. A giant pyramidal cell is shown in layer 5, and its apical dendrite (a.d.) and axon (a) are Preplate = primordial plexiform layer Cortical layers indicated. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

242 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Figure 23–24. The hippocampus and adjoining areas. Adjacent to 1, the multilayered epithelial lamina, is 2, the area dentata. Here the cell columns of the ventricular layer have become looser, and an intermediate layer is not present. The hippocampus sensu stricto, 3, which reaches the temporal pole at this stage, is characterized in general, as compared with the neocortex, by wide marginal and intermediate layers and a narrow ventricular layer. The cell columns of the ventricular layer are loose, and adjacent to them are cells, the axes of which resemble those of the ventricular layer; they represent probably future pyramidal cells (7). The tangenitally arranged cells in the marginal layer are subpial or marginal cells (6), which were also observed in this early phase of hippocampal development by Hippocampus Humphrey (1965) and Kahle (1969). The distances between individual cells in the intermediate layer of the hippocampus sensu stricto are greater than in any other part of the telencephalon. In the absence of special techniques (e.g., radioactive marking) it is scarcely possible to decide whether marginal cells of the present scheme correspond to a ﬁrst wave of early-generated pyramidal cells or simply represent migrating cells from the area dentata. The mesocortex, 4, is between the hippocampus sensu stricto and the neopallium, and possesses the narrowest intermediate layer. The hippocampus sensu lato comprises the areas marked 2, 3, and 4. Mesenchyme is noteworthy between the telencephalic surfaces at the right and the diencephalon at the left. Bar: 0.1 mm. 6

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THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 243

Figure 23–25. The medial and lateral Med. eminence ventricular eminences, and the Lat. eminence hemispheric stalk. The sulcus terminalis is evident medially (upper arrowhead). The subventricular layer of the lateral eminence, from which the caudate nucleus arises, continues into the putamen. The fibers of the external capsule, which are few Caudate at this stage, form a sagittal sheet that nucleus follows approximately the direction of the olfactory tract, but runs more centrally. The fibers stem mostly from the piriform area. The fibers of the internal capsule are visible between the putamen laterally and the primordium of the caudate nucleus Globus medially. The globus pallidus externus at pallidus this relatively caudal level lies in the ext. hemispheric stalk, whereas more rostrally Hemispheric stalk Putamen it is far more telencephalic in position. The internal capsule at this stage contains thalamostriatal, thalamocortical, corticothalamic, and nigrostriatal fibers, probably in that order. (The nigrostriatal bundle can first be discerned at 8 weeks: Freeman et al., 1991.) On their way to and from the diencephalon, the fibers of the internal capsule pass through the hemispheric stalk (His, 1904; Hochstetter, 1919), which is found between two boundaries: the sulcus terminalis on the ventricular surface (upper arrow), and the di-telencephalic sulcus at the external surface (lower arrow). Figures 23–25 and 23–26 are silver-impregnated sections. The bars represent 0.2 mm.

Cortical plate Internal capsule

Figure 23–26. A more ventral section at the level of the interventricular foramen (Fig. 23–5). Neopallial fibers, as well as fibers to and from the region of the lateral ventricular eminence, are visible. Those fibers are part of the internal capsule and are mostly 23 Ð 26 25 thalamocortical. They arise in the nearby dorsal thalamus and cross the di-telencephalic boundary, which is indicated by the sulcus terminalis and the stria terminalis (cf. Fig. 24–10). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

244 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

A Mesocoele

Area membranacea rostralis caudalis V4 Inf. horn

Olfactory ventricle

Lateral recess of V4

"Blindsack"

Figure 23–27. The ventricular system. (A) A left lateral view showing the now small interventricular foramen, and the overlap between the lateral and third ventricles. Anterior and inferior horns (part of the C formation) are well defined, but the posterior horn has not yet appeared. The future aqueduct is becoming delineated by two narrow regions, one of which is at the isthmus rhombencephali. Compared with the corresponding areas in stages 17 and 18, the epithelium of the areae membranaceae caudalis et rostralis is cuboidal rather than flat. No apertures are yet present in the roof of the fourth ventricle. An asterisk marks the obex. (B) A dorsal view of the ventricular system. Two pairs of semicircles can be seen: the left and right lateral ventricles rostrally, and the lateral recesses and the main part of the fourth ventricle caudally. The third ventricle is foreshortened in this perspective, whereas the future aqueduct and its bilateral Blindsack are seen in their full extent. The area choroidea of the roof of the telencephalon medium consists of two cellular rows and is the thinnest portion of the lamina terminalis. An area membranacea rostralis and an area membranacea caudalis appear at stage 18. The caudal area has also been termed the saccular ventricular diverticulum (Wilson, 1937) and the central bulge (Brocklehurst, 1969). It is possible that the area permits the passage of cerebrospinal fluid (as suggested in the mouse), in which case a functional rather than a structural median aperture could be said to be present at this time. It has been claimed that the median and lateral apertures (of Magendie and Luschka) are present at 20 and 220 mm, respectively (Brocklehurst, 1969), but further study of this region is required. It is likely, as has been suggested, that the cerebrospinal fluid is nutritive while vascularization is progressing, while the wall of the brain is increasing in thickness, and while the lateral ventricles are decreasing proportionately. This is supported by the relatively late appearance of capillaries that penetrate the wall of the brain, namely at stages 12 (hindbrain), 13 (midbrain), and 16 (cerebral hemispheres). O’Rahilly and Muller ¨ (1990, Table 1) have provided measurements of the ventricular system at this stage. A three-dimensional reconstruction, prepared ultrasonically, of the ventricles in vivo in an embryo of 29 mm (Blaas et al., 1998) confirms the accuracy of the more detailed graphic reconstruction shown here. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

Vascular plexus B A

Mesencephalon

Mesocoel V4 Alar lamina B Internal cerebellar Sulcus swelling limitans

Ventricular layer

PÐL fissure

Ext. germinal layer Basal lamina Flocculus Rhombic lip

Figure 23–28. The cerebellum at the end of the embryonic period. (A) Photomicrograph of a section through the isthmus (above) and the mesencephalon (below). The decussation of the trochlear nerves (X4) develops in situ in the isthmus and does not migrate caudorostrally, as has been claimed. (B) A more ventral section, in which caudal is shown uppermost. The external cerebellar swelling (at the right) presents the rhombic lip and the ﬂocculus, the latter now being covered by a thin sheath of external germnal layer, which is given off from the rhombic lip. An adjacent new and smaller swelling (unnamed by both Hochstetter and Larsell) contains the primordium of the dentate nucleus and (in more ventral sections) the inferior cerebellar peduncle. Numerous blood vessels penetrate as far as the ventricular layer.

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246 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

C Rhombic lip Velum X4

Taenia Nodule Rh. 1

Taenia

Sulcus limitans

Mesencephalon Ext. germinal layer 4 X4

Taenia of V4 Ext. germinal Sulcus layer of Rh. 1 limitans X4

Sulcus limitans Roof of isthmus Plane of section of photomicrographs

Vermis Flocculus (nodule)

Figure 23–28. (Continued). (C) A reconstruction of the roof of the isthmus (the future superior medullary velum) and rhombomere 1. The external germinal layer (gray) presents a slight median elevation, which is the beginning of the vermis. Below, a reconstruction of the cerebellar hemispheres already showing areas of fusion. (D) A reconstruction (based partly on Hochstetter, 1929) showing the cerebellar hemispheres from behind. On the right a median outline and a superior view of the isthmus and cerebellum indicating (in mauve) the plane of section of the photomicrographs on the facing page. The uppermost three photographs show the isthmus and vermis between the mesencephalic Blindsacks of the two sides. The lowermost view demonstrates fusion between the two cerebellar hemispheres. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 247

"Blindsack"

Isthmus

Vermis Ext. germinal layer

Cerebellar plate

Ext. germinal layer Ventric. layer Fibers Fused ventricular layers

Dense & loose intermediate layers

Figure 23–28. (Continued). (E) The uppermost three photographs show the isthmus and vermis between the mesencephalic Blindsacks of the two sides. The lowermost view demonstrates fusion between the two cerebellar hemispheres. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

g c

Raphe magnus nuclei

Somatic afferent

Visceral afferent

Visceral efferent

Somatic efferent

Inferior cerebellar peduncle

Figure 23–29. Dorsal view of a reconstruction of the rhombencephalon (silver-impregnated), showing nuclei and tracts. The caudal direction is towards the top of the page. The right embryonic half is on the left of the drawing. The cerebellum has not been included. The white line on the right-hand side of the drawing represents the cut edge of the roof of the fourth ventricle. Black triangles indicate the levels of the reconstructed cross sections in Figure 23–30. The nucleus funiculi teretis (Kappenkern of the genu of the facial nerve) is included. The two (ascending and descending) intramural parts of the facial nerve are indicated by the numeral 7. The inset shows the four vestibular nuclei. The rhombic lip, an important proliferative area in the alar plate, is the source of two superﬁcially situated migratory areas: the so-called olivo-arcuate caudally, and the pontine rostrally. Two of the three migratory areas found at stage 23 have been reconstructed (Muller ¨ and O’Rahilly, 1990c, Fig. 1). The term “olivo-arcuate migration” (Essick, 1912), however, is unsatisfactory, because it has been shown (in the monkey) that the olivary nuclei arise mainly from the ventricular layer. The rhombencephalon at this stage is already very complicated and comparable in many respects to that of the newborn (Fig. 26–5). Its rapid development suggests an early onset of functional activity.

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Vestibulo- spinal tr.

and cuneo-

Figure 23–30. Reconstructed coronal sections of the rhombencephalon. The levels of the sections (A)–(F) in rostrocaudal succession are indicated in Figure 23–29 by black triangles. (A) Section showing the nuclei of the trigeminal nerve and the transition to the cerebellum via the inferior cerebellar peduncle. The position of the trigeminal nuclei here is conditioned by the slight obliquity of this slice. The inset in the lower right-hand corner of the page shows fiber bundles of the motor part, of the intermediate, and of the sensory portion of the trigeminal nerve. (B) Area of the abducent and facial nerves, showing the superior olivary nucleus, and the superior vestibular nucleus and its fibers to the medial longitudinal fasciculus. (C) Entry of the cochlear nerve. Ventral and dorsal cochlear nuclei are lateral to the inferior cerebellar peduncle. The fibers from the dorsal cochlear nucleus that run medially constitute the intermediate acoustic striae. A dagger indicates the tectobulbar and tectospinal tracts. (D) Entry of the sensory glossopharyngeal fibers that run directly to the tractus solitarius. Olivocerebellar fibers can be seen passing towards the inferior cerebellar peduncle. (E) and (F) Inferior olivary, vagal, accessory, and hypoglossal nuclei. A small bundle of corticospinal (pyramidal) fibers is present in all the sections.

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250 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Figs. 23 Ð 29 & 23 Ð 31 Three decussations are shown from dorsal to ventral: (a) lemniscal produced by cuneate ﬁbers in the medulla (c); (b) lemniscal produced by gracile ﬁbers in the medulla (g); and a (c) pyramidal in the cervical spinal cord and shown in b c greater detail in Figure 23-32.

Figure 23–31. Section showing in the median plane, from above downwards, spinal cord (cervical region with pyramidal decussation), nerve roots, septum medullae (with olivary nuclei immediately at each side), basilar artery, third ventricle, and diencephalon. Later- ally, and again from above downwards, the jugular process (medial to which is the leptomeningeal or future subarachnoid space), otic capsule (including sections of three semicircular ducts), dura (a prominent line encircling both spinal cord and brain), and a small portion of the cerebral hemisphere. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 251

Cuneatus Gracilis

Lat. corticospinal

Motor neurons

Ant. corticospinal

Figure 23–32. The pyramidal decussation in the transitional region of the medulla oblongata and spinal cord. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

252 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Figure 23–33. The arteries in a dorsal view, with a key drawing on the left. This is the ﬁrst published reconstruction of the arteries at stage 23. The right and left sides were reconstructed separately, and the two sides are slightly different. Most cranial nerves, the optic chiasma, and part of the optic tracts are shown. The main components of the circulus arteriosus have been present since stage 16 (Fig. 16–5) and the circle has been complete since stage 19 (Fig. 21–23). The arteries to the choroid plexus of the lateral ventricles come from one of the deep branches of the anterior cerebral artery (anterior choroid a.) and from the posterior cerebral artery (posterior choroid a.). Two anterior communicating arteries are present, a frequent ﬁnding later in life. Apart from differences in the proportions, the arterial pattern resembles closely that of the adult. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 253

Figure 23–34. Reconstruction of the arteries in a right lateral view with a key drawing below. The overlapping that occurs in a dorsal representation is omitted. The posterior communicating artery is clearer than in Figure 23–33. Noteworthy are the serpentine course of the internal carotid and the many striatal branches that penetrate the anterior perforated substance. The ramifications of the middle cerebral are not shown. The anterior cerebral gives off a branch to the olfactory bulb and significant branches to the medial surface of the cerebral hemisphere. An example of the differing proportions in the embryo is seen in the posterior communicating artery, which joins the internal carotid long before the latter divides into the anterior and middle cerebral arteries. The internal carotid develops early (stages 11–13) and is followed by the posterior communicating (stage 14), basilar and vertebral (stage 16), anterior, middle, and posterior cerebral (stage 17), and finally the anterior communicating (stage 21), thereby completing the circulus arteriosus (Figs. 21–22 and 21–23). Initially the posterior communicating is an important channel, and its distal end constitutes the stem of the posterior cerebral. It supplies the hindbrain until the vertebral system is completed and the basilar artery becomes dominant. The hypoglossal artery disappeared after stage 15, and the stapedial artery likewise at about stage 20, whereas the trigeminal artery is still present. The main channels of the venous system correspond to the reconstructions of a stage 21 (24 mm) embryo shown by Padget (1957). The cavernous sinus is not yet present. The beginning development of the superior sagittal sinus is shown in Figure 23–9. Bilateral foramina for emissary veins are present in the parietal part of the chondrocranium. The capsuloparietal foramen constantly contains a vein that connects the transverse sinus to the external surface of the chondrocranium. A bilateral emissary foramen in the occipital contains a vein that connects the sigmoid sinus with the external surface (Muller ¨ and O’Rahilly, 1980). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

254 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

AB C

Rh. M M

Rh. Di. Di. HemispheresDi.

Hem. Hem.

1 Figure 23–35. Examples of in vivo ultrasonic images at 6–7 2 postfertilizational weeks, i.e., during the embryonic period. (A) 12.9 mm. Obliquely coronal section showing cerebral hemispheres. (B) 15 mm. Sagittal view showing mesencephalic ﬂexure. (C) 15 mm. Another obliquely coronal section showing hemispheres. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 255

Cerebellum Lateral recess

M M Rh.

Di. Cbl Choroid plexus

V4 Medulla Spinal cord oblong.

Figure 23–35. (Continued ) (D) 18 mm. Sagittal view showing the spinal cord. (E) 25 mm. Coronal section, the “hole in the head” view. Courtesy of Dr. Harm-Gerd Blaas, Trondheim, Norway. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

256 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

AB C D E

1 Figure 23–35. (Continued ) In vivo ultrasonic 3D reconstructions of the ventricular system at 5 2 –9 postfertilizational weeks. The isthmic region in these views appears narrower than that seen in graphic reconstructions. (A) 10.1 mm. The rhombencephalic cavity is at the top of the head. (B) 17 mm. The hand is distinct. (C) 21.5 mm. The mesencephalic cavity is relatively large. (D) 29 mm. The “praying feet” position is characteristic. (E) 38 mm. The volume of the cerebral hemispheres keeps increasing. Color scheme for this ﬁgure: Yellow, lateral ventricle. Green, third ventricle. Red, mesencephalic cavity (future aqueduct). Blue, fourth ventricle. Courtesy of Dr. Harm-Gerd Blaas, Trondheim, Norway.

Figure 23–35. (Continued ) These two views are of the embryo marked B on page 254. With the addition of contours they were used in the calculation of volumes of the embryonic body and of the ventricular cavities (Blaas et al., 1998). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE BRAIN AT THE END OF THE EMBRYONIC PERIOD 257

TABLE 23–1. Some Examples of Genes Already Known to Be Implicated in the Development of the Human Nervous System

Genes Neural Region Malformations References

En-2 Mes-rhombencephalon Song et al., 1996 HOXA3 Neural crest of pharyngeal arches Goodman, 2003 HOXD13 (hand) With HOXA13 the only two Goodman, 2003 HOX genes mutated in human HOXA13 (genital) Goodman, 2003 PAX 1 Spina biﬁda Hol et al., 1996 (cited in Dahl et al., 1997) PAX3 Neural plate and early fusion Dysraphia Gerard´ et al., 1995 PAX3 Neural crest Waardenburg syndrome; Baldwin et al., 1992 (cited in mutation in 50% Dahl et al., 1997) PAX5 Mes-rhombencephalic Gerard´ et al., 1995 boundary and spinal cord PAX 6 “Master control gene” Aniridia; Gerard´ et al., 1995 congenital cataract (Peter MacDonald and Wilson, 1996 anomaly) (cited in Dahl et al., 1997) PAX 6 Early morphogenesis of eyes Goodman, 2003 ROBO3 Crossing of corticospinal and Gaze palsy with progressive Jen et al., 2004 somatosensory axons in scoliosis medulla SHH Brain Holoprosencephaly Belloni et al., 1996 SHH Organogenesis of brain, eye, Holoprosencephaly Muenke and Cohen, 2000 somites, spinal cord, craniofacial structures SHH Signal of prechordal plate Holoprosencephaly Goodman, 2003 inducing forebrain SHH Differentiation of ﬂoor plate, Roessler et al., 1996 rostrocaudal axis SIX 3 Deletion on chromosome Oliver et al., 1995 2p21–p22: holoprosencephaly type 2 SIX 3 At 2p21 4 different mutations Schell et al., 1996 in HPE patients Wallis et al., 1999 (cited in Muenke and Cohen, 2000 SIX 3 Gene mutated in some Pasquier et al., 2000 patients with HPE SIX 3 SIX 3 at 2p21 present from Grenadino et al., 1999 5–7 weeks ZIG2 Formation and differentiation Holoprosencephaly with mild Goodman, 2003 of neural tube facial dysmorphism

Examples in Mouse and Rat Based on Current Literature SIX Expressed in neural plate rostrally Otx2 Mesencephalon En-1, En-2 Mes-rhombencephalon Gbx2 Rhmbomere 1, cerebellum Dlx-2 Medial ventricular eminence, ventral thalamus Emx1, 2 Dentate gyrus P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

258 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Figure 23–36. A comparison of the brain at 6 weeks with that at 8 weeks. A median section at stage 17 (in mauve) has been superimposed on one at stage 23, drawn to the same scale and centered on the ﬂoor of the mesencephalon. In the intervening fortnight (1) the brain has increased in size (approximately 30%), (2) the cervical and pontine ﬂexures have become more Stage 17 pronounced, and (3) the roof of the diencephalon has become almost completely covered by the cerebral hemispheres.

Stage 23

The Cerebellum r Develops from the alar plate of both the isthmic and the ﬁrst rhombencephalic neuromeres. The rhombic lip, which is a part of the alar plate, is not the sole origin of the cerebellum. At Stage 23: r The two intraventricular cerebellar components grow towards the median plane and begin to fuse rostrally. r Two areas of fusion are visible: (1) that adjacent to the superior velum would appear to be the nodule and (2) that beginning at the level of the cerebellar hemispheres. r The roof of the isthmus is the superior medullary velum.

Medulloblastoma. The external granular layer of the cerebellum, which appears at this stage and disappears within 1–2 years after birth, is generally believed to be the origin of so-called medulloblastoma, most instances of which occur in the vermis. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE SPINAL CORD NEUROTERATOLOGY 259 THE SPINAL CORD IN THE NEUROTERATOLOGY: EMBRYONIC PERIOD (MYELO)MENINGOCELE

Both the brain and the spinal cord are modifications of a Myelomeningocele involves the neural tube and hence ap- continuous neural tube, so that, although this book is on pears early, e.g., at stage 10 or 11 in the cervical and the brain, it is appropriate to provide a summary of the thoracic regions. At the lumbosacral level, where it is development of the spinal cord. believed by many to be converted from a myeloschisis, The alar and basal laminae of the neural tube (Fig. 21– myelomeningocele arises also during the period of primary 7) are separated by the sulcus limitans. The alar laminae, neurulation (stages 8–12), although it is not a simple fail- essentially afferent in function, are united by the roof plate, ure of neural closure. whereas the basal laminae, essentially efferent (the Bell– Lumbosacral lesions covered by intact skin are be- Magendie “law”), are joined by the floor plate, which is lieved to appear during secondary neurulation (Lemire et induced by the notochord. At 6 weeks the spinal cord shows al., 1975), but it should be stressed that lesions in the tran- ventricular, intermediate, and marginal layers, and all the sitional zone between primary and secondary neurulation spinal nerves are present (stage 17). are not well understood. The following sequence of appearance has been found Numerous embryos and fetuses with myelomeningo- in the human embryo (Marti et al., 1987): (1) cells of the cele have been described (Lemire et al., 1975), including floor plate, (2) motor neurons, which arise in rostrocaudal an embryo of stage 14 with caudal myeloschisis. It was be- and ventrodorsal gradients; (3) cells of the nucleus pro- lieved that the lesion occurred before closure of the neural prius, and (4) sensory neurons (for pain afferents) in the tube; defects in the basement membrane of the neural ec- substantia gelatinosa. Motor neurons, the first neural cells toderm were noted and the condition was considered to to show expression of neuronal antigens, present synapses have been a forerunner of lumbosacral myelomeningocele very early, namely at stage 15 (Okado, 1981). Synapses (Lemire et al., 1965). between primary afferents and interneurons of the sub- Meningocele probably arises late in the embryonic pe- stantia gelatinosa also appear early (stage 17). The first riod (e.g., stages 18–23) or early in the fetal period. The movements observed ultrasonically (Okado, 1981; de Vries, timing of various anomalies, however, is tentative and the 1 1992) occur at about 5 2 postfertilizational weeks (probably retrospective use of embryological timetables for ascertain- stage 16). ment of origin and causes of congenital malformations is The trigeminospinal tract enters the cervical region of hazardous, as frequently stressed by Warkany. the cord already at 6 weeks (stage 17), the dorsal funiculus The possible reopening of a closed neural tube may be is prominent, and the tractus solitarius soon reaches the operative in at least some instances (O’Rahilly and Muller, ¨ thoracic region (stage 19). By the end of the embryonic 1988), especially in cervical or thoracic defects and in period (stage 23), the funiculi gracilis et cuneatus, medial meningoceles. Moreover, experimental support is available. lemniscus, corticopinal tracts, and lateral spinothalamic For example, the fetuses of rats subjected to cyclophos- tract are present (Muller ¨ and O’Rahilly, 1990a). phamide showed fewer mesenchymal cells, reduced cyto- At this time the spinal cord still extends as far as the plasmic processes, and poor organization and differenti- caudal end of the vertebral column (O’Rahilly, Muller, ¨ and ation. These features, as well as degenerative changes in Meyer, 1980, Fig. 4). Subsequently some dedifferentiation the neural epithelium, “appeared to underlie the reopen- takes place caudally and the spinal cord “ascends” to a lum- ing of the closed neural tube” that resulted in exencephaly bar level during the first half of prenatal life, reaching L3 and cranioschisis (Padmanabhan). Perhaps a mesenchy- at birth and generally L1 or L2 in the adult. The dispropor- mal defect may be considered, in a certain sense, to be a tion in growth between the spinal cord and the vertebral locus minoris resistentiae that would allow reopening. column results in the characteristically increasing obliq- It is of interest that neural tube defects at stage 12 are uity of the roots of the spinal nerves from lower cervical more than 40 times more frequent than the number found to coccygeal; those of L2 to Co. 1 constitute the cauda at birth, so that most of the affected conceptuses are lost equina. before birth, probably mainly within the embryonic period (Shiota, 1991). P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

260 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

Characteristics of the Embryonic Period

Prenatal life is conveniently and justifiably divided into embryonic and fetal periods, and that distinction is not arbitrary, as sometimes claimed. The embryonic period: r has a long history of being considered distinct from the fetal period. r is that during which several thousand new features appear with great rapidity, whereas the fetal period is characterized more by the elaboration of existing structures. r is that which has been successfully subdivided into 23 developmental stages, whereas the fetal period, because of the less striking developmental changes, has so far proved resistant to a morphological staging system. r occupies the first 8 postfertilizational weeks, as confirmed by ultrasonography. r is that during which the vast majority of congenital anomalies appear. P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

THE SPINAL CORD NEUROTERATOLOGY 261

Figure 23–37. Summary of some of the major morphological events in terms of stages in a graph of the greatest embryonic length plotted against postfertilizational age.

Chondrification P1: JYS JWDD017-23 JWDD017-ORahilly June 13, 2006 13:30 Char Count= 0

262 Chapter 23: THE BRAIN AT THE END OF THE EMBRYONIC PERIOD

TABLE 23–2. Principal Research Publications on the Nervous System in Staged Human Embryos

Stages Major Topic References

8 Neural folds O’Rahilly and Muller¨ (1981) Prechordal plate Muller¨ and O’Rahilly (2003a) 9 Divisions of brain Muller¨ and O’Rahilly (1983) Primitive streak Muller¨ and O’Rahilly (2004a) Otic primordium O’Rahilly (1963) 10 Fusion of neural folds Muller¨ and O’Rahilly (1985) O’Rahilly and Muller¨ (2002) Optic primordium O’Rahilly (1966) Caudal eminence Muller¨ and O’Rahilly (2004a) 11 Rostral neuropore Muller¨ and O’Rahilly (1986) O’Rahilly and Muller¨ (1989; 2002) 12 Caudal neuropore Muller¨ and O’Rahilly (1987) O’Rahilly and Muller¨ (2002) Hypoglossal nerve O’Rahilly and Muller¨ (1984) Somites O’Rahilly and Muller¨ (2003) Segmentation Muller¨ and O’Rahilly (2003b) 13 Closed neural tube Muller¨ and O’Rahilly (1988a) 14 Cerebral hemispheres Muller¨ and O’Rahilly (1988b) Neuromeres complete Muller¨ and O’Rahilly (1997) 15 Zoning in diencephalon Muller¨ and O’Rahilly (1988c) 16 Neurohypophysial evagination Muller¨ and O’Rahilly (1989a) 17–23 Olfactory system Muller¨ and O’Rahilly (1989b; 2004b) Amygdaloid complex Muller¨ and O’Rahilly (2006) 18–20 Choroid plexuses O’Rahilly and Muller¨ (1990) 21–23 Cortical plate; cerebellum Muller¨ and O’Rahilly (1990b) Ventricular eminences Muller¨ and O’Rahilly (1990b) Ventricles and choroid plexuses O’Rahilly and Muller¨ (1990) Meninges O’Rahilly and Muller¨ (1986) 23 Rhombencephalon Muller¨ and O’Rahilly (1990a) Occipitocervical segmentation Muller¨ and O’Rahilly (1994, 2003a) P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

CHAPTER24

CH TRIMESTER 1, POSTEMBRYONIC PHASE: INTRODUCTION GL

100 mm

13W

he most noticeable external changes in the fetus is greater than a right angle). The “C-shaped structures” are (1) the union of the cerebellar halves and the are listed with Figure 24–5. Tdefinition of the vermis, (2) the increasing concealment of Although this book is concerned primarily with the the diencephalon and mesencephalon, and (later on) of a embryonic period, the fetal period is summarized in sev- part of the cerebellum, by the cerebral hemispheres, (3) eral chapters in order to provide some degree of continuity further approach of the frontal and temporal poles around between the embryonic and the postnatal brain. The sub- the insula, which becomes increasingly buried by opercula, division is based on trimesters because a morphological (4) the appearance of sulci on the hemispheric surface at staging system is not available for the fetal period. Further about the middle of prenatal life, and (5) the decreasing information concerning the fetal brain is available in such conspicuousness of the flexures, although the longitudinal books as those by Barbé (1938), Fontes (1944), Lemire et axis of the cerebral hemispheres is set obliquely in relation al. (1975), and Gilles et al. (1983), and in the useful atlas to the brain stem throughout life (i.e., the “forebrain angle” by Feess-Higgins and Larroche (1987).

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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CHAPTER24

CH TRIMESTER 1: EARLY POSTEMBRYONIC PHASE

GL Approximately 30–50 mm in Greatest Length; Approximately 8–9 Postfertilizational Weeks

50 mm 9W

he period from 8 to 9 weeks, i.e., the week fol- Pain Pathways and Prenatal Pain. Receptors, such as lowing the embryonic period, is exemplified here those in the skin, appear during the embryonic period, as do Tby fetuses of 27.5, 33, and 42 mm GL. It has already been also interneurons in the substantia gelatinosa of the spinal pointed out that morphology and not size is the criterion cord (stage 17). Moreover, the spinothalamic tract and tha- for staging, and this atlas includes an embryo of 33 mm lamocortical fibers are identifiable later in the embryonic as well as a fetus of 27.5 mm. It has been mentioned also period (stages 22 and 23 in the authors’ observations). Tha- that a staging system is not (yet) available for the fetal pe- lamocortical connections are generally considered to be riod, and proposals so far have been based on age and fetal essential for the perception of pain. length, which do not provide (morphological) stages. Corticothalamic fibers are probably present early in Although fusion of the medial walls of the cerebral the fetal period. Thalamocortical fibers form temporary hemispheres does not occur during the embryonic period, synapses in the cortical subplate during trimester 2 and the events during the fetal period are not as clear. Fusion penetrate the cortical plate in trimester 3, at which time was denied by Hochstetter (1929), whereas others have sup- thalamic inputs reach the somatosensory cortex. The func- ported fusion “between the banks of the median groove” tional significance of these immature pathways is not clear, formed in the floor of the longitudinal fissure “by the in- and pain-suppressing systems are not as mature as pain- folding of the lamina reuniens of His” (Rakic and Yakovlev, conducting ones. Moreover, it is possible that information 1968). The cavum septi pellucidi is discussed with Fig- concerning pain is transferred differently before and after ure 26–7. birth. Myelination, however, is not necessary for pain either At the end of the embryonic period proper the spinal before or after birth (Fitzgerald, 1993). In addition, there cord still reaches to the caudal end of the vertebral col- is reason to believe that adverse neonatal experiences may umn (O’Rahilly, Muller, ¨ and Meyer, 1980, Fig. 4). Some alter the development of the brain, as well as subsequent dedifferentiation then takes place caudally and the spinal behavior (Anand and Scalzo, 2000). cord “ascends” to a lumbar level during the first half of It may be concluded that, although nociperception prenatal life. (the actual perception of pain) awaits the appearance of consciousness, nociception (the experience of pain) is Precision present some time before birth. In the absence of disproof, it is merely prudent to assume that pain can be experienced A double m is not used in mamillary because the term even early in prenatal life (Dr. J. Wisser, Zurich): ¨ the fetus is derived from the Latin mamilla, which in turn is a should be given the benefit of the doubt. diminutive of mamma, which does have a double m.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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266 Chapter 24: EARLY POSTEMBRYONIC PHASE

Figure 24–1. 33 mm. Lateral view showing the cranial nerves. The brain is still as compact as in stage 23. Most of the hemispheric surface is neopallial. The lateral olfactory fibers are indicated. In the cerebellum, the germinal layer covers only a part of the flocculonodular primordium. Olivo-arcuate migratory material is shown by stippling. The ganglia are identified in the key drawing.

fibers

Figures 24–1 to 24–7 are from a fetus of 33 mm (silver- is now present and the inferior olivary nucleus has ﬁve impregnated). In contrast to stage 23, the external capsule components. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

EARLY POSTEMBRYONIC PHASE 267

Figure 24–2. Graphic reconstruction from sagittal sections to show a median view of the brain at 33 mm. The asterisk marks the junction with the spinal cord. The commissural plate is now impressive. The rostral part of the roof of the third ventricle is folded. The entrance of the lateral prosencephalic fasciculus (Stammbundel ¨ ) into the diencephalon is shown, as is the stria terminalis arching over it at the di-telencephalic border. Corticipetal fibers that participate in the formation of the primordial plexiform layer arrive early (ca. stage 16, Marin-Padilla, 1988a, b). In experimental mammals corticifugal fibers have also been observed before the cortical plate forms. Three nuclear areas (stippled) are beginning to be outlined in the thalamus. (See also Fig. 24–3.) The thalamostriatal and striatothalamic fibers are connected mostly with what may later become the dorsomedial nucleus. The facial colliculus (arrow) is noticeable on the floor of the rhombencephalon. The central stem of the chondrocranium (hatched) has been included, as well as the left optic nerve and the eye. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

268 Chapter 24: EARLY POSTEMBRYONIC PHASE

Figure 24–3. 33 mm. Projection of diencephalic tracts. The entrance of the Stammbundel ¨ (Fig. 24–2) has not been included. The dorsal thalamus (stippled) takes up almost half of the medial surface. Some of the diencephalic nuclei are shown (hatched). The subthalamic and entopeduncular nuclei, and the globus pallidus externus, are clearly identiﬁable but have not been represented in the reconstruction. The preoptico-hypothalamotegmental tract is indicated by a dagger. The accessory optic tract ends in the region of the subthalamic nucleus, as described by Gilbert (1935) and Cooper (1946b), although the ﬁbers in the adult are connected to the mesencephalic lateral and dorsal terminal nuclei (Fredericks et al., 1988).

Figure 24–4. 33 mm. Schematic presentation of the inferior olivary nucleus. In addition to the accessory olivary nucleus (medial to the hypoglossal nerve) and the principal olivary nucleus (lateral to the hypoglossal nerve) seen in stage 23, further subdivisions can now be distinguished: (1) the medial accessory olivary nucleus, a rostral part with tall cells; (2) a mediocaudal portion consisting of medium-sized cells related to internal arcuate fibers; (3) probably the caudal medial accessory nucleus, a group between the first two and containing small cells; (4) probably the dorsal accessory nucleus, situated dorsolaterally and containing small cells; and (5) the main nucleus, the most voluminous part, which consists of tall cells. Projections to the cerebellum were present already in stage 23 (Fig. 23–30D). The olivocerebellar fibers join the inferior cerebellar peduncle. In cross sections the olivo-arcuate migrating cells are seen as superficial and intermediate strands, and the cellular axes are arranged tangentially. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

EARLY POSTEMBRYONIC PHASE 269 C-Shaped Structures

A B

1 2 3 Thalamus Mamillary 4 Putamen body

Amygdaloid nuclei

Indusium griseum C

1 Caudate nucleus 2 Choroid plexus I.v.f. 3 Fornix & fimbria 4 Indusium & Hippocampus Corpus callosum

1 2 3 4

Figure 24–5. Associated with the growth of the relatively fixed corpus striatum and the expansion of the cerebral hemispheres in a curved direction to form the temporal lobes, a number of structures develop in a C-shaped manner: (A) the caudate nucleus (head, body, and tail); (B and C) the choroid plexus and the choroid fissure through which it passes; the fornix (columns, body, and crura) and its continuation, the fimbria; the hippocampus and dentate gyrus, the rostral portions of which are found later merely as a remnant termed the indusium griseum; (C) the corpus callosum, which halts (as the splenium) without descending into the temporal lobe.

Central part

D Cingulate gyrus

Ant. horn Inf.horn

Parahippocampal gyrus

Figure 24–6. C-shaped structures (Continued ). (D) the lateral ventricle (anterior horn, central part, and inferior horn); (E) the limbic lobe (cingulate and parahippocampal gyri); and the frontal, parietal, and temporal lobes of the hemisphere. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

270 Chapter 24: EARLY POSTEMBRYONIC PHASE

Figure 24–7. 33 mm. Lateral view showing the ventricles. Some recesses are well formed, e.g., the supramamillary and the inframamillary, whereas others, e.g., the suprapineal, are not clear. The long cavity of the isthmus is narrowing because of the growth of the cerebellum, but it still extends into a well-developed isthmic recess.

TABLE 24–1. Important C-Shaped Structures in the Brain

Structure Stage of C-Shaped Appearance Figure 24–5 Number inB&C

Caudate nucleus 23 A 1 Choroid plexus 22,23 B,C 2 Fornix and ﬁbria Fetal period B,C 3 Hippocampus 22 B,C 4 Corpus callosum Fetal period C Inferior horn of lateral ventricle 22,23 Figure 24–6D P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

EARLY POSTEMBRYONIC PHASE 271

Ventricular Cortical Figure 24–8. 27.5 mm. The cerebral cortex. The layer plate cortical plate is present on the surface of the entire neopallium and is thickest (approximately 12 rows of cells) mostly where it began in stage 21: in the lateral wall opposite the lateral ventricular eminence (Fig. 24–10). The subpial layer occupies approximately half the thickness of the cortical plate, which is relatively less than in stage 23. The subplate is at least twice the thickness of the cortical plate, which is substantially greater than in stage 23. This is based on an increase of ﬁbers, some of which lead to the lateral prosencephalic fasciculus (Fig. 24–11). Serotonin and vesicular monoamine transporter ﬁbers are present in the subplate and intermediate layer (Verney et al., 2002). Synapses in early fetuses are present above and below the cortical plate, but never within it (Molliver et al., 1973). The key drawing is a graphic reconstruction.

Intermediate Subpial layer Subplate layer

Figs 24 Ð 10 11 8

Figures 24–8 to 24–15 are from a fetus of 27.5 mm By the end of the trimester thalamocortical ﬁbers pen- (silver-impregnated). The brain is slightly more developed etrate the cortical plate and intensive synaptogenesis be- than that of the 33 mm fetus; e.g., the cortical plate now gins to occur (Kostovic and Rakic, 1990), followed later extends to the occipital pole, and the brain is no longer as by a considerable decrease in synaptic number and den- compact. Additional features include the external capsule, sity (Huttenlocher and Dabholkar, 1997). Synapses become the hippocampal sulcus, and choroid villi in the roof of mature during the ﬁrst postnatal year and new synapses can the third ventricle. The photomicrographs from this fetus form throughout life, particularly in the parahippocampal are oriented so that the rostral end is uppermost. Figures region. 24–8 to 24–11 show a lateral view, with bars representing 0.15 mm. Figures 24–12 to 24–15 show a medial view, with bars representing 0.2 mm. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

272 Chapter 24: EARLY POSTEMBRYONIC PHASE

Lateral ventricle

V3 1

2 Tel. Di.

Hemispheric stalk

Inferior horn

Figure 24–9. Unexpected migration from the telencephalon to the diencephalon. 1. Migration from a thin cellular layer near the di-telencephalic junction (cf Fig. 21–6) to the pulvinar and other thalamic components (Letiniˇc and Kostovi´c, 1997). 2. Migration from cells coating the corpus striatum adjacent to the sulcus terminalis to the pulvinar. These cells proliferate until the end of the fetal period (Rakic and Sidman, 1969).

TABLE 24–2. Simpliﬁed Classiﬁcation of the Main Morphological Divisions and Subdivisions of the Cerebellum

Stage of Appearance (F, fetal period)

Cerebellar hemispheres & vermisa Corpus cerebelli Anterior lobe F Fissura prima F Posterior lobe F Horizontal ﬁssure F Fissura secunda F Posterolateral ﬁssure 17 Flocculonodular lobeb 23 Flocculus 21 Nodule 23 Cerebellar peduncles Superior 18 Middle F Inferior 18

a Most of the hemispheres and vermis consist of the paleocerebellum (spinocerebellum) and the neocerebellum (corticopontocerebellum). bThe ﬂocculonodular lobe is the archicerebellum (vestibulocerebellum). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

EARLY POSTEMBRYONIC PHASE 273

Figure 24–10. 27.5 mm. The corpus striatum, internal capsule, and adjacent structures. The claustrum is well developed, and a clear connection with the ventricular layer of the olfactory area still exists (Fig. 24–15). The external capsule has appeared. Fibers of the internal capsule are seen to reach the diencephalon through the hemispheric stalk, which is delimited by the sulcus terminalis. The key drawing shows the area included in the photomicrograph. The arrival and origin of the ﬁbers in the subplate are depicted. The ventricular eminences are said to expand to about 10 times the maximum thickness observed in other regions of the CNS during the second month, but reach their peak only at the middle of prenatal life (Rakic and Sidman, 1982). Their growth is supported by the striatal arteries (Nelson et al., 1991), which mature earlier than the arteries of the cerebral wall, that is, they develop a muscularis between 20 and 22 weeks. The ventricular layer contains a network of vessels that possess no muscularis at any age. The regression of the ventricular layer is accompanied by a regression of the capillaries (Nelson et al., 1991). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

274 Chapter 24: EARLY POSTEMBRYONIC PHASE

Figure 24–11. 27.5 mm. An enlargement of the internal capsule at a more dorsal level. The key drawing is a graphic reconstruction.

Internal capsule Subplate Cortical plate

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EARLY POSTEMBRYONIC PHASE 275

Figure 24–12. 27.5 mm. The hippocampus is clearly recognizable because of its thinner ventricular layer, which is contiguous to the lamina epithelialis. The third ventricle is visible below, and its folded roof seems to show the beginning development of choroid villi. The thick ﬁber bundle on each side of the roof area is the stria medullaris thalami. The choroid plexuses of the lateral ventricles are well shown.

Pre- subiculum

Hippo- campus

Stria medullaris Lamina thalami epithelialis

Figure 24–13. 27.5 mm. The hippocampus more ventrally has joined the prosencephalic septum. The hippocampal sulcus has appeared and is contiguous to the rhinal sulcus, as shown in the key drawing with Figure 24–11. The falx cerebri is evident. The lateral ventricles are seen to be continuous with the cavity of the telencephalon medium, which in turn blends with the third ventricle between the thalami. See also Figure 24–10. The sulcus Hippocampus terminalis lies between the ventricular eminence and the dorsal thalamus. Lamina terminalis

l.-v.f.

Sulcus terminalis

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276 Chapter 24: EARLY POSTEMBRYONIC PHASE

L Olfactory tract M Olfactory bulb Anterior olfactory nucleus Olfactory tubercle M L Amygdaloid nuclei

Figure 24–14. Development of the olfactory tract. (A) Schematic ventral view of the telencephalon at stage 23 showing medial (M) and lateral (L) olfactory ﬁbers. (B) The postnatal olfactory features. Modiﬁed from Muller ¨ and O’Rahilly (2004c, Cells Tissues Organs) by permission of S. Karger AG, Basel.

Olfactory ventricle Figure 24–15. 27.5 mm. The dorsal portions of the olfactory bulbs are separated from the prosencephalic septum by the circular sulcus. The olfactory ventricles are evident. The falx cerebri has developed in the loose tissue of the subarachnoid space. Dark-appearing tissue emanating from the ventricular and subventricular layers of the right-hand olfactory bulb leads to the claustrum. The transient subpial granular layer, which appears before the end of trimester 1, seems to arise from the same area as the claustrum (Fig. 22–12). Two streams of cells have been observed at 14 weeks: one from the medial and the other from the lateral angle of the subventricular layer of the olfactory bulb (Gadisseux et al., 1992). The cells form a continuous lamina. The subpial granular layer represents a precursor pool for reelin-producing neurons that complement earlier-generated cells [Cajal–Retzius cells in the primordial plexiform layer] during the critical period of cortical migration (Meyer et al., 1999a). Reelin is essential for neuronal migration and cortical lamination. The nucleus basalis (of Meynert) develops during the fetal period. Cholinesterase-reactive ﬁbers arising from it Circular sulcus are distributed to the neocortex and the limbic cortex by the end of trimester 2 (Kostovi´c, 1986). Septum Telencephalic part of third ventricle Commissural plate P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

EARLY POSTEMBRYONIC PHASE 277

Figure 24–16. 42 mm. Lateral view, based on a solid (Born) reconstruction. The membranous labyrinth has been added. The insula is becoming deeper. The interval between the diencephalon and the rhombencephalon is wider than in stage 23, and the pontine ﬂexure is less marked. Parts of the diencephalon, as well as the mesencephalon, still remain uncovered by the cerebral hemispheres. The (caudal) mesencephalic Blindsack is visible. The intraventricular part of the cerebellum lies within the fourth ventricle and the extraventricular portion is subdivided by the posterolateral ﬁssure.

Figures 24–16 to 24–18 are from a fetus of 42 mm that was studied by Streeter (1918), Hines (1922), and Padget (1948, 1957). In Figure 24–16 and in subsequent illustrations, an orientation more similar to that of the adult is shown; i.e., the cerebral hemispheres have been “lifted” into a more horizontal position and the brain stem is almost vertical.

A coronal plane

tal tomea Orbi plane

A coronal plane

plane

A transverse

Figure 24–17. 42 mm. The brain in situ. The face is positioned more or less vertically to allow easier comparison with the adult. The head is less spherical than in stage 23, and its rostrocaudal axis is lengthening. This seems to allow more space for the brain, which is now less compact. Padget (1948, Fig. 21) reconstructed the arteries of this fetus. Planes have been added to show that prenatally a transverse plane through the trunk does not correspond to the orbitomeatal plane in the adult, which is accepted as the horizontal standard. Similarly, coronal planes are not comparable. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

278 Chapter 24: EARLY POSTEMBRYONIC PHASE

Figure 24–18. 42 mm. Median view. (A) The prosencephalic septum is relatively reduced in its rostrocaudal extent. The paraphysis is inconspicuous compared with that of stage 23. The dorsal thalamus now extends over half of the lateral diencephalic wall. The marginal ridge between the dorsal and ventral thalami is no longer clear, although the sulcus medius is visible (Fig. 24–28). The posterior commissure and the commissure of the superior colliculi are separated. The floor of the mesencephalon has become greatly thickened by an increase in ascending and descending fibers. The isthmic groove, formerly the isthmic recess, is scarcely visible. The rostrocaudal extent of the fourth ventricle is relatively less. The ventral thalamus becomes so reduced that the former dorsal thalamus, now termed merely the thalamus, borders directly on the subthalamus, as established by Richter (1965) using Fig. 24 Ð 28 excellent fetal preparations. (B) The overlapping of the left cerebral hemisphere on the left half of the diencephalon. The hippocampus, the dentate area, the area epithelialis, and the choroid fissure are shown as if the prosencephalon were transparent. The lamina affixa is cross-hatched. The olfactory bulb is no longer directed caudally, a change that is perhaps related to a rostral extension of the nasal cavities (Hochstetter, 1919). In slightly older fetuses the olfactory bulb grows rostrally and becomes thinner and longer, concomitant with the lengthening of the frontal part of the cerebral hemisphere. The site of the entrance of the lateral prosencephalic fasciculus into the diencephalon is stippled. Based partly on Hines (1922). The levels of two sections, Figures 24–27 and 24–28, are indicated. Three-dimensional reconstructions, prepared Fig. 24 Ð 27 ultrasonically, of the ventricles in vivo in fetuses of 38 or 40 mm are illustrated by Blaas et al. (1995, 1998). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

EARLY POSTEMBRYONIC PHASE 279

Epiphysis Vermis Nodule Hemisphere C B Flocculus M Internal A cerebellar Vermis swelling

Figure 24–19. Topographical changes in the cerebellum of the first trimester. The flocculonodular lobe (or vestibulocerebellum) is the archicerebellum, which is formed differently from the rest of the vermis and is considered by some not to belong to the cerebellum sensu stricto. Both the vermis and the hemispheres will contribute to the paleocerebellum (or spinocerebellum) and the neocerebellum (or corticopontocerebellum). (A) At stage 20 the floccular region begins to become tilted from a rostrolateral to an occipitolateral position. The internal cerebellar swellings are well-separated. Further growth leads to their fusion, which begins in stage 23. (B) At 9 weeks (42 mm) the flocculonodular lobe is pointed in an occipital direction. Growth of the extraventricular cerebellum leads to an eversion of the cerebellar hemispheres and a lengthening of the vermis, resulting in the shape of a dumbbell. (C) At 13 weeks (95 mm) several folia and fissures can be distinguished in the vermis. B and C are based on reconstructions in Streeter (1912, where No. 86, 30 mm, is given incorrectly instead of No. 886, 42 mm).

1 1 ANT. V4 1

POST. Prepyr. Pyr. PL Uv. 2 PL PL Pyr. Uv. Prepyr. PL Nodule 2

Figure 24–20. Median section through embryonic and fetal vermian region showing chief fissures and folia. (See also Table 24-2). Modified from Rauber-Kopsch, Anatomie des Menschen. Abbreviations: 1, fissura prima. 2, fissura secunda. ANT., anterior lobe. PL, posterolateral fissure. POST., posterior lobe. Prepyr., prepyramidal fissure. Pyr., pyramid. Uv., uvula.

Fusion of the cerebellar hemispheres, although not hemispheres began to unite at stage 23, thereby initiating accepted by Sidman and Rakic (1982), had been supported the formation of the vermis (Fig. 23–26). The fusion is by Streeter (1912), Jakob (1929), Hochstetter (1939), and probably not completed, however, until the end of the ﬁrst Larsell (1947), and is conﬁrmed here. The paired cerebellar trimester (Feess-Higgins and Larroche, 1987). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

280 Chapter 24: EARLY POSTEMBRYONIC PHASE

FISSURES FOLIA Horizontal Tuber A 1 Prepyramidal Pyramid 1 Hemisphere 2 2 Postpyr. = secunda 3 Uvula 3 Posterolateral Nodule

1 Horizontal 2 B Tonsil 3

1 Pyramid Paraflocculus 2 Flocculus Uvula Tonsil 3 Nodule Paraflocculus

Flocculus C

Figure 24–21. Simplified dorsal view of the fetal cerebellum with only the chief features indicated. The fissura prima is not visible in these views. (A) at 13 weeks (95 mm) from the same embryo as in Figure 24–19C. (B) and (C) later in the first half of prenatal life. Based on Streeter in Keibel and Mall (1912).

Histogenesis of the Cerebellum. Homeobox genes are life. Their maturation continues after birth (Zecevic and believed to be involved in the initial development of the Rakic, 1976). Modiﬁed radial glial (Bergmann) cells are external germinal layer, and interaction with glial ﬁbers is necessary for the migration of the Purkinje cells (Choi and necessary for the internal cellular migration. Cell prolifer- Lapham, 1980). ation in the external germinal layer is the main cause of Photomicrographs of the fetal cerebellum have been the increase in the cerebellar surface. published by Rakic and Sidman (1970), Zecevic and Rakic Piriform (Purkinje) cells are generated at the begin- (1976), and Choi and Lapham (1980). ning of the fetal period (Rakic and Sidman, 1970) and their The development of the human cerebellum is different characteristic shape is attained by the middle of prenatal from that in the rat (Muller ¨ and O’Rahilly, 1990a,b). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

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Marginal Ventricular

Stage 13 14 1518 23

LAYERS: Intermediate Molecular Molecular Æ fiber Ext. germinal Piriform Piriform

Granular B

White matter

Deep nucleus Ependyma

Ventricle Ventricular

Figure 24–22. (A) The embryonic period as interpreted by the authors. A marginal layer becomes added (stage 14) to the ventricular layer. An intermediate layer is seen at stages 15–18. A sheath of fibers is developing superficially at stage 18. The external germinal layer begins to appear in stage 23. The dentate nucleus will form from a cellular lamina between two layers of fibers. (See Figure 21–19.) (B) The fetal period. The external germinal layer, which began to form at the end of the embryonic period, continues to receive cells from the rhombic lip. Near the end of the fetal period its cells migrate internally (purple arrow) and gives rise to the internal granular layer and basket cells. The external germinal layer disappears after birth. In the adult (last column) two Purkinje cells are shown, one in a sagittal, the other in a transverse plane. Their axons reach the deep nuclei. A mossy fiber is shown leading to a glomerulus which contains a mossy fiber rosette. The glomerulus is contacted by granule and Golgi cells. The dendrites of Purkinje, granular, and Golgi cells reach the molecular layer. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

282 Chapter 24: EARLY POSTEMBRYONIC PHASE

Figure 24–23. 46 mm. A nearly median section. The dorsal thalamus, which appears dark because it is cut at the level of the ventricular layer, is well shown. It is separated from the ventral thalamus by a band of gray material, which is probably the tract of the zona intrathalamica. When the individual thalamic nuclei are said to appear depends on the criteria selected, and these are mainly the establishment of cell-poor boundaries and the presence of nerve fibers, followed by differentiation into nuclear groups. Further information: Dekaban (1954), Fabiani and Barontini (1956), Yamadori (1965). The lateral geniculate body shows lamination during trimester 2. The pulvinar, which begins to develop at the commencement of trimester 2, is derived mainly from the medial ventricular eminence and grows greatly during the second half of prenatal life. Migrating cells from the medial ventricular eminence cover the fetal corpus striatum adjacent to the sulcus terminalis (constituting the “corpus gangliothalamicum” of Rakic and Sidman, 1969) and are said to participate in the formation of other thalamic nuclei (Letinić, and Kostović, 1997). See Figure 24–9. The epiphysis cerebri, the posterior commissure, and the commissure of the superior colliculi are all recognizable. The three subdivisions of the axis (termed X, Y, and Z by O’Rahilly, Muller, ¨ and Meyer, 1983, in their account of the occipitocervical region) are evident. A key drawing is provided with Figure 23-6. Inf. cerebellar peduncle P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

EARLY POSTEMBRYONIC PHASE 283

Figure 24–24. An ultrasonic image at 35 mm. The mesencephalon and the diencephalon can be identiﬁed, and the choroid plexus of the lateral ventricle (cf. Fig. 24–26) is evident. Courtesy of Dr. Harm-Gerd Blaas, Trondheim, Norway. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

284 Chapter 24: EARLY POSTEMBRYONIC PHASE

Figure 24–25. (A) dorsal and (B) lateral views of the brain at 42 mm, with parts of the hemisphere removed. In A the external capsule, not clearly distinguishable in stage 23, is now visible. In B the basal nuclei, choroid ﬁssure, and internal and external capsules are exposed. The part of the cerebral hemisphere removed here is indicated in Figure 24–28 by a dotted line. These instructive views are (with a few corrections) based on Kollmann’s Handatlas der Entwicklungsgeschichte des Menschen (1907). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

CHAPTER24

CH TRIMESTER 1: LATER POSTEMBRYONIC PHASE

GL Approximately 50–100 mm in Greatest Length;

100 Approximately 9–13 Postfertilizational Weeks mm

13W

he cerebral hemispheres continue their rapid en- is more evident and is developing connections with olfac- largement and reach a size approximately three tory centers and with the amygdaloid nuclei. Folia and ﬁs- Ttimes that at the end of the embryonic period. The cor- sures are appearing in the vermis cerebelli. The posterior pus callosum and the fornix are noteworthy among the horn of the lateral ventricle is beginning to evaginate. expanding C-shaped structures. The increase of the fore- Mathematical and hormonal criteria have been used brain angle during trimester 1 brings about a “rotation” (by Guyot) to indicate an advance in fetal development of the olfactory bulbs such that they now point caudoros- when the GL is approximately 90 mm at some 90 postfer- trally rather than rostrocaudally. The anterior commissure tilizational days.

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286 Chapter 24: LATER POSTEMBRYONIC PHASE

Fig. 24 Ð 26

Figure 24–26. A sagittal section at 40 mm. The relatively great size of the choroid plexus is noticeable. The key shows the hippocampal thickening. (The cortical plate is present in most of the hemispheres.) The dorsal thalamus is closely related to the ventricular eminences. Tha- lamocortical ﬁbers are already numerous, although the thalamic nuclei have yet to form. The habenulo-interpeduncular and mamillotegmental tracts can be followed to the mesencephalic tegmentum. The decussation of the trochlear nerves is identiﬁable in the isthmus. The internal cerebellar swelling is large. The rhombic lip can be seen here and again further caudally at the end of the medulla oblongata. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

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Figure 24–27. 50 mm. A coronal section showing the anterior commissure, the caudate nucleus, the internal capsule, and the putamen. Based on a photomicrograph in Feess-Higgins and Larroche (1987).

Figure 24–28. 37 mm. A coronal section showing the interventricular foramina and a number of important relationships. Based on an excellent photo-micrograph in Richter (1965). The dotted line indicates the part of the cerebral hemisphere removed in Figure 24–25B. Cholinesterase-reactive ﬁbers from the nucleus basalis complex are distributed widely to the neocortex and limbic cortex by the end of trimester 2 (Kostovi´c, 1986).

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288 Chapter 24: LATER POSTEMBRYONIC PHASE

Figure 24–29. The arterial system at A 42 mm. The internal carotid artery is shown in black, and the basilar by horizontal hatching. (A) Left lateral view. The various vessels are identiﬁed in the inset: the three cerebral arteries (AC, MC, PC), the anterior and posterior choroid, the PC posterior communicating (P.co.), superior cerebellar (Sup.cbl), and the anterior and posterior inferior cerebellar arteries (AICA, PICA). MC Ant. & post. choroid (B) Basal view. “The arteries resemble the adult conformation . . . at about AC 40 mm” (Padget, 1957). In both views the choroid plexuses of the lateral and fourth ventricles are included. These drawings are based on graphic reconstructions made by Padget (1948), whose work should be studied for further details. The venous system at 40 mm has B Ext. been illustrated by Padget (1957, Fig. 13), & common according to whom “the adult pattern of carotid most venous sinuses and cerebral veins can be recognized” by 80 mm, although “several important anastomoses typical of adult sinuses usually do not appear until after birth.”

AC MC Ant. & post. choroid PC Ant. & P.Co. post. Sup. cbl PC choroid P.Co. Sup. cbl

AlCA AlCA MC AC Pl CA

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Figure 24–30. 75 mm Developing (approximately 12 weeks). This is atrium a horizontal section through the interventricular foramina. The longitudinal ﬁssure is evident rostrally, and the tectum caudally. Many features are already arranged more or less as in the adult, e.g., the sequence of corpus striatum, internal capsule, thalamus, and third ventricle, as well as the sequence of lateral and medial geniculate bodies, and tectum. The aqueduct is still relatively large, and the corpus callosum is limited to the rostral region. Several structures show the characteristic C-shaped disposition; e.g., the lateral ventricle, hippocampus, and caudate nucleus are each sectioned twice. The lateral ventricle (shown also in the upper right-hand drawing) is sectioned in its anterior and inferior horns. The atrium of the lateral ventricle is the trigonal junction of the central part with the inferior and posterior horns. The key drawings are at 88 mm (left) and 78 mm (right). The section is based on a photomicrograph in Feess-Higgins and Larroche (1987), and the outline of the lateral ventricle is after Westergaard (1971). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

290 Chapter 24: LATER POSTEMBRYONIC PHASE

Figure 24–31. Because the trunk of the corpus callosum is sometimes found in the absence of a genu, it has been proposed by Kier and Truwit (1996) that the ﬁrst part of the corpus callosum to become visible is the front portion of the trunk, which then develops bidirectionally, thereby forming the genu and the splenium. The genu was found always to project in front of a reference line from the mamillary body through the anterior commissure and corpus callosum. Their interpretation is shown. (A) 13 weeks (105 mm), (B) 15 weeks (125 mm), and (C) adult. A and B are modiﬁed from Hochstetter. Stippling, trunk. Yellow, genu a, anterior commissure. m, mamillary body. Callosal development involves (1) a “subcallosal sling,” (2) a median “glial wedge” and glia of the indusium griseum, and (3) pioneering axons from the cingulate cortex (Ren et al., 2006). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

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Figure 24–32. Median sections through the brain stem at (A) 54 mm (10 postfertilizational weeks), (B) 68 A mm (11 weeks), (C) 80 mm (12 weeks). A sequence of six key features is numbered; these were distinguishable already at 6 weeks (Fig. 17–6, key), the main difference being that the anterior commissure and the corpus callosum had not yet become differentiated within the commissural plate. The sequence continues to be evident later and in the adult. The mesocoelic recess, which is shallow in A, (asterisk) becomes very deep later. Based on Hochstetter (1929). Bar: 2 mm.

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292 Chapter 24: LATER POSTEMBRYONIC PHASE

D E Figure 24–32. (Continued ) Median sections through the brain stem at (D and E) about 100 mm (13 weeks) and (F) 125 mm (15 weeks). The trunk of the corpus callosum becomes elongated within a few days (compare D with E) and the genu is well developed in F. A more complete view of the brain at 100 mm is shown Figure 24-33. Based on Hochstetter (1929). Bars: 2 mm.

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Figure 24–33. 100 mm (approximately 13 weeks). This is a median section at the end of trimester 1. The medial surface of the left cerebral hemisphere is stippled. The corpus callosum is still small, so that the roof of the third ventricle is exposed at the bottom of the longitudinal fissure. The pineal region and its associated recesses and commissures are well-developed. The aqueduct is still relatively wide. (A graph of its cross-sectional area correlated with age is given by Lemire et al., 1975, p. 98.) The vermis is small. (The number of folia seen in the vermis increases greatly during trimesters 2 and 3, as shown in a graph by Lemire et al., 1975, p. 150.) The tegmental portion of the brain stem is voluminous. Although the forebrain is at an angle (of approximately 116◦) with the brain stem, the flexures characteristic of the embryonic period proper have now become difficult to detect. The parts marked a and b are described with Figure 26–3. The section of the brain stem is based on Hochstetter (1919), and the inset showing the lateral ventricle is from a cast by Day (1959). Details of the medial surface of the prosencephalon at 95 mm are given in Figure 26-3B. P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

294 Chapter 24: LATER POSTEMBRYONIC PHASE

Figure 24–34. 95 mm (approximately 13 weeks). Anteromedial view of some major fiber tracts. The right half of the brain stem has been preserved intact. In the rostral part of the telencephalon everything has been removed except the fiber tracts, thereby exposing the corpus callosum, the column and commissure of the fornix, two divisions of the anterior comissure, and the internal capsule, which last subdivides the corpus striatum into the caudate and lentiform nuclei. On the left side of the brain, the connection from the stria terminalis to the anterior commissure is shown. Various features are identified in the key drawing. Based on Streeter in Keibel and Mall (1912). It is to be noted that fibers in the corpus callosum have already crossed the median plane.

The development of the fornix can be summarized as the columns arise as connections between the hippocampal follows. The earliest components of the fornix, present al- system and the mamillary nuclei (Figs. 25–1 and 26–9B). ready at stage 20, are the precommissural ﬁbers from the The commissure of the fornix develops as the corpus cal- septal nuclei to the (as yet poorly developed) hippocampus losum becomes identiﬁable (55 mm, 10 weeks, Rakic and (Fig. 20–13). Early in the fetal period (at about 9-11 weeks) Yakovlev, 1968; 105 mm, 13 weeks, Hochstetter, 1929). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

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Adult Fetal

1 r C te es rim T B A

Figure 24–35. Lengthening and “rotation” of the olfactory bulb during the fetal period. (A) Showing the olfactory bulb at stage 23. (B) Near the end of trimester 1. (C) At the beginning of trimester 2. The above-left diagram shows the forebrain angle (of Hirako), which seems to increase during trimester 1 but decrease later (Koya, 1963).

25 mm

M 38 mm A

53 mm

68 mm

96 mm B

96 Insula 68 mm 53 Figure 24–36. Outlines of the brain 38 during trimester 1, drawn to the same scale, 25 showing the considerable enlargement. mm (A) Left lateral views. The diencephalon and mesencephalon become increasingly covered by the cerebral hemispheres. Correspondingly the insula becomes more and more apparent. (B) Superimposed views of the cerebral hemisphere (based on Hochstetter, 1919). P1: JYS JWDD017-24 JWDD017-ORahilly July 29, 2006 14:33 Char Count= 0

296 Chapter 24: LATER POSTEMBRYONIC PHASE

Ant. communicating Ant. cerebral

Middle cerebral

Int. carotid

Post. communicating

Post. cerebral Sup. cerebellar Basilar Vertebral

Figure 24–37. The circulus arteriosus (of Willis) at 65 mm (11 weeks). Courtesy of Dr. Alexander Barry, University of California, Davis. P1: JYS JWDD017-25 JWDD017-ORahilly June 13, 2006 13:40 Char Count= 0

CHAPTER25 CH TRIMESTER 2

GL Approximately 100–250 mm in Greatest Length; 250 Approximately 13–26 Postfertilizational Weeks mm

26W

ulci begin to appear on the surface of the cere- The pyramidal tracts do not begin to be myelinated until bral hemisphere at about the middle of prena- shortly before birth, although myelinated fibers are present Stal life. The data of Larroche have been schematized by at the level of the pyramidal decussation by the middle of Lemire et al. (1975, pp. 235 and 236) and further details prenatal life (Wo´zniak and O’Rahilly, 1982). are given by Gilles et al. (1983, pp. 96–99). The progression A solid reconstruction of a brain at 145 mm has been is well displayed in a series of photographs in Feess-Higgins illustrated by Velasco-Villamar (1967). and Larroche (1987, pp. 14 and 15). Cerebral asymmetry A basal view of the brain at 150 mm (about 17 weeks) is present at the latest during trimester 2. The maturation is shown in Figure 25-5. of the fetal brain can be correlated with the microscopi- Functional cortical innervation of spinal gray matter cal development of the renal glomeruli (Dorovini-Zis and is probably in place by 22–26 postfertilizational weeks (Dr. Dolman, 1977). Synapses increase significantly in number G.J. Clowry, Newcastle-upon-Tyne, personal communica- at the beginning of trimester 2 (Kostović and Rakic, 1990). tion, 1998). By the middle of trimester 2 at least two subcortical afferent At 22–26 postovulatory weeks, afferent fibers accumu- systems “wait” (Rakic, 1977) in the subplate, namely thala- late in the subplate; subsequently they penetrate the cor- mocortical fibers and those of the basal forebrain. Electrical tical plate. Cortical responses occur and depend on deep activity can be detected in the hippocampal region and in synapses and deep dendritic maturation (Kostović and Ju- the diencephalon. das, 2002). The supracallosal portion of the hippocampus begins For a long period, the cerebral wall is irrigated by blood to regress early in trimester 2 and later becomes the indu- vessels that consist of simple endothelial channels. A vas- sium griseum. At about the same period, the characteristic cular network within the cortex develops between 22 and interlocking C formation of the hippocampus and the den- 24 weeks. A muscularis is acquired only near term and tate gyrus becomes noticeable, at approximately 150 mm. postnatally (Nelson et al., 1991). The crura cerebri, although identifiable during Projecting callosal neurons are present both in the trimester 1, have become prominent bundles on the ven- cortical plate and in the subplate at 25–32 postovulatory tral surface of the midbrain by the middle of prenatal life. weeks. Those in the cortical plate develop earlier and are Myelination, as detected by light microscopy, begins the first to project axons through the corpus callosum (de in the CNS at about 20 weeks; by electron microscopy, Azevedo et al., 1997). It is believed that median glial struc- evidence in the spinal cord can be found late in trimester 1. tures guide callosal axons to cross the median plane and, The data of Yakovlev and LeCours have been schematized together with pioneering axons in the cingulate cortex, are by Lemire et al. (1975, pp. 44–46), and numerous tables important in the development of the corpus callosum (Ren and graphs are provided by Gilles et al. (1983, Chapter 12). et al., 2006).

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298 Chapter 25: TRIMESTER 2

Developing Figure 25–1. Approximately 230 atrium mm (about 24–26 weeks). This horizontal section is taken near the end of trimester 2. It resembles very closely a corresponding section through the adult brain, except for the almost total absence of sulci and gyri. Moreover, the insula is not yet buried by its opercula. The level of the section is that of the interthalamic adhesion and the epiphysis cerebri. (The interthalamic adhesion appears at about the junction of trimesters 1 and 2, and disappears at approximately 40–60 years of age, as shown in a graph in Lemire et al., 1975, p. 179). The third ventricle is sectioned twice, as is also the caudate nucleus. The anterior and posterior horns of each lateral ventricle are evident. Also shown are the pulvinar (a), the habenula (b), and the suprapineal recess (c). The section is based on a photomicrograph in Feess-Higgins and Larroche (1987). The right lateral view of the ventricular system (after Kier, 1977) illustrated in an inset shows the triangular part of the lateral ventricle, where the inferior and posterior horns diverge. This part is frequently referred to in radiology as the atrium, and its ﬂoor is the collateral trigone. P1: JYS JWDD017-25 JWDD017-ORahilly June 13, 2006 13:40 Char Count= 0

TRIMESTER 2 299

Amygdaloid complex

Figure 25–2. A comparison of coronal sections at (A) 20 mm (stage 20, 7 weeks) and (B) 240 mm (approximately 24–28 weeks), at the junction of trimesters 2 and 3. Section B1 is slightly anterior to section B2. A comparison between the embryonic and the fetal sections indicates the further development after 7 weeks. Some of the fetal features are already foreshadowed even at 8 weeks (stage 23). The most striking difference is in the corpus callosum, which, after 100 mm, extends rapidly in a caudal direction, thereby covering the roof of the third ventricle. Hence, during the embryonic period, the longitudinal fissure leads directly onto the roof of the third ventricle, whereas beginning in trimester 2, the fissure becomes blocked below by the corpus callosum. Another very important feature is the descent of the fibers of the internal capsule. They traverse the region of the ventricular eminences at the end of the embryonic period, and during the fetal period (B, brown arrow) they pass first between two telencephalic structures, the putamen and the caudate nucleus, and then between two diencephalic components, the globus pallidus and the thalamus. Even in the adult brain, slight histological (vascular) differences can be seen between the two telencephalic elements and the two diencephalic constituents, emphasizing their different prosencephalic origins. At least two subcortical afferent systems are said to “wait” in the subplate in the second half of trimester 2: thalamocortical fibers and basal forebrain fibers (Kostović et al, 1992). Shortly thereafter, thalamocortical fibers penetrate the cortical plate, where intensive synaptic formation is occurring (Kostović et al., 1992). The first sign of the nucleus basalis complex has been shown by cholinesterase reactivity at the beginning of the fetal period, and reactive bundles develop also (Kostović, 1986). P1: JYS JWDD017-25 JWDD017-ORahilly June 13, 2006 13:40 Char Count= 0

300 Chapter 25: TRIMESTER 2

TABLE 25–1. Relationships of Internal Capsule in the abbreviation CA can still be used (as proposed here) for Fetus and in the Adult Cellular Areas 1 to 4. In a different system, ﬁve hippocampal ﬁelds are designated H1 to H5. Laterally Medially The hippocampal formation is the “earliest group of cortical areas in humans” and “hippocampal pathways de- Telencephalon: Telencephalon: velop prior to isocortical pathways” (Hevner and Kinney, Putamen Caudate nucleus Internal 1996). capsule The dentate gyrus possesses a pool of progenitor cells Diencephalon: Diencephalon: that continues to produce new granule cells throughout Globus pallidus Thalamus and Subthalamus life. The embryonic development of the hippocampus and dentate gyrus has already been illustrated in Figures 15–4, THE HIPPOCAMPAL 16–6B, C, 16–11, 18–2, 20–13, 21–17, and 23–24. FORMATION

The dentate gyrus, the hippocampus, the subiculum, and NEUROTERATOLOGY: the parahippocampal gyrus (entorhinal area) are conve- AGENESIS OF THE CORPUS niently grouped as the hippocampal formation. CALLOSUM The hippocampus was probably first observed by Achillini of Bologna (1463–1512). It was named by Aranzi Agenesis of the corpus callosum, a complete or partial lack (Arantius) of Bologna (1530–1589), who described it as “a of callosal fibers between the cerebral hemispheres, is dis- raised, partially attached, whitish substance” showing “an covered usually as an accidental finding. The anterior com- uneven, bent form that resembles the appearance of a hip- missure may be enlarged, providing supplementary neo- pocampus, that is, a sea-horse.” The name is an example of cortical interconnections. It is assumed that the condition Witz der Namengebung (Burdach). The alternative name arises in the commissural plate, the callosal component of Cornu Ammonis, now avoided as are other eponyms, was which may fail to develop or may not grow caudally. At least used by Winslow (1669–1760) because of a supposed re- some instances may represent a failure of commissuration semblance to the curling horn of a ram, which was the rather than an agenesis. Defects of the corpus callosum crest of the Egyptian deity Ammon. and the adjacent region are considered by some to be types The name Cornu Ammonis gave rise to the abbre- of cerebral dysraphia. viation CA and the structure was divided by Lorente de More than 50 syndromes involve callosal agenesis, Nó into CA1 to CA4; CA4 is now frequently included in which may be autosomal dominant, autosomal recessive, CA3. Although the preferred term is hippocampus, the or X-linked. Moreover, some 40 genes are relevant. P1: JYS JWDD017-25 JWDD017-ORahilly June 13, 2006 13:40 Char Count= 0

TRIMESTER 2 301

TABLE 25–2. Summary of Development of Hippocampal Formation A. Embryonic Period Figure Hippocampus Dentate Area Fibers

15–4 Hippocampal thickening on both sides of lamina terminalis 16–6 B,C Hippocampal thickening extends from future frontal to future temporal pole. 16–11 Thickening is accompanied by a cell- free marginal layer 18–2 Hippocampal primordium has grown Dentate area is a small rim intercalated and reaches forebrain septum between hippocampal thickening and area epithelialis. 18–5 Rostral and temporal parts are alike 20–13 Hippocamposeptal and precommissural ﬁbers 21–17 Thin sheath of marginal cells appears Migrating cells form primordium opposite hippocampal thickening of dentate area 23–24 About 5 rows of scattered marginal cells B. Fetal Period GL (mm) Weeks Hippocampus Dentate Gyrus Fibers

32 8 Migrating cells Fimbria 44 9 Distinct pyramidal layer. Patches of cells (Fig. 25–3A) Columns of fornix CA 1–3 distinguishable 1 49 9 2 H1, H2, and H3 can be distinguished 1 50–83 9 2 –12 Marginal cells in marginal layer 56 10 Spherical cell mass (Fig. 25–3B). Hippocampal commissure Fimbriodentate sulcus 61 10 Polymorphic and granular layers Alveus forming 1 65 10 2 Marginal layer with Cajal–Retzius cells 79–85 12 Granular layer more distinct Alveus complete and clearly separated from H3 120 14 Involution complete; hippocampal matrix wider than subicular 150 17 Fig. 25–3C Formation of synapses mainly in marginal layer 200 21 Fig. 25–3D; ventricular layer Connections in subdivisions seems to be exhausted of hippocampus ≥300 32–45 Hippocampus has grown in volume; by 20 weeks walls of hippocampal sulcus are fused; molecular layer still has some Cajal–Retzius cells Newborn Hippocampal surface only one-third of adult area

Sources: A: based on authors’ research. B: based on data from various authors, including Humphrey (1965), Rakic and Yakovlev (1968), Kahle (1969), Bogolepova (1995), Hevner and Kinney (1996), and Bogolepova (1997). P1: JYS JWDD017-25 JWDD017-ORahilly June 13, 2006 13:40 Char Count= 0

302 Chapter 25: TRIMESTER 2

A B Figure 25–3. Development of the hippocampal formation. (A) and (B) During trimester 1. The embryonic development is characterized mainly by cellular production and migration (Table 25-2). The rostral, middle, and occipital regions are alike before the appearance of the corpus callosum. Here the occipital (retrocommissural) part is represented. (A) 1 A horizontal section at 49 mm (9 2 weeks), at the level of the insula. The rectangle indicates the portion (at 44 mm) shown in A’. (A) A structure resembling cortex represents the future pyramidal layer of the hippocampus. The marginal layer of the dentate area is very broad. (B) A horizontal section at 85 mm (12 weeks). The pyramidal layer (hippocampal plate) is continuous with the dentate primordium and with the cortical plate. The rectangle indicates the portion (at 56 mm) shown in B.(B) A stream of migrating cells leads from the ventricular layer to the dentate primordium. The hippocampal sulcus is evident. The curved, Cellular Areas, CA 1–3, are marked. The ﬁmbria has appeared and is well-delineated near the dentate area. A and B are modiﬁed from drawings, and A¢ B¢ A and B are based on photomicrographs, in Humphrey (1965). P1: JYS JWDD017-25 JWDD017-ORahilly June 13, 2006 13:40 Char Count= 0

TRIMESTER 2 303

C Figure 25–3. Continued (C) and (D) Development of the hippocampal formation during trimester 2. Cellular production and migration continue. As the corpus callosum develops, the more rostral parts of the hippocampal primordium regress. The formation, which became curved and multilayered in trimester 1, becomes S-shaped and then rolled during trimester 2. (C) A coronal section at 150 mm (17 weeks). The width of the pyramidal layer in CA1 narrows progressively from the subiculum towards CA2 to CA4. Its cells D are small and immature. Three layers can be identiﬁed already in the dentate gyrus. The dentate area presents a wide marginal layer, the subiculum is double-layered, and the entorhinal cortex is bipartite. (D) At 203 mm (21 weeks). The pyramidal layer is still populated with mostly immature neurons, as is also the dentate gyrus. Fibers connecting the entorhinal cortex, hippocampus, and subiculum are present by about 19 weeks, and connections between other subdivisions of the hippocampal formation may F be established about one week later. Connections E with the neocortex, however, are still only Inf. beginning at 22 weeks (Hevner and Kinney, horn 1996). (E) Summary of the change in shape from 9 weeks to curved and multilayered at 10 weeks, Fimbria S-shaped at 17 weeks, and infolded at 21 weeks. & alveus (F) The hippocampal formation of the adult. C and D are drawn from photomicrographs in Subiculum Arnold and Trojanowski (1996). With the completion of the hippocampal arch, it reaches from the olfactory bulb to the region of the uncus. Its transformation into induseum griseum begins rostrally during trimester 2 (Kier et al., 1995, 1997). Presubiculum Stippling, ﬁmbria. Black, dentate gyrus. Horizontal hatching, hippocampus. Orange-brown, pia mater. The subiculum and the parahippocampal gyrus are left white. P1: JYS JWDD017-25 JWDD017-ORahilly June 13, 2006 13:40 Char Count= 0

Figure 25–4. The hypophysis cerebri. (A) Sagittal section through 3rd ventricle the fetal organ. The cleft represents the cavity of the initial Stalk NH adenohypophysial pouch. (B) The greater part of both the adenohypophysis and the neurohypophysis lies in the Cleft Pars hypophysial fossa of the sphenoid tuberalis bone (still cartilaginous here). intermedia distalis Hypophysial ADENOHYPOPH. fossa Sphenoid

ANTERIOR POSTERIOR

fibers

AB C

Figure 25–5. A comparison of basal views of the brain at (A) 31 mm (stage 23, 8 weeks), (B) 68 mm (11 weeks), (C) ca 130 mm (ca. 15 weeks), (D) ca. 210 mm (22 weeks). The inferior views illustrate the development of some of the olfactory structures (olfactory bulb and striae in white in A to C). Already at 8 weeks (A) the lateral olfactory fibers (striae laterales or gyrus olfactorius lateralis), which had formed by stage 17, reach the area of the amygdaloid nuclei (although mitral cells are only beginning to be present in the olfactory bulb). Medial olfactory fibers (striae mediales or gyrus olfactorius medialis) are shown in B and C. (Some fibers also are already present at stage 17.) The striae are sometimes termed gyri because they are covered by a small amount of gray matter. The lateral olfactory tract reaches the temporal lobe and is continued by the gyrus ambiens (C). The changing relationship of the olfactory structures can be studied further in views by Macchi (1951). The optic nerves, chiasma, and tracts in A to C are shown in black, as is also the trigeminal nerve. View A is based on Muller ¨ and O’Rahilly (1990b), B is after Hochstetter (1919), C is after Kollmann’s Handatlas der Entwicklungsgeschichte des Menschen and Corning’s Lehrbuch der Entwicklungsgeschichte des Menschen, D is by courtesy of Marvin D. Nelson, M.D., Children’s Hospital, Los Angeles.

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CHAPTER26

CH TRIMESTER 3 AND

335 mm THE NEWBORN

GL Approximately 250–335 mm in Greatest Length; Approximately 26 Postfertilizational Weeks to Birth

he sulci and gyri increase rapidly in number dur- Probably the most valuable treatise on the cerebral ing trimester 3, although they are not quite as hemispheres during the fetal period is that by Kahle (1969), Tnumerous as in the adult. Their sequential appearance is because, unlike more recent accounts, it is based on a listed in Table 26–1 (p. 306). series of careful graphic reconstructions. Studies of the The duration of prenatal life is generally about 38 post- fetal cerebral cortex, in continuity with those of Conel on fertilizational weeks, the mean being 264 days. The range the newborn, and on the postnatal cortex of 1 to 6 years, 35 to 40 postfertilizational weeks is considered to indi- have been published by Rabinowicz (1986, for references). cate an infant at “term.” Commonly used figures at birth Useful photomicrographs, drawings, and measurements of are about 335 mm for the greatest length (exclusive of the neocortical areas during the fetal period have been pub- lower limbs) and about 500 mm for the crown–heel length. lished by Mar´ın-Padilla (1970, 1988a, and 1992). The biparietal diameter is approximately 95 mm and the The subplate of the primary visual cortex disappears head circumference is of the order of 350 mm. The body during the last prenatal weeks, whereas that of the pre- weight at birth varies from 2500 to 4000 g or more, with an frontal cortex persists as long as 6 months after birth average of about 3350 g. The brain weight, which also varies (Kostović and Rakic, 1990). The changes include relocation considerably, ranges from about 300 to 400 g at birth and of fibers in the cortical plate, incorporation of subplate neu- continues to increase rapidly up to the fourth year, more rons in the gyral white matter, and cell death. Postnatally, slowly up to the twelfth year. cortico-cortical and association fibers continue to grow, A useful general summary of the central nervous and overproduction of dendritic spines as well as excessive system in the newborn has been provided by Robinson synaptogenesis have been recorded. and Tizard (1965). An important account of the brain stem of two newborns was published by Sabin (1900, Precision cf. Fig. 26–5B). It contains precise drawings of two series It is incorrect to refer to the trunk of the corpus callo- of sections: 22 coronal and 27 transverse. See also Sabin sum as its body, because the entire structure is a body, (1901, 1902). Photomicrographs and drawings of the mo- Latin corpus. Moreover, the central part of the lateral tor cortex of a newborn have been published by Mar´ın- ventricle is not a body because all parts of the ventricle Padilla and Mar´ın-Padilla (1982) and by Mar´ın-Padilla are cavities. (1992).

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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306 Chapter 26: TRIMESTER 3 AND THE NEWBORN

TABLE 26–1. The Usual Sequence of Appearance of Cerebral Sulci and Gyri Arranged in Groups

Sulci Gyri Group Weeks Lateral Medial Lateral Medial

A 10–15 Lateral Callosal

B 16–19 Parieto-occipital Cingulate Gyrus rectus calcarine cingulate Cuneus

C 20–23 Central Collateral Superior temporal Parahippocampal Superior temporal (T1)

D 24–27 Precentral Occipitotemporal Precentral Inferior temporal (T2) Middle temporal Postcentral Inferior temporal Superior frontal (F1) Medial & lateral Intraparietal occipitotemporal Postcentral Superior frontal Superior & inferior parietal lobules

E 28–31 Inferior frontal (F3) Middle frontal Middle frontal (F2) Inferior frontal Pars triangularis

F 32–35 Paracentral lobule

Source: Based largely on data supplied by Marvin D. Nelson, M.D., Los Angeles.

Tectum A

Tegmentum Cerebral Substantia nigra peduncle

Crus cerebri B

Figure 26–1. A likely migration (arrow) of alar (A) into basal (B) territory has long been suspected in the midbrain. Moreover, the origin of the different cells of the substantia nigra is highly complex (Verney et al., 2001a,b). This section at the junction of trimesters 2 and 3 shows that the adult form and features have clearly been attained. P1: JYS JWDD017-26 JWDD017-ORahilly June 13, 2006 13:42 Char Count= 0

TRIMESTER 3 AND THE NEWBORN 307

Figure 26–2. Medial view of the right half of a brain at about 28 postfertilizational weeks. The corpus callosum, which has become elongated and curved, shows the rostrum, genu, trunk, and splenium. The maximum splenial thickness at about this time has been found to be greater in female fetuses in one study (deLacoste et al., 1986) but not in another (Clark et al., 1989). The asterisk indicates the parieto-occipital sulcus. Bar: 10 mm. From Kier and Truwit (1996). Courtesy of E. Leon Kier, M.D., Yale University School of Medicine.

Sexual Differentiation of the Brain It has been proposed that autism, under the inﬂu- Although the importance of estrogen is acknowledged, un- ence of prenatal androgens, may represent an “extreme certainty persists regarding “the onset of estrogen synthe- male brain:” the white matter is greater, the internal cap- sis in the [human] brain, the sensitivity to estrogen of dis- sule and corpus callosum are proportionally reduced, and tinct neuronal populations, and the appearance of sexual the amygdaloid body is abnormally large (Baron-Cohen dimorphisms” (Beyer, 1999). et al., 2005). P1: JYS JWDD017-26 JWDD017-ORahilly June 13, 2006 13:42 Char Count= 0

308 Chapter 26: TRIMESTER 3 AND THE NEWBORN

Choroid fissure

Commissure of fornix

Indusium griseum & hippocampus

Corpus callosum

Fornix

Stria terminalis

Thalamus

Ant. commissure

Figure 26–3. A comparison of the medial surface of the forebrain at (A) 80, (B) 95, (C) 150, and (D) approximately 265 mm. The left thalamus has been sectioned sagittally (shaded by horizontal lines). In A, B, and C the entire brain stem has been removed, whereas in D it has been sectioned transversely at the level of the midbrain and its caudal portion has been eliminated. The considerable increase in length of the corpus callosum (shown in yellow) after 100 mm can readily be appreciated by comparing B and C. In D the corpus callosum shows clearly the rostrum, genu, central part, and splenium. The commissural plate beneath the corpus callosum becomes attenuated (C) to form the septum pellucidum. Modified from models in Keibel and Mall (1912). The upper right-hand drawings show schematically the arrangement of the pia mater over the corpus callosum at 100 mm, 170 mm, and at birth. As the corpus callosum grows posteriorly, a pial layer (b) is reflected backwards over the original layer (a), so that a double fold is formed. This is the velum interpositum, between the two layers of which blood vessels can pass forward beneath the corpus callosum, through the transverse fissure (asterisk). These vessels contribute to the tela choroidea of the third ventricle. P1: JYS JWDD017-26 JWDD017-ORahilly June 13, 2006 13:42 Char Count= 0

TRIMESTER 3 AND THE NEWBORN 309

Figure 26–4. Left lateral views of the b M brain during the ﬁrst half of prenatal life. The gradual concealment of the g b midbrain is evident. The future insula a I (I) is relatively stationary, whereas, accompanying the sweep of the 30 mm developing temporal pole (γ ), the I future occipital pole (β) is displaced g along a similarly curved path (inset). By a b approximately 200 mm the central sulcus begins to appear and the frontal, 53 mm frontoparietal, and temporal opercula are covering the insula. a I g b 68 mm g a

a I b

96 mm g Frontoparietal

Frontal Temporal

ca 200 mm

Functional Considerations structural maturation of the nervous system. Movements Cerebral electrical activity has been recorded ex utero in include startles, hiccups, isolated limb movements, and the embryonic period, and potentials have been detected head rotation; later during trimester 1 they include breath- in utero in trimester 3 both abdominally and per vaginam. ing movements, yawning, sucking, and swallowing (of am- Prenatal behavior includes movements, sleep (accom- niotic fluid), all of which are similar to those occurring panied by rapid eye movements in trimester 3) and wakeful- postnatally. All motor patterns seem to be present by the be- 1 ness. Cardiac motion ban be detected by ultrasound at 3 /2 ginning of trimester 2, when movement is almost constant. weeks at a rate of 100 per minute. Body movements can be Functional development of the cochlea takes place recognized ultrasonically at 5–6 weeks (stage 16) and con- during trimesters 2 and 3. Hearing (by bone conduction sist initially of extension and flexion of the neck and the tho- in a fluid environment) and response to sounds occur by racic region. Reflex and spontaneous movements probably the middle of prenatal life, and a little later the fetus can begin simultaneously. More complex movements follow discriminate between different frequencies and between rapidly and form coordinated patterns dependent on the speech stimuli; music is welcomed. P1: JYS JWDD017-26 JWDD017-ORahilly June 13, 2006 13:42 Char Count= 0

See Figure 23 Ð 29

Somatic afferent

Visceral afferent

Visceral efferent

Somatic efferent

Inferior cerebellar peduncle

Figure 26–5. Dorsal views of the rhombencephalon (A) at 8 postfertilizational weeks (stage 23: cf. Figs. 23–29 and 23–30) and (B, C)intwo different reconstructions from the newborn. The arrangement of the nuclei and tracts, as well as the location of the rhombencephalic nuclei at 8 weeks, are very similar to those in the newborn. The striking resemblance between the rhombencephalon of the newborn and that of the embryo at 8 weeks is based on the circumstance that the fundamental organization of the rhombencephalon is attained much earlier than that of other parts of the brain. Figure 26–5B is based on a reconstruction by Sabin (1901). Figure 26–5C is after Hikji (1933). The neurons in the nucleus of the tractus solitarius are still immature at birth (Denawit-Saubi´e et al., 1994).

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Central Figure 26–6. The main cerebral sulci and gyri mentioned in Table 26–1. Intraparietal F1

F2 Parieto-occipital

F3 Cingulate Callosal

T1 T2

SULCI

Calcarine

Collateral Occipitotemporal

Frontal Sup. & inf. parietal

Precentral Postcentral

Temporal Paracentral lobule

GYRI Cingulate

Cuneus Parahippocampal

Med. & lat. occipitotemporal

B Cavum anterius

Cavum Corpus posterius A callosum

Figure 26–7. The cavum septi pellucidi is a closed, C 100% median cleft between the two laminae of the septum pellucidum. It may perhaps develop by necrosis within the commissural plate. It is constant up to about 250 mm, its posterior portion (cavum Vergae) is usually closed by birth, and its anterior portion by about 3 postnatal months. It remains open subsequently in about 50% 20%. (A) A coronal section at about the middle of prenatal life. (B) A median section early in the third trimester. Three more or less parallel features are (1) the 20% pericallosal continuation of the anterior cerebral arteries (not shown here), (2) the corpus callosum, and (3) the cavum septi pellucidi. (C) A graph of the percentage of ≠ 6 presence (ordinate) plotted against 0–7 postnatal months Birth months (abscissa) (Shaw and Alvord, 1969).

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Figure 26–8. Superior view of the brain around the time of birth. Acknowledgement with Figure 26–9.

A C

Figure 26–9. The brain around the time of birth. (A) and (B) Lateral and medial photographs. Courtesy of Marvin D. Nelson, M.D., and Floyd H. Gilles, M.D., Children’s Hospital, Los Angeles. (C) and (D) Lateral and medial views at 335 mm GL, 490 mm CH, biparietal diameter 94 mm, occipitofrontal diameter 108 mm, head circumference 355 mm, body weight 3,340 g, and fresh brain weight 403 g. The pattern of sulci and gyri is essentially similar to that of the adult. The names given here apply to the gyri. Arrows indicate the central and parieto-occipital sulci. Abbreviations: Fl, 2, 3, superior, middle, and inferior frontal gyri, Tl, 2, 3, superior, middle, and inferior temporal gyri; a., angular gyrus; s., supramarginal gyrus. Based on photographs in Feess-Higgins and Larroche (1987).

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TRIMESTER 3 AND THE NEWBORN 313

Figure 26–10. (A) and (B) The arterial system of the newborn. The vessels A marked are the three cerebral arteries (A.C., M.C., P.C.), the posterior communicating (P. co.), the anterior choroidal (A. chor.), the superior cerebellar (Sup. cbl), and the anterior and posterior inferior cerebellar arteries (AICA, PICA). The asterisk indicates the hypophysis. The posterior communicating is relatively large prenatally and in the newborn. In the adult, however, the blood ﬂow in the posterior cerebral (initially merely a collateral branch of the posterior communicating) has been transferred from the carotid to the basilar system. These drawings are based on graphic reconstructions made by Padget (1948), whose work should be studied for further details. The venous system has been illustrated by Padget (1957, Fig. 17).

Anterior & middle cerebral

Internal carotid

Posterior communicating

Posterior cerebral

Basilar

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314 Chapter 26: TRIMESTER 3 AND THE NEWBORN

A B

C D

Figure 26–11. Examples of images during trimester 2. (A) and (B) Horizontal sections at 23 postmenstrual weeks. (C) and (D) Views of the maternal pelvis showing the fetal brain at 26 postmenstrual weeks. All four views present some pathological features. Courtesy of Robert Harris, M.D., Dartmouth Hitchcock Medical Center, Hanover, NH. P1: JYS JWDD017-26 JWDD017-ORahilly June 13, 2006 13:42 Char Count= 0

PRENATAL LIFE 315

TABLE 26–2. Examples of Events, Features, and Substances in the Prenatal Brain

Substances and/or Events Reference

A. Embryonic Period Nasal plate contains TH-ir neuronsa Verney et al. (1996) GnRH-ir cells migrating to forebrain Verney et al. (1996), Schwanzel-Fukuda et al. (1996) Calbindin-ir postmitotic cell bodies in mesencephalic floor plate Verney et al. (2001a,b) Reelin-positive cells (subpial neurons) in neocortical anlage form a continuous horizontal Meyer et al. (2000)b row at telencephalic surface GABA dispersed in different layers of the ventricular eminence(s) Verney (2003) Calretinin-ir neurons in mesencephalic floor plate Verney et al. (2001a,b) Calbindin-ir axons in thalamocortical bundle of internal capsule Enzymes of the catecholamine pathwaya Zecevic and Verney (1995) Preplate (primordial plexiform layer) with reelin-ir cells Meyer et al. (2000) Calretinin-positive cells continuous with CR-ir cells in the ventricular zone GABA-positive cells and fibers in primordial plexiform layer Zecevic and Milosevic (1997) GABA neurons may establish contacts with other terminals or cells Compartmentalization of the preplate: subpial monolayer of horizontal CR-ir cells Meyer et al. (2000) Reelin-positive subpial cells Calretinin pioneering cells with first corticofugal fibers Meyer et al. (2000) Cortical plate Muller¨ and O’Rahilly (1990b) Retrobulbar reelin-ir cells migrating to “marginal zone” of cortex Meyer et al. (2000) GABA-ir cells in zona limitans intrathalamica and ventral thalamus Kultas-Ilinsky et al. (2004) B. Trimester 1, Postembryonic Phase VMAT2 (vesicular monoamine transporter) Verney et al. (2002) SERT serotonin transporter GABA (γ -amino butyric acid)-immunoreactivity in the telencephalic wall Zecevic and Milosevic (1997) Initial organization of cortical development Neurofilament protein-labelled fibers, calretinin-ir, calbindin-ir neurons (in ascending Zecevic et al. (1999) caudorostral gradient) Cells of motor thalamic nuclei express calcium-binding protein, fibers coexpress GABA Kultas-Ilinsky et al. (2004) TH-ir axons in nucleus accumbens and amygdaloid complex coexpress the calbindin Verney et al. (2001b) D28K phenotype NPH (carrier molecule of vasopressin and oxytocin) in cells arising from hypothalamic Mai et al. (1997) sulcus (potentially functional hypothalamohypophysial system) D1R (dopamine receptor 1)-ir in striosomal bodies and neuropil Brana et al. (1996) GAD67-positive local circuit neurons in the thalamic nuclei (outside afferent receiving Kultas-Ilinsky et al. (2004) territory of basal nuclei) Apoptosis-regulatory Bcl-2 oncoprotein in hippocampus and brainstem Chan and Yew (1998) Synaptophysin indicates synaptogenesis in corpus striatum Ulfig et al. (2000)

(Continued ) P1: JYS JWDD017-26 JWDD017-ORahilly June 13, 2006 13:42 Char Count= 0

316 Chapter 26: PRENATAL LIFE

TABLE 26–2. (Continued )

Substances and/or Events Reference

C. Trimester 2 SERT-ir fibers in the internal capsule Verney et al. (2002) 4 neuropeptides produced by several neuron-populations are present in the corpus Brana et al. (1995) striatum: SRIF (somatostatin), ENK (enkephalin), SP (substance P), DYN (dynorphin) Monocarboxylate transporters MCT1 and MCT2 in the visual cortex Fayol et al. (2004) Immunoreactivity of neural cell adhesion molecule L1 in parallel fibers of the molecular Tsuru et al. (1996) layer and in the Purkinje cell layer of cerebellum Slit-2 required for guiding both pre- and post-crossing callosal axons (repels the growth Shu and Richards (2001) cones away from the median plane) Subpial granular layer expresses calretinin and reelin Meyer and Wahle (1999b) NPY (neuropeptide Y)-ir neurons in subplate Delalle et al. (1997) Diffuse and cellular AKAP (a kinase anchoring protein) 79-immunity in striatum Ulfig et al. (2001a,b) Migration of ventricular cells into cortex coincides with maximum density of Meyer et al. (1999) reelin-producing cells of subpial granular layer Synaptotagmin-ir fibers in subplate and cortical plate Ulfig et al. (2002) Vimentin-positive radial glia in thalamus and corpus striatum Ulfig et al. (1999) Calretinin and SMI in ventral parts of dorsal thalamus Kultas-Ilinsky et al. (2004) Edg-2 involved in myelination Briese and Ulfig (2003) Synaptoporin-ir fibers in subplate and cortical plate Ulfig et al. (2002) Synaptogenesis in auditory and prefrontal cortices Huttenlocher and Dabholkar (1997)

a See also Table 17–3 for development of dopaminergic neurons. bNeocortical formation using immunohistochemistry for reelin, calretinin and glutamic acid decarboxylase. P1: JYS JWDD017-26 JWDD017-ORahilly June 13, 2006 13:42 Char Count= 0

PRENATAL LIFE 317

Figure 26–12. Graph showing fresh brain weight plotted against estimated weeks after fertilization. This is a Gompertz prediction with a 95% conﬁdence band. After McLennan, Gilles, and Neff in Gilles, Leviton, and Dooling (1983).

Figure 26–13. The diameter of the ﬁxed fetal brain (n = 156) modiﬁed from Dunn (1921). The measurements are from the frontal to the occipital pole, and from the right to the left temporal pole. P1: JYS JWDD017-26 JWDD017-ORahilly June 13, 2006 13:42 Char Count= 0

CHAPTER26 SUPPLEMENT: EARLY

100 cm POSTNATAL LIFE

Years 510

Figure 26–1. (A) A boy at 14 postnatal days, showing the myelin in the thalamic region, brain stem, and cerebellum. (B) A girl at 20 postnatal days. The hypophysis, optic chiasma and tracts, and mamillary bodies (superimposed) are clearly visible, as are the corpus callosum, epiphysis, tectum, tentorium cerebelli, and fourth ventricle.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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320 Chapter 26: EARLY POSTNATAL LIFE

C Figure 26–14. (Continued ) (C) At 3 years, most of the adult features are already clearly visible. Structures seen more readily in this image include the septum pellucidum, the aqueduct, and the spheno-occipital joint. In the cerebellum the ﬁssura prima, the nodule, and the tonsil are distinguishable. Many of the white areas represent either fat or bone marrow, whereas solid bone does not produce signals.

Postnatal Prolongation of accelerated, growth rates during the ﬁrst postnatal year Fetal growth follow the fetal trends shown by other primates. Indeed it has been estimated that were birth to be delayed in propor- Human development shows a general retardation relative tion to retarded development in general, then existence in to other primates, resulting in retention of juvenile fea- utero would be increased to 21 months. The maintenance tures (neoteny). The human infant is relatively undevel- of fetal growth rates postnatally allows the brain to increase oped and helpless at birth, and the completion of growth considerably in mass. By plotting brain weight versus body and maturation is postponed. It has been proposed (par- weight it has been shown that the high fetal slope of the ticularly by Adolf Portmann) that because human birth is graph is, in the human, continued well into postnatal life. P1: JYS JWDD017-26 JWDD017-ORahilly June 13, 2006 13:42 Char Count= 0

EARLY POSTNATAL LIFE 321

Figure 26–14. (Continued ) (D) A coronal view at 2 postnatal months, showing myelination bilaterally in the white matter of the cerebellum. (E) At 4 years, showing the considerable advance in myelination, e.g., in the corona radiata, corpus callosum, fornices, thalami, colliculi, arbor vitae of the cerebellum, and cerebellar peduncles. The lateral, third, and fourth ventricles are distinguishable, as are also the tentorium cerebelli and the cerebellar folia. A–E, courtesy of Marvin D. Nelson, M.D., Children’s Hospital, Los Angeles.

Myelin(iz)ation prenatal life (Wo´zniak and O’Rahilly, 1982), in the pyrami- Myelination in the central nervous system begins after its dal tracts it begins late in trimester 3 and is not completed onset in the peripheral system in trimester 2. It contin- until about two years. Cortical association ﬁbers are among ues for a number of years after birth at a gradually de- the last to become myelinated. creasing rate. In the CNS, myelination is undertaken by At birth the human brain is only moderately myeli- oligodendrocytes and is very slow, and one axon can be en- nated (Fig. 26–14A,B) and the cerebral hemispheres con- veloped in several sheaths. The determination of the onset tain little myelin. Myelin can be shown histologically in the and end of myelination depends on whether light or elec- brain stem, the cerebellar white matter, and the posterior tron microscopy is used, and the appearances on magnetic limb of the internal capsule, with extensions to the thala- resonance images lag about a month behind histological mus and the basal nuclei. Myelination is greatest during data. the ﬁrst two postnatal years and is practically complete Myelination expresses the functional maturity of the in early adulthood, although it continues throughout life. brain and is correlated with psychomotor development, Tables showing the progress of myelination are available although transmission of impulses and functional activ- (e.g., Larroche, 1966; Gilles et al., 1983). ity begin before myelin sheaths develop. Large afferent A few examples of magnetic resonance imaging serve tracts become myelinated early, and tracts that appear early to illustrate the increasing degree of myelination. Postnatal in development generally undergo early myelination, e.g., myelination in the central nervous system has been stud- the medial longitudinal fasciculus. Although myelination ied extensively by Brody and Kinney and their colleagues is found in the pyramidal decussation by the middle of (Brody et al., 1987; Kinney et al., 1988). P1: JYS JWDD017-BIB JWDD017-ORahilly July 4, 2006 14:18 Char Count= 0

BIBLIOGRAPHY

The references provided here are almost entirely limited to studies of normal human prenatal development. Some references to neuroteratological conditions are included.

Adelmann, H.B. 1966 Marcello Malpighi and the Evolution of Embryol- Bartecko, K., and Jacob M. 1999 Comparative study of shape course and ogy. Cornell University Press, Ithaca, NY. disintegration of the rostral notochord in some vertebrates, especially Alcolado, R., Weller, R.O., Parrish, E.P., and Garrod, D. 1988 The cranial humans. Anat. Embryol., 200:345–366. arachnoid and pia mater in man. Neuropathol. Appl. Neurobiol., 14:1– Bartelmez, G.W. 1923 The subdivisions of the neural folds in man. J. 17. Comp. Neurol. 35:231–295. Alexandre, J.-H., and Pineau, H. 1970 Détermination de la taille assise et Bartelmez, G.W., and Blount, M.P. 1954 The formation of neural crest de l’âge des anencéphales. Arch. Anat. Cytol. Pathol., 18:265–270. from the primary optic vesicle in man. Contrib. Embryol. Carnegie Anand, K.J.S., and Scalzo, F.M. 2000 Can adverse neonatal experiences Inst., 35:55–71. alter brain development and subsequent behavior. Biol. Neonate, 77: Bartelmez, G.W., and Dekaban, A.S. 1962 The early development of the 69–82. human brain. Contrib. Embryol. Carnegie Inst., 37:13–32. André-Thomas, and de Ajuriaguerra, A. 1959 Etude anatomo-clinique de Bartelmez, G.W., and Evans, H.M. 1926 Development of the human l’anencéphalie. In G. Heuyer, M. Feld, and J. Gruner (eds.), Malfor- embryo during the period of somite formation. Contrib. Embryol. mations congénitales du cerveau. Masson, Paris, pp. 207–267. Carnegie Inst., 17:1–67. Andy, O.J., and Stephan, H. 1968 The septum in the human brain. J. Bayer, S.A., and Altman, J. 2002 The Spinal Cord from Gestational Week Comp. Neurol., 133:383–409. 4 to the 4th Postnatal Month. CRC Press, Boca Raton, Florida. Ariëns Kappers, C.U. 1932 Principles of development of the nervous Bayer, S.A., and Altman, J. 2004 The Human Brain during the Third system (neurobiotaxis). In W. Penfield (ed.), Cytology and Cellular Trimester. CRC Press, Boca Raton, Florida. Pathology of the Nervous System, Vol. 1. Hoeber, New York, pp. 73– Bayer, S.A., Altman, J., Russo, R.J., et al., 1993 Timetables of neurogenesis 89. in the human brain based on experimentally determined patterns in Ariëns Kappers, J. 1955 The development of the paraphysis cerebri in man the rat. Neurotoxicol., 14:83–144. with comments on its relationship to the intercolumnar tubercle and Beau, A. 1939 Etude´ sur le développement du cerveau postérieur.G. its significance for the origin of cystic tumors in the third ventricle. Thomas, Nancy. J. Comp. Neurol., 102:425–509. Belloni, E., Muenke, M., Roessler, E., et al. 1996 Identification of Sonic Ariëns Kappers, J. 1966 Strukturelle und funktionelle Anderungen¨ im hedgehog as a candidate gene responsible for holoprosencephaly. telencephalen Plexus chorioideus des Menschen während der Onto- Nature Genet., 14:353–360. genesese. Wiener Z. Nervenheilk. Grenzgeb., Suppl. 1:30–48. Beyer, C. 1999 Estrogen and the developing mammalian brain. Anat. Arnold, S.E., and Trojanowski, J.Q. 1996 Human fetal hippocampal devel- Embryol., 199: 379–390. opment: I. Cytoarchitecture, myeloarchitecture, and neuronal mor- Blaas, H.-G., Eik-Nes, S.H., Kiserud, T., et al. 1995a Early development of phologic features; II. The neuronal cytoskeleton. J. Comp. Neurol., the hindbrain: A longitudinal ultrasound study from 7 to 12 weeks of 367:274–292, 293–307. gestation. Ultrasound Obstet. Gynecol., 5:151–160. Ashwell, K.W.S., Waite, P.M.E., and Marotte, L. 1996 Ontogeny of the Blaas, H.-G., Eik-Nes, S.H., Kiserud, T., et al. 1995b Three-dimensional projection tracts and commissural fibres in the forebrain of the tam- imaging of the brain cavities in human embryos. Ultrasound Obstet. mar wallaby (Macropus eugenii): timing in comparison with other Gynecol., 5:228–232. mammals [including the human]. Brain Behav. Evol., 47:8–22. Blaas, H.-G., Eik-Nes, S.H., Berg, S., et al. 1998 In-vivo three-dimensional Augustine, J.R. 1996 Circuitry and functional aspects of the insular lobe ultrasound reconstructions of embryos and early fetuses. Lancet, in primates including humans. Brain Res. Rev., 22:229–244. 352:1182–1186. deAzevedo, L.C., Hedin-Pereira, C., and Lent, R. 1997 Callosal neurons in Blaas, H.-G., Eik-Nes, S.H., and Isaksen, C.V. 2000a The detection of spina the cingulate cortical plate and subplate of human fetuses. J. Comp. bifida before 10 gestational weeks using two- and three-dimensional Neurol., 386:60–70. ultrasound. Ultrasound Obstet. Gynecol., 16:25–29. Barbé, A. 1938 Recherches sur l’embryologie du système nerveux central Blaas, H.-G., Eik-Nes, S.H., Vainio, T., et al. 2000b Alobar holo- de l’homme. Masson, Paris. prosencephaly at 9 weeks gestational age visualized by two- and Barinaga, M. 1996 Guiding neurons to the cortex. Science, 274:1100– three-dimensional ultrasound. Ultrasound Obstet. Gynecol., 15:62– 1101. 65. Baron-Cohen, S., Knickmeyer, R.C., and Belmonte, M.K. 2005 Sex dif- Blaas, H.-G., Eriksson, A.G., Salvesen, K.A.,˚ et al. 2002 Brains and faces ferences in the brain: implications for explaining autism. Science, in holoprosencephaly: Pre- and postnatal description of 30 cases. Ul- 310:819–823. trasound Obstet. Gynecol., 19:24–38.

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

323 P1: JYS JWDD017-BIB JWDD017-ORahilly July 4, 2006 14:18 Char Count= 0

324 BIBLIOGRAPHY

Bogolepova, I.N. 1995 Ontogenesis of cytoarchitecture of human hip- Comptson A., Zajicek, J., Sussman, J., et al. 1997 Glial lineages and myeli- pocampus. Acta Anat., 152: 260 (abstract). nation in the central nervous system. J. Anat, 190:161–200. Bogolepova, I.N. 1997 The limbic system as a model of cytoarchitectonical Conklin, J.L. 1968 The development of the human fetal adenohypophysis. changes in the developing brain. In S. U. Dani, A. Hori, and G. F.Walter Anat. Rec., 160:79–91. (eds.), Principles of Neural Aging, Elsevier, Amsterdam. Cooper, E.R.A. 1946a The development of the human red nucleus and Borkowski, W.J., and Bernstine, R.L. 1955 Electroencephalography of the corpus striatum. Brain, 69:34–44. fetus. Neurology (N.Y.), 5:362–365. Cooper, E.R.A. 1946b Accessory optic tracts in the human fetus. Brain, Bossy, J. 1966 Diverticule télencéphalique de la région du neuropore 69:45–49. antérieur chez un embryon humain de 35 mm V.C. Bull. Assoc. Anat. Copp, A.J. 2005. Neurulation in the cranial region – normal and abnormal (Nancy), 50: 200–210. [in rodents, including comparisons with human]. J. Anat., 207:623– Bossy, J. 1980 Development of olfactory and related structures in staged 635. human embryos. Anat. Embryol., 161:225–236. Crawford, J.D., Cadera, W., and Vilis, T. 1991 Generation of torsional and Bossy, J., Godlewski, G., and Maurel, J.C. 1976 Etude de l’asymétrie droite- vertical eye position signals by the interstitial nucleus of Cajal. Sci- gauche du planum temporale chez le foetus humain. Bull. Assoc. Anat. ence, 252:1551–1553. (Nancy), 60/169: 253–258. Crosby, C.E. Humphrey, T., and Lauer, E.W. 1962 Correlative Anatomy of Brana, C., Charron, G., Aubert, D., et al. 1995 Ontogeny of the striatal neu- the Nervous System. Macmillan, New York. rons expressing neuropeptide genes in the human fetus and neonate. Crosby, R.W., and Cody, J. 1991 Max Brödel, the Man Who Put Art into J. Comp. Neurol., 360:488–505. Medicine. Springer, New York. Brana, C., Caille, I., Pellevoisin, C., et al. 1996 Ontogeny of the striatal Dahl, E., Koseki, H., and Balling, R. 1997 Pax genes and organogenesis. neurons expressing the D1 dopamine receptor in human. J. Comp. BioEssays, 19:755–765. Neurol., 370:23–34. Dani, S.U., Hori, A., and Walter, G.F. (eds.) 1997 Principles of Neural Briese, M., and Ulfig, N. 2003 Expression of the G-protein-coupled re- Aging. Elsevier, Amsterdam. ceptor endothelial differentiation Gene-2 in the developing human Dart, R.A. 1924 The anterior end of the neural tube and the anterior end forebrain with reference to myelination. Neuroembryology, 2:114– of the body. J. Anat., 58:181–205. 122. Day, R.W. 1959 Casts of foetal lateral ventricles. Brain, 82:109–115. Brocklehurst, G. 1969 The development of the human cerebrospinal fluid Dekaban, A.S. 1954 Human thalamus: II. Development of the human pathway with particular reference to the roof of the fourth ventricle. thalamic nuclei. J. Comp. Neurol., 100:63–97. J. Anat., 105:467–475. Dekaban, A.S. 1963 Anencephaly in early human embryos. J. Neu- Brody, B.A., Kinney, H.C., Kloman, A.S., and Gilles, F.H. 1987 Sequence ropathol. Exp. Neurol., 22:533–548. of central nervous system myelination in human infancy: I. An au- Dekaban, A.S., and Bartelmez, G.W. 1964 Complete dysraphism in 14 topsy study of myelination. J. Neuropathol. Exp. Neurol., 46:283– somite human embryo. Am. J. Anat., 115:27–41. 301. Delalle, I., Evers, P. Kostović, I., and Uylings, H.B.M. 1997 Laminar distri- Brown, J.W. 1990 Prenatal development of the human nucleus ambiguus bution of neuropepetide Y-immunoreactive neurons in human pre- during the embryonic and early fetal periods. Am. J. Anat., 189:267– frontal cortex during development. J. Comp. Neurol., 379:515–522. 283. DeMyer, W. 1975 Median facial malformations and their implications for Brun, A. 1965 The subpial granular layer of the foetal cerebral cortex in brain malformations. Birth Defects, XI:155–181. man. Its ontogenesis and significance in congenital cortical malfor- DeMyer, W. 1987 Holoprosencephaly (cyclopia-arhinencephaly). In P.J. mations. Acta Pathol. Microbiol. Scand., Suppl. 179, 13:1–98. Vinken, G.W. Bruyn, and H.L. Klawans (eds.), Handbook of Clinical Butler, H., and Juurlink, B.H.J. 1987 An Atlas for Staging Mammalian Neurology. Vol. 6, Elsevier, Amsterdam. Revised Series, pp. 225–244. and Chick Embryos. CRC Press, Boca Raton, FL. Denawit-Saubié, M., Kalia, M., Pierrefiche, O., et al. 1994 Maturation Bystron, I., Molnár, Z., Otellin, V., and Blakemore, C. 2005 Tangential of brain stem neurons involved in respiratory rhythmogenesis: Bio- networks of precocious neurons and early axonal outgrowth in the chemical, bioelectrical and morphological properties. Biol. Neonate, embryonic human forebrain. J. Neurosci., 25:2781–2792. 65:171–175. Chan, W.Y., and Yew, D.T. 1998 Apoptosis and Bcl oncoprotein expression Denker, H-W. 2004 Early human development: New data raise important in the human fetal central nervous system. Anat. Rec., 252:165–175. embryological and ethical questions relevant for stem cell research. Chi, J.G., Dooling, E.C., Gilles, F.H.1977 Gyral development of the human Naturwissenschaften, 91:1–21. brain. Ann. Neurol., 1:86–93. Detrait, E.R., George, T.M.,Etchevers, H.C., et al. 2005 Human neural tube Choi, B.H. 1987 Cortical dysplasia associated with massive ectopia of neu- defects: Developmental biology, epidemiology, and genetics. Neuro- rons and glial cells within the subarachnoid space. Acta Neuropathol., toxicol. Teratol., 27: 515–524. 73:105–109. Dorovini-Zis, K., and Dolman, C.L. 1977 Gestational development of Choi, B.H., 1988 Developmental events during the early stages of cerebral brain. Arch. Pathol. Lab. Med., 101:192–195. cortical neurogenesis in man. Acta Neuropathol., 75:441–447. Doucette, R. 1993 Glial cells in the nerve fiber layer of the main olfactory Choi, B.H. 1994 Role of the basement membrane in neurogenesis and bulb of embryonic and adult mammals. Microsc. Res. Tech., 24:113– repair of injury in the central nervous system. Microsc. Res. Tech., 130. 28:193–203. Dunn, H.L. 1921 The growth of the central nervous system in the human Choi, B.H., and Lapham, W. 1980 Evolution of Bergmann glia in de- fetus. J. Comp. Neurol., 33:405–491. veloping human fetal cerebellum: A Golgi electron microscopic and Essick, C.R. 1912 The development of the nuclei pontis and the nucleus immuno-fluorescent study. Brain Res., 190:369–383. arcuatus in man. Am. J. Anat., 13:25–54. Clancy, B., Darlington, R.B., and Finlay, B.L. 2001 Translating develop- Fabiani, F., and Bartonini, F. 1956 I primi stadi ontogenetici del talamo mental time across mammalian species. Neuroscience, 105:7–17. ottico umano. Rass. Studi Psichiat., 45:1184–1154. Clark, S., Kraftsik, R., van der Loos, H., and Innocenti, G.M. 1989 Forms Fayol, L., Baud, O., Monier, A., et al. 2004 Immunocytochemical expres- and measures of adult and developing human corpus callosum: Is sion of monocarboxylate transporters in the human visual cortex at there sexual dimorphism? J. Comp. Neurol., 280:213–230. midgestation. Dev. Brain Res., 148:69–76. Cleland, J. 1883 Contribution to the study of spina bifida, encephalocele, Feess-Higgins, A., and Larroche, J.-C. 1987 Le dévelopment du cerveau and anencephalus. J. Anat. Physiol., 17:257–292. foetal humain. Atlas anatomique. INSERM-CNRS, Masson, Paris. P1: JYS JWDD017-BIB JWDD017-ORahilly July 4, 2006 14:18 Char Count= 0

BIBLIOGRAPHY 325

Fields, R.D., and Stevens-Graham B. 2002 New insights into neuron–glia Hewitt, W. 1958 The development of the human caudate and amygdaloid communication. Science, 298:556–559. nuclei. J. Anat., 92:377–382. Fitzgerald, M. 1993 Development of pain pathways and mechanisms. Hikij, K. 1933 Zur Anatomie des Bodens der Rautengrube beim Neuge- In Anand K.J.S., and McGrath, P.J. (eds) Pain in Neonates. Elsevier, borenen. Anat. Anz., 75:406–442. Amsterdam. Hines, M. 1922 Studies in the growth and differentiation of the telen- Fontes, V. 1944 Morfologia do cortex cerebral (desenvolvimento). Insti- cephalon in man. The fissura hippocampi. J. Comp. Neurol., 34:73– tuto de Antonio Aurélio da Costa Ferreira, Lisbon. 171. Forster, F.1968 Ein einfacher Apparat zum Zeichen von Blockbildern und His, W. 1890 Die Entwickelung des menschlichen Rautenhirns vom Ende Stereo-Blockbildern. Jahrb. Schweiz. Sekundarlehrerkonf., pp. 1–24. des ersten bis zum Beginn des dritten Monats: I. Verlängertes Mark. Fredericks, C.A., Giolli, R.A., Blanks, R.H.I., and Sadun, A.A. 1988 The Abh. KS Gesellsch. Wissensch., 29:3–74. human accessory optic system. Brain Res., 454:116–122. His, W. 1895 Die anatomische Nomenclatur. Nomina anatomica. Arch. Freed, C.R., Breeze, R.E., Rosenberg, N.L., et al. 1992 Survival of im- Anat. Physiol., Anat. Abth., Suppl., 1–183. planted fetal dopamine cells and neurologic improvement 12 to 46 His, W. 1904 Die Entwickelung des menschlichen Gehirns während der months after transplantation for Parkinson’s disease. N. Engl. J. Med., ersten Monate. Untersuchungsergebnisse. Hirzel, Leipzig. 327:1549–1555. Hochstetter, F. 1913 Uber¨ die Entwickelung der Plexus chorioidei der Freeman, T.B., Spence, M.S., Boss, B.D., et al. 1991 Development of Seitenkammern des menschlichen Gehirns. Anat. Anz., 45:225– dopaminergic neurons in the human substantia nigra. Exp. Neurol., 238. 113:344–353. Hochstetter, F. 1919 Beiträge zur Entwicklungsgeschichte des men- Freeman, T.B., Sanberg, P.R., and Isacson, O. 1995 Development of the schlichen Gehirns. I. Teil. Deuticke, Vienna. human striatum. Implications for fetal striatal transplantation in the Hochstetter, F. 1923 Beiträge zur Entwicklungsgeschichte des men- treatment of Huntington’s disease. Cell Transplant., 4:539–545. schlichen Gehirns. II. Teil. 1. Lieferung. Die Entwicklung der Zir- Friant, M. n.d. Anatomie comparée du cerveau. Prisma, Paris. beldruse ¨ . Deuticke, Vienna. Fujimoto, E., Miki, A., and Mizoguti, H. 1989. Histochemical study of the Hochstetter, F. 1929 Beiträge zur Entwicklungsgeschichte des men- differentiation of microglial cells in the developing human cerebral schlichen Gehirns. II. Teil, 3. Lieferung. Die Entwicklung des Mittel- hemispheres. J. Anat., 166:253–264. und Rautenhirns. Deuticke, Vienna. Gadisseux, J.-F., Goffinet, A.M., Lyon, G., and Evrard, P. 1992 The human Hochstetter, F. 1934 Uber¨ die Entwicklung und Differenzierung der transient subpial granular layer: An optical, immunohistochemical, Hüllen des Ruckenmarkes ¨ beim Menschem. Morphol. Jahrb., 74:1– and ultrastructural analysis. J. Comp. Neurol., 324:94–114. 104. Gardner, E., O’Rahilly, R., and Prolo, D. 1975 The Dandy–Walker and Hochstetter, F. 1939 Uber¨ die Entwicklung und Differenzierung der Arnold–Chiari malformations. Arch. Neurol., 32:393–407. Hüllen des menschlichen Gehirnes. Morphol. Jahrb., 83:359–494. Gaunt W.A., and Gaunt, P.N. 1978 Three Dimensional Reconstruction in Hochstetter, F. 1954 Uber¨ die Herstellung besonders instruktiver Licht- Biology. Pitman, Tunbridge Wells. bilder der Körperoberfläche von Keimlingen. Ciba-Symposium, 2:52– Gérard, M., Abitbol, A.-L. Delezoide, J.L., et al. 1995 PAX-genes expression 57. during human embryonic development, a preliminary report. C.R. Hokfelt, T., Martensson, R., Bjorklund, A., et al. 1984 Distributional map Acad. Sci., 318:57–66. of tyrosinehydroxylase-immunoreactive neurons in the rat brain. In A. Geschwind, N.W., and Galaburda, A.M. 1985 Cerebral lateralization: Bi- Bjorklund, T. Hokfelt (eds.), Handbook of Chemical Neuroanatomy, ological mechanisms, associations, and pathology. Arch. Neurol., vol. 2. Elsevier, Amsterdam. 42:428–459, 521–552, 634–654. Hoving, E.W. 1993 Frontoethmoidal Encephaloceles. A Study of Their Gilbert, M.S. 1935 The early development of the human diencephalon. J. Pathogenesis. Doctoral dissertation, Rijksuniversiteit Groningen, The Comp. Neurol., 62:81–115. Netherlands. 175 pp. Gilbert, P.W. 1957 The origin and development of the human extrinsic Humphrey, T. 1965 The development of the human hippocampal forma- ocular muscles. Contrib. Embryol. Carnegie Inst., 34:59–78. tion correlated with some aspects of its phylogenetic history. In R. Gilles, F.H., Leviton, A., and Dooling, E.C. 1983 The Developing Human Hassler and H. Stephan (eds.), Evolution of the Forebrain. Thieme, Brain. Wright-PSG, Boston. Stuttgart. Gilles, F.H., Nelson, M.D., and Gonzalez-Gomez, I. 1992 Human telen- Humphrey, T.1968 The development of the human amygdala during early cephalic angiogenesis: An update. In K. Fujisawa and Y. Morimatsu embryonic life. J. Comp. Neurol., 132:135–165. (eds.), Development and Involution of Neurones. Japan Science Soci- Hunter, R.H. 1934 Extroversion of the cerebral hemispheres in a human ety Press, Tokyo, pp. 31–41. embryo. J. Anat., 59:82–85. Goodman, F.R. 2003 Congenital abnormalities of body patterning: em- Huttenlocher, P.R., and Dabholkar, A.S. 1997 Regional differences in bryology revisited. Lancet, 362:651–662. synaptogenesis in human cerebral cortex. J. Comp. Neurol., 387:167– Grenadino, B., Gallardo, M.E., Lopez-Rios, I., et al. 1999 Genomic cloning, 178. structure, expression pattern, and chromosomal location of the hu- Inke, G., and Palkovits, M. 1963 Die embryonale Entwicklung des Sub- man SIX3 gene. Genomics, 55: 100–105. commissuralkomplexes (Subcommissuralorgan und seine Kompo- Hansen, P.E.,Ballesteros, M.C., Soila, K., et al. 1993 MR imaging of the de- nenten) beim Menschen. Anat. Anz., 113: 240–254. veloping brain: Part 1. Prenatal development. RadioGraphics, 13:21– Jacobs, M.J. 1970 The development of the human motor trigeminal com- 36. plex and accessory facial nucleus and their topographic relations with Hayaran, A., Wadhwa, S., and Bijlani, V. 1992 Cytoarchitectural develop- the facial and abducens nuclei. J. Comp. Neurol., 138:161–194. ment of the human dentate nucleus: A Golgi study. Dev. Neurosci, Jakob, A. 1929 Das Kleinhirn. In W. von Möllendorff (ed.), Handbuch der 14:181–194. mikroskopischen Anatomie des Menschen, Vol. 4 (1). Springer, Berlin. Hevner, R.F., and Kinney, H.C. 1996 Reciprocal entorhinal–hippocampal pp. 674–916. connections established by human fetal midgestation. J. Comp. Neu- Jen, J.C., Chan, W-M, Bosley, T.M.,et al. 2004 Mutations in a human ROBO rol., 372:384–394. gene disrupt hindbrain axon pathway crossing and morphogenesis. Heuser, C.H., and Corner, G.W. 1957 Developmental horizons in human Science, 304:1509–1556. embryos. Description of age group X, 4 to 12 somites. Contrib. Em- Johnston, J.B. 1909 The morphology of the forebrain vesicle in verte- bryol. Carnegie Inst., 36:29–39. brates. J. Comp. Neurol., 19:457–539. P1: JYS JWDD017-BIB JWDD017-ORahilly July 4, 2006 14:18 Char Count= 0

326 BIBLIOGRAPHY

Kahle, W. 1956 Zur Entwicklung des menschlichen Zwischenhirns. Larsell, O. 1947 The development of the cerebellum in man in relation to Dtsch. Z. Nervenheilk., 175:259–318. its comparative anatomy. J. Comp. Neurol., 87:85–129. Kahle, W. 1969 Die Entwicklung der menschlichen Grosshirnhemisphäre. Lemire, R.J., Beckwith, J.P., and Warkany, J. 1978 Anencephaly. Raven Schriftenr. Neurol., 1:1–116. Press, New York. Kehrli, P., Maillot, C., and Wolff Quenot, M.J. 1995 Les gaines des nerfs Lemire, R.J., Shepard, T.H., and Alvord, E.C. 1965 Caudal myeloschisis crâniens dans la paroi latérale de la loge parasellaire. Neurochirurgie, (lumbosacral spina bifida cystica) in a five millimeter (Horizon XIV) 41:403–412. human embryo. Anat. Rec., 152: 9–16. Keibel, F., and Mall, F.P. 1912 Manual of Human Embryology, Vol. 2. Lemire, R.J., Loeser, J.D., Leech, R.W., and Alvord, E.C. 1975 Normal Lippincott, Philadelphia. and Abnormal Development of the Human Nervous System. Harper Kier, E.L. 1977 The cerebral ventricles: A phylogenetic and ontogenetic & Row, Hagerstown, MD. study. Radiology of the skull and brain. Anat. Pathol., 3:2787–2914. Letiniˇc, K., and Kostović, I. 1997 Transient Fetal structure, the ganglio- Kier, E.L., and Truwit, C.L. 1996 The normal and abnormal genu of the thalamic body, connects telencephalic germinal zone with all thalamic corpus callosum: An evolutionary, embryologic, anatomic, and MR regions in the developing human brain. J. Comp. Neurol., 384:373– analysis. Am. J. Neuroradiol., 17: 1631–1641. 395. Kier, E.L., Fulbright, R.K., and Bronen, R.A. 1995 Limbic lobe embryology Macchi, G. 1951 The ontogenetic development of the olfactory telen- and anatomy: Dissection and MR of the medial surface of the fetal cephalon in man. J. Comp. Neurol., 95:245–305. cerebral hemisphere. Am. J. Neuroradiol., 16:1847–1853. Macdonald, R., and Wilson, S.W. 1996 Pax proteins and eye development. Kier, E.L., Kim, J.H., Fulbright, R.K., and Bronen, R.A. 1997 Embryology Curr. Opin. Neurobiol., 6:49–56. of the human fetal hippocampus: MR imaging, anatomy, and histology. Mai, J., Lensing-Höhn S., Ende, A.A., et al. 1997 Developmental organiza- Am. J. Neuroradiol., 18: 525–532. tion of neurophysin neurons in the human brain. J. Comp. Neurol., Kinney, H.C., Brody, B.A., Kloman, A.S., and Gilles, F.H. 1988 Sequence 385:477–489. of central nervous system myelination in human infancy. J. Neu- Marin, O. Yaron, A., Bagri, A., et al. 2001 Sorting of striatal and corti- ropathol. Exp. Neurol., 47:217–234. cal interneuorns regulated by semaphorin–neuropilin interactions. Klinthworth, G.K. 1967 The ontogeny and growth of the human tento- Science, 293:872–875. rium cerebelli. Anat. Rec., 158:433–441. Mar´ın-Padilla, M. 1970 Prenatal and early postnatal ontogenesis of the Kostović, I. 1986 Prenatal development of nucleus basalis complex and human motor cortex. A Golgi study: 1. The sequential development related fiber systems in man: A histochemical study. Neuroscience, of the cortical layers. Brain Res., 23:167–183. 17:1047–1077. Mar´ın-Padilla, M. 1978 Dual origin of the mammalian neocortex and Kostović, I., and Judas, M. 2002 Correlation between the sequential in- evolution of the cortical plate. Anat. Embryol. (Berlin), 152:109– growth of afferents and transient patterns of cortical lamination in 126. preterm infants. Anat. Rec., 267:1–6. Mar´ın-Padilla, M. 1983 Structural organization of the human cerebral Kostović, I., and Rakic, P. 1990 Developmental history of the transient cortex prior to the appearance of the cortical plate. Anat. Embryol. subplate zone in the visual and somatosensory cortex of the macaque (Berlin), 168:21–40. monkey and human brain. J. Comp. Neurol., 297:441–470. Mar´ın-Padilla, M. 1985 Early vascularization of the embryonic cerebral Kostović, I., Kneˇzević, S., Wisnieswski, H.M., and Spilich, G.J. (eds.) 1992a cortex: Golgi and electron microscopic studies. J. Comp. Neurol., 241: Neurodevelopment, Aging and Cognition. Birkhäuser, Boston. 237–249. Kostović, I., Petanjek, Z., Delalle, I., and Judas, M. 1992 Developmental Mar´ın-Padilla, M. 1988a Early ontogenesis of the human cerebral cortex. reorganization of the human association cortex during perinatal and Cerebral Cortex, 7:1–34. postnatal life. In I. Kostović, S. Kneˇzević, H.M. Wisniewski, and G.J. Mar´ın-Padilla, M. 1988b Embryonic vascularization of the mammalian Spilich (eds.), Neurodevelopment, Aging and Cognition. Birkhäuser, cerebral cortex. Cerebral Cortex, 7:479–509. Basel. Mar´ın-Padilla, M. 1991 Cephalic axial skeletal–neural dysraphic disorders: Koya, T. 1963 The forebrain angle of the human embryo [in Japanese]. Embryology and pathology. Can. J. Neurol. Sci., 18:153–169. Hirosaki Med. J., 15:250–263 Mar´ın-Padilla, M. 1992 Ontogenesis of the pyramidal cells of the mam- Kuhlenbeck, H. 1973 The Central Nervous System of Vertebrates. Overall malian neocortex and developmental cytoarchitectonics: A unifying Morphologic Pattern, Vol. 3, Part II. Karger, Basel, pp. 1–768. theory. J. Comp. Neurol., 321:223–240. Kuhlenbeck, H. 1977 The Central Nervous System of Vertebrates. Deriva- Mar´ın-Padilla, M. 1995 Prenatal development of fibrous (white matter), tives of the Prosencephalon: Diencephalon and Telencephalon. Vol. 5, protoplasmic (gray matter), and layer I astrocytes in the human cere- Part I, Karger, Basel, pp. 461–888. bral cortex: A Golgi study. J. Comp. Neurol., 357:554–572. Kuhlenbeck, H. 1978 The Central Nervous System of Vertebrates. Mam- Mar´ın-Padilla, M., and Mar´ın-Padilla, M.T. 1982 Origin, prenatal devel- malian Telencephalon, Vol. 5, Part II. Karger, Basel, pp. 1–478. opment and structural organization of layer I of the human cerebral Kultas-Ilinsky, K., Fallet, C., and Verney, C. 2004 Development of the (motor) cortex. Anat. Embryol. (Berlin), 164:161–206. human motor-related thalamic nuclei during the first half of gesta- Markowski, J. 1922 Entwicklung der Sinus durae matris und der tion, with special emphasis on GABAergic circuits. J. Comp. Neurol., Hirnvenen des Menschen. Bull. Int. Acad. Polon. Sci. Lett. (Suppl), 476:267–289. pp. 1–269. deLacoste, M.-C., Holloway, R.L., and Woodward, D.J. 1986 Sex differences Marti, E., Gibson, S.J., Polak, J.M., et al. 1987 Ontogeny of peptide- and in the fetal human corpus callosum. Hum. Neurobiol., 5:93–96. amine-containing neurones in motor, sensory and autonomic regions Larroche, J.-C. 1966 The development of the central nervous system dur- of rat and human spinal cord, dorsal root ganglia and rat skin. J. Comp. ing intrauterine life. In F. Falkner (ed.), Human Development, Saun- Neurol., 266:332–359. ders, Philadelphia, pp. 257–276. Meyer, G., Goffinet, A.M., and Fairén, A. 1999a What is a Cajal-Retzius Larroche, J.-C. 1981 The marginal layer in the neocortex of a 7-week-old cell? Cerebral Cortex, 9:765–775. human embryo. Anat. Embryol. (Berlin), 162:301–312. Meyer, G., Schaaps, J.P, Moreau, L., et al. 2000 Embryonic and early fetal Larroche, J.-C., and Houcine, O. 1982 Le néo-cortex chez l’embryon et development of the human neocortex. J. Neurosci., 20:1858–1868. le foetus humain. Apport du microscopeelectronique ´ et du Golgi. Meyer, G., and Wahle, P. 1999b The paleocortical ventricle is the origin Reprod. Nutr. Dev., 22:163–170. of reelin-expressing neurons in the marginal zone of the fetal human Larroche, J-C., and Jardin, L. 1985 Cited by Mar´ın-Padilla (1988a). neocortex. Eur. J. Neurosci., 11:3937–3944. P1: JYS JWDD017-BIB JWDD017-ORahilly July 4, 2006 14:18 Char Count= 0

BIBLIOGRAPHY 327

Molliver, M.E., Kostović, I., and van der Loos, H. 1973 The development Müller, F., O’Rahilly, R., and Tucker, J.A. 1981 The human larynx at the of synapses in cerebral cortex of the human fetus. Brain Res., 50:403– end of the embryonic period proper: I. The laryngeal and infrahy- 407. oid muscles and their innervation. Acta Otolaryngol. (Stockholm), Molnár, Z., and Butler, A.B. 2002 The corticostriatal junction: A crucial 91:323–336. region for forebrain development and evolution. BioEssays, 24:530– Müller, F., O’Rahilly, R., and Tucker, J.A. 1985 The human larynx at the 541. end of the embryonic period proper: 2. The laryngeal cavity and the Mrzijak, L., Uylings, H.B.M., Kostović, I., van Eden, C.G. 1988 Prenatal de- innervation of its lining. Ann. Otol. Rhinol. Laryngol. (Stockholm), velopment of neurons in the human prefrontal cortex: I. A qualitative 94:607–617. study. J. Comp. Neurol., 271:355–386. Müller, F., and O’Rahilly, R. 2003a The prechordal plate, the rostral end of Muenke, M., and Cohen, M.M. 2000 Genetic approaches to understanding the notochord, and nearby median features in staged human embryos. brain development: Holoprosencephaly as a model. Ment. Retard. Dev. Cells Tissues Organs, 173:1–20. Disab. Res. Rev., 6:15–21. Müller, F., and O’Rahilly, R. 2003b Segmentation in staged human em- Müller, F., and O’Rahilly, R. 1980 The human chondrocranium at the broys. The occipitocervical region revisited. J. Anat., 203:297–315. end of the embryonic period proper, with particular reference to the Müller, F., and O’Rahilly, R. 2004a The primitive streak, the caudal emi- nervous system. Am. J. Anat., 159:33–58. nence and related strutures in staged human embroys. Cells Tissues Müller, F., and O’Rahilly, R. 1983 The first appearance of the major divi- Organs, 177:2–20. sions of the human brain at stage 9. Anat. Embryol., 168:419–432. Müller, F., and O’Rahilly, R. 2004b Olfactory structures in staged human Müller, F.,and O’Rahilly, R. 1984 Cerebral dysraphia (future anencephaly) embryos with special reference to the future limbic system. Cells Tis- in a human twin embryo at stage 13. Teratology, 30:167–177. sues Organs, 178:93–116. Müller, F., and O’Rahilly, R. 1985 The first appearance of the neural tube Müller, F., and O’Rahilly, R. 2004c Embryonic development of the central and optic primordium in the human embryo at stage 10. Anat. Em- nervous system. In G. Paxinos and J.K. Mai (eds.), The Human Nervous bryol., 172:157–169. System, 2nd ed. Elsevier Academic Press, Amsterdam, pp. 22–48. Müller, F., and O’Rahilly, R. 1986a The development of the human brain Müller, F.,and O’Rahilly, R. 2006 The amygdaloid complex and the medical and the closure of the rostral neuropore at stage 11. Anat. Embryol. and lateral ventricular eminences in staged human embroys. J. Anat., (Berlin), 175:205–222. 208:547–564. Müller, F., and O’Rahilly, R. 1986b Somitic–vertebral correlation and ver- Nelson, M.D., Gonzalez-Gomez, I., and Gilles, F.H. 1991 The search for tebral levels in the human embryo. Am. J. Anat., 177:1–19. human telencephalic ventriculofugal arteries. Am. J. Neuroradiol., Müller, F., and O’Rahilly, R. 1987 The development of the human brain, 12:215–222. the closure of the caudal neuropore, and the beginning of secondary Nieuwenhuys, R., Voogd, J., Huijzen, Ch. van 1988 The Human Central neurulation at stage 12. Anat. Embryol., 176:413–430. Nervous System, 3rd ed. Springer, Berlin. Müller, F., and O’Rahilly, R. 1988a The development of the human brain Okado, N. 1981 Onset of synapse formation in the human spinal cord. J. from a closed neural tube at stage 13. Anat. Embryol., 177:203–224. Comp. Neurol., 201:211–219. Müller, F.,and O’Rahilly, R. 1988b. The first appearance of the future cere- Oliver, G., Mailhos, A., Wher, R., et al. 1995 Six3, a murine homologue bral hemispheres in the human embryo at stage 14. Anat. Embryol., of the sine oculis gene, demarcates the most anterior border of the 177:495–511. developing neural plate and is expressed during eye development. Müller, F., and O’Rahilly, R. 1988c The development of the brain, includ- Development, 121:4045–4055. ing the longitudinal zoning in the diencephalon at stage 15. Anat. O’Rahilly, R. 1963 The early development of the otic vesicle in staged Embryol. (Berlin), 179: 55–71. human embryos. J. Embryoal. Exp. Morphol., 11:741–755. Müller, F., and O’Rahilly, R. 1989a The human brain at stage 16, includ- O’Rahilly, R. 1965 The optic, vestibulocochlear, and terminal- ing the initial evagination of the neurohypophysis. Anat. Embryol. vomeronasal neural crest in staged human embryos. In J.W. Rohen (Berlin), 179:551–569. (ed.) Second Symposium on Eye Structure. Schattauer, Stuttgart, Müller, F.,and O’Rahilly, R. 1989b The human brain at stage 17, including pp. 557–564. the appearance of the future olfactory bulb and the first amygdaloid O’Rahilly, R. 1966 The early development of the eye in staged human nuclei. Anat. Embryol. (Berlin), 179:353–369. embryos. Contrib. Embryol. Carnegie Inst., 38:1–42. Müller, F., and O’Rahilly, R. 1989c Mediobasal prosencephalic defect, in- O’Rahilly, R. 1968 The development of the epiphysis cerebri and the sub- cluding holoprosencephaly and cyclopia, in relation to the develop- commissural complex in staged human embryos. Anat. Rec., 160: ment of the human forebrain. Am. J. Anat., 185:391–414. 488–489. Müller, F., and O’Rahilly, R. 1990a The human brain at stages 18–20, O’Rahilly, R. 1973 Developmental Stages in Human Embryos. Part A: including the choroid plexuses and the amygdaloid and septal nuclei. Embryos of the First Three Weeks (Stages 1 to 9). Carnegie Institution Anat. Embryol., 182:285–306. of Washington, Washington, D.C., Publication No. 631. Müller, F., and O’Rahilly, R. 1990b The human brain at stages 21–23, O’Rahilly, R. 1975 The prenatal development of the human eye. Exp. Eye with particular reference to the cerebral cortical plate and to the Res., 21:93–112. development of the cerebellum. Anat. Embryol., 182:375–400. O’Rahilly, R. 1983a The timing and sequence of events in the development Müller, F., and O’Rahilly, R. 1990c The human rhombencephalon at the of the human endocrine system during the embryonic period proper. end of the embryonic period proper. Am. J. Anat., 189:127–145. Anat. Embryol., 166:439–451. Müller, F., and O’Rahilly, R. 1991 Development of anencephaly and its O’Rahilly, R. 1983b The timing and sequence of events in the development variants. Am. J. Anat., 190:193–218. of the human eye and ear during the embryonic period proper. Anat. Müller, F., and O’Rahilly, R. 1994 Occipitocervical segmentation in staged Embryol. (Berlin), 168:87–99. human embryos. J. Anat., 185:251–258. O’Rahilly, R. 1988 One hundred years of human embryology. Issues Rev. Müller, F. and O’Rahilly, R. 1997a Development of the human central ner- Teratol., 4:81–128. vous system. In S.U. Dani, A. Hori, and G.F. Walter (eds.), Principles O’Rahilly, R. 1996 Making planes plain. Clin. Anat., 10:128–129. of Neural Aging. Elsevier, Amsterdam, pp. 175–191. O’Rahilly, R., and Gardner, E. 1979 The initial development of the brain. Müller, F.,and O’Rahilly, R. 1997b The timing and sequence of appearance Acta Anat., 104:123–133. of neuromeres and their derivatives in staged human embryos. Acta O’Rahilly, R., and Muller, ¨ F. 1981 The first appearance of the human Anat., 158:83–99. nervous system at stage 8. Anat. Embryol. (Berlin), 163:1–13. P1: JYS JWDD017-BIB JWDD017-ORahilly July 4, 2006 14:18 Char Count= 0

328 BIBLIOGRAPHY

O’Rahilly, R., and Muller, ¨ F. 1984a Embryonic length and cerebral land- related structures in staged human embryos during the first 5 weeks marks in staged human embryos. Anat. Rec., 209:265–271. of development. Am. J. Anat., 171:243–257. O’Rahilly, R., and Muller, ¨ F.1984b The early development of the hypoglos- O’Rahilly, R., Muller, ¨ F., Hutchins. G.M., and Moore, G.W. 1987 Computer sal nerve and occipital somites in staged human embryos. Am. J. Anat., ranking of the sequence of appearance of 73 features of the brain and 169:237–257. related structures in staged human embryos during the sixth week of O’Rahilly, R., and Muller, ¨ F. 1985 The origin of the ectodermal ring in development. Am. J. Anat., 180:69–86. staged human embryos of the first 5 weeks. Acta Anat., 122:145–157. O’Rahilly, R., Muller, ¨ F., Hutchins, G.M., and Moore, G.W. 1988 Computer O’Rahilly, R., and Muller, ¨ F. 1986 The meninges in human development. ranking of the sequence of appearance of 40 features of the brain and J. Neuropathol. Exp. Neurol., 45:588–608. related structures in staged human embryos during the seventh week O’Rahilly, R., and Muller, ¨ F. 1987a Developmental Stages in Human of development. Am. J. Anat., 182:295–317. Embryos Including a Revision of Streeter’s “Horizons” and a Sur- O’Rahilly, R., Muller, ¨ F., and Meyer, D.B. 1980 The human vertebral col- vey of the Carnegie Collection. Carnegie Institution of Washington, umn at the end of the embryonic period proper: 1. The column as a Washington, DC, Publication No. 637. whole. J. Anat., 131:565–575. O’Rahilly, R., and Muller, ¨ F.1987b The developmental anatomy and histol- O’Rahilly, R., Muller, ¨ F., and Meyer, D.B. 1983 The human vertebral col- ogy of the human central nervous system. In P.J.Vinken, G.W. Bruyin, umn at the end of the embryonic period proper: 2. The occipitocervical and H.L. Klawans (eds.), Handbook of Clinical Neurology. Elsevier, region. J. Anat., 136: 181–195. Amsterdam. O’Rahilly, R., Muller, ¨ F., and Meyer, D.B. 1990a The human vertebral O’Rahilly, R., and Muller, ¨ F. 1988 “Neuroschisis” in human embryos. Ter- column at the end of the embryonic period proper: 3. The thoraci- atology, 38:189. columbar region. J. Anat., 168:81–93. O’Rahilly, R., and Muller, ¨ F. 1989a Bidirectional closure of the rostral O’Rahilly, R., Muller, ¨ F., and Meyer, D.B. 1990b The human vertebral col- neuropore in the human embryo. Am. J. Anat., 184:259–268. umn at the end of the embryonic period proper: 4. The sacrococcygeal O’Rahilly, R., and Muller, ¨ F. 1989b Interpretation of some median anoma- region. J. Anat., 168:95–111. lies as illustrated by cyclopia and symmelia. Teratology, 40:409–421. O’Rourke, N.A., Sullivan, D.P., Kaznowski, C.E., et al. 1995 Tangential O’Rahilly, R., and Muller, ¨ F.1990 Ventricular system and choroid plexuses migration of neurons in the developing cerebral cortex. Development, of the human brain during the embryonic period proper. Am. J. Anat., 121:2165–2176. 189:285–302. Orts Llorca, F. 1977 Morfogenesis de los tuberculos mamilares (“Corpora O’Rahilly, R., and Muller, ¨ F. 1994 Neurulation in the normal human em- mamillaria”). Arch. Neurobiol. (Madrid), 40:139–164. bryo. In Neural Tube Defects, Ciba Foundation Symposium No. 181. Padget, D.H. 1948 The development of the cranial arteries in the human Wiley, Chichester. embryo. Contrib. Embryol. Carnegie Inst., 32:205–261. O’Rahilly, R., and Muller, ¨ F. 1996a The nervous system. In O’Rahilly and Padget, D.H. 1957 The development of the cranial venous system in Müller (eds.), Human Embryology and Teratology, 2nd ed., Wiley- man, from the viewpoint of comparative anatomy. Contrib. Embryol. Liss, New York, pp. 361–416. Carnegie Inst., 36:79–140. O’Rahilly, R., and Muller, ¨ F. 1996b Prenatal development of the brain. In Padget, D.H. 1970 Neuroschisis and human embryonic maldevelopment. I. Timor-Tritsch A. Monteagudo, and H.L. Cohen (eds.), Ultrasonog- J. Neuropathol. Exp. Neurol., 29:192–216. raphy of the Prenatal and Neonatal Brain. Appleton & Lange, East Padmanabhan, R. 1990a Electron-mircroscopic studies on the pathogen- Norwalk, CT, pp. 1–10. esis of exencephaly and cranioschisis induced in the rat after neural O’Rahilly, R., and Muller, ¨ F. 1999 Summary of the initial development of tube closure: role of the neuroepithelium and choroid plexus. Acta the human nervous system. Teratology, 60:39–41. Anat., 137:5–18. O’Rahilly, R., and Muller, ¨ F. 2000 Prenatal ages and stages: measures and Padmanabhan, R. 1990b Scanning electron-microscopic studies on the errors. Teratology, 61:382–384. pathogenesis of exencephaly and cranioschisis induced in the rat after O’Rahilly, R., and Muller, ¨ F. 2001a Human Embryology and Teratology, neural tube closure. Acta Anat., 138:97–110. 3rd ed., Wiley-Liss, New York. Pasquier, L., Dubourg, C., Blayau, M., et al. 2000 A new mutation in O’Rahilly, R., and Muller, ¨ F. 2001b Prenatal development of the brain. In the six-domain of SIX3 gene causes holoprosencephaly. Eur. J. Hum. I. Timor-Tritsch, A. Monteagudo, and H.L. Cohen (eds.), Ultrasonog- Genet., 8:797–800. raphy of the Prenatal and Neonatal Brain, 2nd ed. McGraw-Hill, New Pearson, A.A. 1941 The development of the nervus terminalis in man. J. York, pp. 1–12. Comp. Neurol., 75:39–66. O’Rahilly, R., and Muller, ¨ F. 2001c The nervous system. In O’Rahilly and Pearson, A.A. 1946 The development of the motor nuclei of the facial Müller, Human Embryology and Teratology, 3rd ed. Wiley-Liss, New nerve in man. J. Comp. Neurol., 85:461–476. York, pp. 395–453. Peter, K., Wetzel, G., and Heiderich, F. 1938 Handbuch der Anatomie des O’Rahilly, R., and Muller, ¨ F.2002 The two sites of fusion of the neural folds Kindes. Bergmann, Munich. and the two neuropores in the human embryo. Teratology, 65:162– Puelles, L., and Verney, C. 1998 Early neuromeric distribution of tyrosine- 170. hydroxylase-immunoreactive neurons in human embryos. J. Comp. O’Rahilly, R., and Muller, ¨ F. 2003 Somities, spinal ganglia, and centra. Neurol., 394:283–308. Enumeration and interrelationships in staged human embroys, and Quesenberry, P.J., Dooner, G., Dooner, M., and Abedi M. 2005 Ignora- implications for neural tube defects. Cells Tissues Organs, 173:75– tio elenchi: Red herrings in stem cell research. Science, 308:1121– 92. 1122. O’Rahilly, R., Muller, ¨ F., and Bossy, J. 1986 Atlas des stades du Rabinowicz, T. 1986 The differentiated maturation of the cerebral cortex. développement des formes extérieures de l’encéphale chez l’embryon In F.Falkner and J.M. Tanner (eds.), Human Growth, 2nd ed. Plenum, humain. Arch. Anat. Histol. Embryol., 69:3–39. New York, pp. 385–410. O’Rahilly, R., Muller, ¨ F., and Bossy, J. 1990 Atlas des stades du Rager, G. 1972 Die Entstehung der Insel (Insula Reilii) beim men- développement de l’encéphale chez l’embryon humainetudi´ ´ e par des schlichen Embryo. Z. Morphol. Anthropol., 64:245–278. reconstructions graphiques du plan médian. Arch. Anat. Histol. Em- Raimondi, A.J., Sato, K., and Shimoji, T. 1984 The Dandy–Walker Syn- bryol., 72:3–34. drome. Karger, Basel. O’Rahilly, R., Muller, ¨ F., Hutchins, G.M., and Moore, G.W. 1984 Computer Rakic, P. 1965 Mesocoelic recess in the human brain. Neurology, 15:708– ranking of the sequence of appearance of 100 features of the brain and 715. P1: JYS JWDD017-BIB JWDD017-ORahilly July 4, 2006 14:18 Char Count= 0

BIBLIOGRAPHY 329

Rakic, P. 1974 Embryonic development of the pulvinar-LP complex in Shu, T., and Richards L.J. 2001 Cortical axon guidance by the glial man. In I.S. Cooper, M. Riklan, and P. Rakic (eds.), The Pulvinar-LP wedge during the development of the corpus callosum. J. Neurosci., Complex. Thomas, Springfield, IL, pp. 3–35. 21:2749–2756. Rakic, P. 1977 Prenatal development of the visual system in the rhesus Shuangshoti, S., and Netsky, M.G. 1966 Histogenesis of choroid plexus in monkey. Phil. Trans. Roy. Soc. Lond. B, 278:245–260. man. Am. J. Anat., 118:283–315. Rakic, P. 1984 Organizing principles for development of primate cerebral Sidman, R. L., and Rakic, P. 1973 Neuronal migration, with special refer- cortex. In S.C. Sharma (ed.), Organizing Principles of Neural Devel- ence to developing human brain: a review. Brain Res., 62:1–35. opment. Plenum, New York, pp. 21–48. Sidman, R.L., and Rakic, P. 1982 Development of the human central ner- Rakic, P. 1991 Development of the Primate cerebral cortex. In M. Lewis vous system. In W. Haymaker and R.E. Adams (eds.), Histology and (ed.), Child and Adolescent Psychiatry. Williams & Wilkins, Balti- Histopathology of the Nervous System. Thomas, Springfield, IL, pp. more, pp. 11–28. 3–145. Rakic, P.,and Sidman, R.L. 1969 Telencephalic origin of pulvinar neurons Siebert, J.R., Cohen, M.M., Sulik, K.K., Shaw, C.-M., and Lemire, R.J. 1990 in the fetal human brain. Z. Anat. Entwick., 129:53–82. Holoprosencephaly. An Overview and Atlas of Cases. Wiley-Liss, New Rakic, P., and Sidman, R.L. 1970 Histogenesis of cortical layers in hu- York. man cerebellum, particularly the lamina dissecans. J. Comp. Neurol., Smith, T.E., Siegel, M.K., and Bhatnagar, K.P. 2001 Reappraisal of the 139:473–500. vomeronasal system of catarrhine primates: ontogeny, morphology, Rakic, P.,and Yakovlev, P.I.1968 Development of the corpus callosum and functionality, and persisting questions. Anat. Rec., 265:176–192. cavum septi in man. J. Comp. Neurol., 132:45–72. Smith, T.D., Siegel, M.I., Mooney, M.P., et al. 1997 Prenatal growth of the Rao, M.S. 1999 Multipotent and restricted precursors in the central ner- human vomeronasal organ. Anat. Rec., 248:447–455. vous system. Anat. Rec., 257:137–148. Smith, T.E., Bhatnagar, K.P., and Shimp, K.L. 2002 Histological defini- Ren, T., Anderson, A., Shen, W.-B., et al. 2006 Imaging, anatomical, and tion of the vomeronasal organ in humans and chimpanzees, with a molecular analysis of callosal formation in the developing human fetal comparison to other primates. Anat. Rec., 267:166–176. brain. Anat. Rec., 288A:191–204. Song, D-L, Chalepakis, G., Gruss, P., and Joyner, A.L. 1996 Two Pax- Retzius, G. 1896 Das Menschenhirn. Studien in der makroskopischen binding sites are required for early embryonic brain expression of Morphologie, 2 volumes. Norstedt, Stockholm. an Engrailed-2 transgene. Development, 122:627–635. Rhodes, R.H. 1979 A light microscopic study of the developing human Sternberg, H. 1929 Über Spaltbildungen des Medullarrohres bei jungen neural retina. Am. J. Anat. 154:195–209. menschlichen Embryonen, ein Beitrag zur Entstehung der Anen- Richter, E. 1965 Die Entwicklung des Globus pallidus und des Corpus sub- cephalie und der Rachischisis. Virchows Arch., 272:325–375. thalamicum. Monogr. Gesamtgeb. Neurol. Psychiat, (Berlin), 108:1– Streeter, G.L. 1912 The development of the nervous system. In F. Keibel 132. and F.P.Mall (eds.), Manual of Human Embryology, Vol. 2. Lippincott, Rioch, D.M., Wislocki, G.B., O’Leary, J.L. 1940 A précis of preoptic, hy- Philadelphia, pp. 1–156. pothalamic and hypophysial terminology with atlas. Res. Tubl. Ass. Streeter, G.L. 1915 The development of the venous sinuses of the dura Nerv. Ment. Dis., 20:3–30. mater in the human embryo. Am. J. Anat., 18:145–178. Robinson, R.J., and Tizard, J.P.M. 1965 The central nervous system in the Streeter, G.L. 1918 The developmental alterations in the vascular system new-born. Br. Med. Bull., 22:49–55. of the brain of the human embryo. Contrib. Embryol. Carnegie Inst., Roessler, E., Belloni, E., Gaudenz K., et al. 1996 Mutations in the human 8:5–38. Sonic Hedgehog gene cause holoprosencephaly. Nat. Genet., 14:357– Streeter, G.L. 1919 Factors involved in the formation of the filum termi- 360. nale. Am. J. Anat., 25:1–11. Ruano Gil, D. 1965 Grave malformacion encefalica (encefalosquisis) en Streeter, G.L. 1927 Archetypes and symbolism. Science, 65:405–412. un embrion humano da 10.25 mm con un humano gemelo normal. Sun, T., Patoine, Ch., Abu-Khalil, A., et al. 2005 Early asymmetry of gene An. Desarrollo, 13:149–160. transcription in embryonic human left and right cerebral cortex. Sci- Sabin, F.R. 1900 A model of the medulla oblongata, pons and midbrain of ence, 308:1794–1798. a newborn babe. Johns Hopkins Hosp. Rep., 9:925–1023. Tanimura, T., Nelson, T., Hollingworth, R.R., and Shepard, T.H. 1971 Sabin, F.R. 1901 An Atlas of the Medulla and Midbrain. Friedenwald, Weight standards for organs from early fetuses. Anat. Rec., 171:227– Baltimore. 236. Sabin, F.R. 1902 A note concerning the model of the medulla, pons and Tiedemann, F. 1816 Anatomie und Bildungsgeschichte des Gehirns im midbrain of a new-born babe as reproduced by F. Ziegler. Anat. Anz., Foetus des Menschen. Steinische Buchhandlung, Nurnberg. ¨ 22:281–289. Tiedemann, F. 1823 Anatomie du cerveau, contenant l’histoire de son Schachenmayr, W., and Friede, R.I. 1978 The origin of subdural neomem- développement dans le foetus. Baillière, Paris. branes: I. Fine structure of the dura-arachnoid interface in man. Am. Timor-Tritsch, I., Monteagudo, A., and Cohen, H.L. 2001 Ultrasonogra- J. Pathol., 92:53–68. phy of the Prenatal and Neonatal Brain, 2nd ed. McGraw-Hill, New Schell, U., Wienberg, J., Kohler, A., et al. 1996 Molecular characterization York. of breakpoints in patients with holoprosencephaly and definition of Tobenas-Dujardin, A.C., Duparc, F., Ali, N., et al. 2005. Embryology of the the HPE2 critical region 2p21. Hum. Mol. Genet., 5:223–229. internal carotid artery dural crossing. Surg. Radiol. Anat., 27:495– Schwanzel-Fukuda, M., Crossin, K.L., Pfaff, D.W., et al. 1996 Migration 501. of luteinizing hormone-releasing hormone (LHRH) neurons in early Tole S., and Patterson, P.H. 1995 Regionalization of the developing fore- human embryos. J. Comp. Neurol., 366:547–557. brain: A comparison of FORSE-1, Dlx-2, and BF-1. J. Neurosci., Sensenig, E.C. 1951 The early development of the meninges of the spinal 15:970–980. cord in human embryos. Contrib. Embryol. Carnegie Inst., 34:45–157. Toledano, A. 1992 Evolution of cholinergic cortical innervation after Sharp, J.A. 1959 The junctional region of cerebral hemisphere and third nbM lesioning (an experimental Alzheimer model). In I. Kostović, ventricle in mammalian embryos. J. Anat., 93:159–168. S. Kneˇzević, H.M. Wisniewski, and G.J. Spilich (eds.), Neurodevelop- Shaw, Ch.-M., and Alvord, E.C. 1969 Cava septi pellucidi et Vergae: Their ment, Aging and Cognition. Birkhäuser, Basel. normal and pathological states. Brain, 92:213–224. Tsuru, A., Mizuguchi, M. Uyemura, K., and Takashima, S. 1996 Immuno- Shiota, K. 1991 Development and intrauterine fate of normal and abnor- histochemical expression of cell adhesion molecule L1 during devel- mal human conceptuses. Congenital Anomalies, 31:67–80. opment of the human brain. Early Hum. Dev., 45:93–101. P1: JYS JWDD017-BIB JWDD017-ORahilly July 4, 2006 14:18 Char Count= 0

330 BIBLIOGRAPHY

Turkewitsch, N. 1933 Die Entwicklung der Zirbeldruse ¨ beim Menschen. Verney, C., Lebrand, C., and Gaspar, P. 2002 Changing distribution Morphol. Jahrb., 72:379–345. of monoaminergic markers in the developing human cerebral cor- Turkewitsch, N. 1935 Die Entwicklung des Aquaeductus cerebri des tex with special emphasis on the serotonin transporter. Anat. Rec., Menschen. Morphol. Jahrb., 76:421–447. 267:87–93. Ulfig, N., Neudörfer, F., and Bohl, J. 1999 Distribution patterns of Vernier, P., Moret, F., Callier, S., et al. 2004 The degeneration of dopamine vimentin-immunoreactive structures in the human prosencephalon neurons in Parkinson’s disease. Ann. N.Y. Acad. Sci., 1035:231– during the second half of gestation. J. Anat., 195:87–100. 249. Ulfig, N., Setzer, M., Neurdörfer, F.,and Sarethki, U. 2000 Changing distri- de Vries, D.J.I.P. 1992 The first trimester. In J.G. Nijhuis (ed.), Fetal Be- bution patterns of synaptophysin-immunoreactive structures in the haviour. Oxford University Press, Oxford, pp. 19–50. human dorsal striatum of the fetal brain. Anat. Rec., 258:198–209. Westergaard, E. 1971 The lateral cerebral ventricles of human foetuses Ulfig, N., Neudörfer, F., and Bohl, J. 2001a Development-related expres- with a crown–rump length of 26–178 mm. Acta Anat., 79:409–421. sions of AKAP79 in the striatal compartments of the human brain. Wilson, J.T. 1937 On the nature and mode of origin of the foramen of Cells Tissues Organs, 168:319–329. Magendie. J. Anat., 71:423–436. Ulfig, N., Neudörfer, F., Feldhaus, C., et al. 2001b Neue Perspektiven Windle, W.F. 1970 Development of neural elements in human embryos of zur entwicklungsgeschichtlichen Bedeutung des humanen Gan- four to seven weeks gestation. Exp. Neurol. (Suppl. 5), 28:44–83. glienhugels. ¨ Verh. Anat. Ges., 96:99. Wo´zniak, W., and O’Rahilly, R. 1980 The times of appearance and the Ulfig, N., Vuksic, M., and Bohl, J. 2002 The subplate of the human fetal developmental sequence of the cranial parasympathetic ganglia in brain displays changing patterns of synaptotagmin and synaptoporin staged human embryos. Anat. Rec., 196:255A–256A. expression. Verh. Anat. Ges., 97:286–287. Wo´zniak, W., and O’Rahilly, R. 1982 An electron microscopic study of Velasco-Villamar, I. 1967 Sobre la organización del allocortex diagonalis. myelination of pyramidal fibres at the level of the pyramidal decussa- An. Anat. (Zaragoza), 16:109–179. tion in the human fetus. J. Hirnforsch., 23:331–342. Verney, C. 2003 Phenotypic expression of monoamines and GAGA in the Yamada, S., Uwabe, Ch., Fujii, S., and Shiota, K. 2004 Phenotypic variabil- early development of human telencephalon, transient or not transient. ity in human embryonic holoprosencephaly in the Kyoto Collection. J. Chem. Neuroanat., 26:283–292. Birth Defects Res. A., 70:495–508. Verney, C., and Derer, P. 1995 Cajal-Retzius neurons in human cerebral Yamadori, T. 1965 Die Entwicklung der Thalamuskerne mit ihren ersten cortex at midgestation show immunoreactivity for neurofilament and Fasersystemen bei menschlichen Embryonen. J. Hirnforsch., 7:393– calciumbinding proteins. J. Comp. Neurol., 359:144–153. 413. Verney, C., Zecevic, N., Nikolic, B., et al. 1991 Early evidence of catechol- Yo, T., Fukatsu, J., Ishikawa, T., et al. 1957 On the forebrain angle in the aminergic cell groups in 5- and 6-week-old human embryos using ty- brain of human fetus. Hirosaki Med. J., 8:234–238. rosine hydroxylase and dopamine-β-hydroxylase immunocytochem- Yoshida, M., Suda, Y., Matsuo, I., et al. 1997 Emxl and Emx2 functions in istry. Neurosci. Lett., 131:121–124. development of dorsal telencephalon. Development 124:101–111. Verney, C., Milosevic, A., Alvarez, C., and Berger, B. 1993 Immunocyto- Zecevic, N., and Milosevic, A. 1997 Initial development of γ -aminobutyric chemical evidence of well-developed dopaminergic and noradrener- acid immunoreactivity in the human cerebral cortex. J. Comp. Neu- gic innervations in the frontal cerebral cortex of human fetuses at rol., 380:495–506. midgestation. J. Comp. Neurol., 336:331–344. Zecevic, N., and Rakic, P. 1976 Differentiation of Purkinje cells and their Verney, C., Amaroui, A.E., and Zecevic, N. 1996 Comigration of tyrosine relationship to other components of developing cerebellar cortex in hydroxylase- and gonadotropin-releasing hormone-immunoreactive man. J. Comp. Neurol., 167:27–48. neurons in the nasal area of human embryos. Dev. Brain Res., 97:251– Zecevic, N., and Verney, C. 1995 Development of the catecholamine 259. neurons in human embryos and fetuses, with special emphasis on Verney, C., Zecevic, N., and Puelles, L. 2001a Structure of longitudinal the innervation of the cerebral cortex. J. Comp. Neurol., 351:509– brain zones that provide the origin for the substantia nigra and ventral 535. tegmental area in human embryos. J. Comp. Neurol., 429:22–44. Zecevic, N., Milosevic, A., Rakic, S., and Marin-Padilla, M. 1999 Early Verney, C., Zecevic, N., and Ezan, P. 2001b Expression of calbindin D28K development and composition of the human primordial plexiform in the dopaminergic mesotelencephalic system in embryonic and fetal layer: an immunohistochemical study. J. Comp. Neurol., 412:241– human brain. J. Comp. Neurol., 429:45–58. 254. P1: JYS JWDD017-GLOSS JWDD017-ORahilly June 13, 2006 14:49 Char Count= 0

GLOSSARY

The terms are listed by their key nouns, e.g., Rhombic lip under Lip, rhombic.

Amygdala: See Nuclei, amygdaloid. Brocklehurst (1969) and to the saccular ventricular Apoptosis: A process of controlled cell elimination, e.g., diverticulum of Wilson (1937), and is believed to be many if not most postmitotic, postmigratory, well- the site of the future median aperture of the fourth differentiated neurons are eliminated during the for- ventricle. mation of synapses. Defects in apoptosis may underlie Bundles, forebrain: See Fasciculi, prosencephalic. various neurodegenerative disorders. Canal, neurenteric: A more or less vertical passage (per- Archipallium: The cerebral cortex of the hippocampal for- pendicular to the embryonic disc) that appears dur- mation. It is separated from the neopallium by the ing stage 8 as a result of increasing breakdown of the peri-archicortex (presubiculum), and it becomes dis- floor of the notochordal canal (q.v.). Both canals com- tinguishable at stage 21 (Fig. 21-17). mence in common, dorsally in the primitive pit, and Area dentata: The zone between the hippocampus sensu the neurenteric canal may be regarded as the remains stricto and the area epithelialis. It develops into the of the notochordal canal at the level of the primitive dentate gyrus and, during the embryonic period, is node. The neurenteric canal connects the amniotic characterized by having only a ventricular layer (Fig. cavity (at the primitive pit) with that of the umbilical 21-4). vesicle (or so-called yolk sac) (Fig. 9-3E). The canal in Area epithelialis: The field between the area dentata and stages 8 and 9 and its site in stages 10 to 12 are im- the lamina terminalis (Figs. 21-4 and 21-17). It con- portant landmarks in development and teratogenesis sists of one to two, and later more, rows of cells, which, (Muller ¨ and O’Rahilly, 2004a). as development proceeds, contain dark inclusions. In Canal, notochordal: An oblique passage that appears in the the fetal period, a part of it becomes the lamina affixa. notochordal process during stage 8 (Fig. 8-2). Area hippocampi: This is characterized at first by an early Catecholamine cell groups (Tables 17-3 and 26-2): dopa- appearing telencephalic marginal layer, and this is minergic, noradrenergic, and adrenergic neurons the only part of the telencephalon that possesses a (Zecevic and Verney, 1995). Monoamines have most marginal layer (Fig. 16-11). A ventricular thickening probably also a trophic function (Verney et al., forms in the dorsomedial wall of the cerebral hemi- 2002). sphere (Fig. 15-4). It is C-shaped already at stage 18. Cells, Cajal-Retzius: Among the early-formed neurons Area reuniens: A term used by His for the junctional (Fig. 17-19) as revealed by reeler-immunoreactivity region of the prosencephalon, the hypophysial pri- (Zecevic et al., 1999). They are tangentially arranged mordium, the tip of the notochord, the roof of the bipolar neurons within the primordial plexiform layer. foregut, and the oropharyngeal membrane. Those in the future molecular layer mature late in Areae membranaceae: Two very thin areas of endothelioid trimester 2 (Verney and Derer, 1995) and are most cells in the roof of the fourth ventricle (Fig. 17-5). The evident near the middle of prenatal life (Tsuru et al., epithelium is thinnest at 6 weeks, whereas at the end of 1996). Reelin produced by the Cajal-Retzius cells is the embryonic period, the thin cells become replaced responsible for the normal migration of the neurons by cuboidal cells. The area membranacea rostralis is from the ventricular layer to the periphery of the wall adjacent to the cerebellar primordium. The area mem- of the brain. Once the cortical plate develops, the branacea caudalis corresponds to the central bulge of Cajal-Retzius cells are external to (“above”) it. The

The Embryonic Human Brain: An Atlas of Developmental Stages, Third Edition. By O’Rahilly and Muller ¨ Copyright C 2006 John Wiley & Sons, Inc.

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fetal Cajal-Retzius cells are transformed embryonic the rostralmost three occipital somites caudal to the C-R cells and have triangular, inverted pyramidal, or rostral cardinal vein. The dermatomic cells cannot be fusiform cells bodies from which two or more long distinguished from the myotomic cells, nor can pos- horizontal dendrites emerge. sible contributions from neural crest and epipharyn- A distinction has been made between Cajal and geal material of the vagus nerve be excluded. The re- Retzius cells (Meyer et al., 1999a): the former lie closer location of the cells in the tongue is achieved before to the pia, are smaller, and are frequently triangular or the arrival of the hypoglossal nerve. (O’Rahilly and piriform, and they appear when the Retzius cells have Müller, 1984b). The hypoglossal cord forms (at least already largely disappeared. some of) the muscles of the tongue. A reconstruction The thick horizontal fiber extends throughout the of the hypoglossal cell cord at stage 12 (Muller ¨ and surface of the cerebral cortex for a considerable dis- O’Rahilly, 1987, Fig. 6B) is in agreement with experi- tance and establishes contacts with the apical den- mental findings in the rat, in which, at a similar stage, drites of all pyramidal neurons, regardless of their lo- neural crest and dermatomyotomic cells of the occip- cation (layers 6, 5, 4, 3, 2) or different functional role. ital somites migrate within and dorsal to pharyngeal The transfer of neuronal information from the Cajal– arches 3 and 4. Retzius cells to all pyramidal neurons may be nec- Cord, neural: The neural tissue in the caudal eminence of essary for all of the latter to acquire and to maintain embryos with a closed caudal neuropore. It becomes their funtional activity (Mar´ın-Padilla, 1988a). Here, as canalized secondarily. The development of spinal cord in other regions, the use of immunological neuronal (at stages 12 to about 17–20) from this solid material markers would enable such cells to become identifi- is termed secondary neurulation (Fig. 12-13). able at earlier stages, as is being found already in other species. Cord, spinal: Embryologically, the part of the neural tube caudal to the last (the hypoglossal) rhombomere Cells, stem: See Stem cells, neural. (Rh.D). Cerebellum: This part of the hindbrain is derived mostly Corpus striatum (Fig. 19-6): The lentiform and caudate from the entire alar laminae of rhombomere 1 but nuclei, which become connected by alternating striae partly from the isthmus rhombencephali. The sources of white and gray matter (hence the name). The puta- of cellular production are mainly the rhombic lip of men and the caudate nucleus are telencephalic and rhombomere 1 and the ventricular layer of the alar arise from the lateral ventricular eminence (experi- laminae (Fig. 18-18). The cerebellar primordium, dis- mental evidence exists in the rat), whereas the globus tinguishable at stage 13 (Fig. 13-2), becomes the cere- pallidus (externus and internus) is diencephalic and bellar plate (q.v.) at about stage 18 (Fig. 18-1), by arises from the subthalamus. which time cerebellar swellings (q.v.) have appeared. Crest, neural: Cells that appear at the neurosomatic junc- The cerebellar hemispheres develop early in the fe- tion (i.e., between neural ectoderm and somatic ec- tal period, and the vermis is formed from the median portion of the hemispheres. See also Swellings, toderm) and are probably almost exclusively derived cerebellar. from the neural ectoderm. Most of the crest cells of the brain leave the neural folds before closure of the neural Cerebrum: From Latin, meaning brain. In ancient us- tube (Figs. 10-5 to 7). They participate in the formation age the larger convoluted mass as distinct from the of the cranial ganglia (Fig. 11-2). The spinal ganglia smaller (the cerebellum). At the time of His it included appear as cellular condensations of neural crest only the mesencephalon (cf. cerebral peduncles), but be- at stage 13 (Fig. 13-8B-C). The migration of neural came restricted to the prosencephalon, or to the te- crest cells depends on the extracellular matrix through lencephalon, or to the cerebral hemispheres. Hence which they travel. Migratory neural crest cells possess the term has practically no scientific value, in con- stem cell-like properties. trast to the almost indispensable adjective (e.g., the Decussation: An intersection, the two lines of the letter middle cerebral artery). X, as in the optic chiasma. Further examples are the Commissures of brain: In this book the term “commis- pyramidal decussation (Fig. 23-32), the decussation sure” is used as soon as fibers cross the median plane, of the superior colliculi (e.g., of the tectobulbar fibers, although fibers growing medially are present long be- Fig. 15-5), and that of the fibers of the trochlear nerves fore they cross. Examples are the anterior and poste- (Fig. 19-15). See also Commissures. rior commissures, and the corpus callosum. See also Dopaminergic centers: Early accumulations of dopamin- Decussation. ergic cells that form the interpeduncular nucleus, the Cord, hypoglossal cell: A dense cellular prolongation ventral tegmental area, the substantia nigra, and the formed by the dermatomyotomic material of at least amygdaloid complex (Fig. 17-13). P1: JYS JWDD017-GLOSS JWDD017-ORahilly June 13, 2006 14:49 Char Count= 0

GLOSSARY 333

Ectoderm, neural (or neuroectoderm): The pseudostrati- Fissures: (1) In the forebrain a term reserved for three fied epithelium derived from the embryonic ectoderm grooves, the floors of which are not completed by (which, in turn, comes from the epiblast) and that cortical tissue, i.e., the longitudinal, transverse, and gives rise to the neural plate (Fig. 8-2) and to neural choroid fissures; (2) the numerous grooves on the sur- crest. The mitotic figures are found superficially, adja- face of the cerebellum. cent to the amniotic cavity initially and, as the neural Floor plate (Figs. 9-5 and 21-7): The ventromedial cells tube develops, beside the future ventricular cavity and of the epinotochordal part (dorsal to the notochordal central canal. plate or notochord) of the neural plate or tube. It Eminence, caudal: the mesenchymal replacement of the is induced by the notochord. It expresses Shh,it primitive streak at stage 10 (Fig. 10-9), present until influences motor neuron differentiation by contact- stages 14, 15 and providing caudal structures such mediated diffusible factors, and it attracts commis- as notochord, somites, neural cord, and hindgut (Fig. sural axons through the secretion of netrinproteins. 12-15). The floor plate differs regionally: cells in the midbrain Eminences, ventricular (Table 19-1 and Fig. 15-2): two can induce the production of dopaminergic neurons, large intracerebral swellings characterized by an ex- whereas those of the rhombencephalon develop into ceptional persistence of their subventricular layer. the septum medullae (Figs. 20-18 and 19). The term ventricular eminences or elevations (G.J. Fovea isthmi: See Recess, isthmic. Lammers) is preferred to the inaccurate designa- Formation, hippocampal: A covenient term for the den- tions ganglionic eminence (Ganglienhugel) ¨ or striatal tate gyrus, the hippocampus, the subiculum, and the ridges. parahippocampal gyrus. See also Hippocampus. The medial ventricular eminence (Fig. 14-2) is a thickening of diencephalic origin. It expands rostrally, Ganglion, facio-vestibulocochlear: The common pri- gives rise to most of the amygdaloid nuclei (exper- mordium (stage 10) that first appears for the ganglia imental evidence exists in the rat), and in the fetal of the facial and vestibulocochlear nerves (Fig. 11-2). period contributes a part of the dorsal thalamus. (See It consists of neural crest to which the otic vesicle Migration.) contributes. The facial and vestibulochochlear compo- The lateral ventricular eminence (Fig. 15-2), which nents become distinguishable from each other at stage appears after the medial, is a protuberance in the baso- 13. It is not clear whether, at that time, the non-facial lateral wall of the cerebral hemisphere. It represents part contains both vestibular and cochlear elements. the telencephalic part of the basal nuclei, and it ex- Glia or neuroglia (a singular noun meaning glue): The pands caudally (Fig. 17-4). non-neural interstitial tissue of the nervous system. Later, the medial and lateral ventricular eminences The first glial cells to arise are the radial glial cells, overlap (Figs. 18-5 and 19-7) and expand towards the from which other types may develop (Mar´ın-Padilla, temporal pole (Fig. 22-6). At the end of the embry- 1995). Glia arises from three main sources: (1) the onic period, both eminences lie along the floor of the ventricular and subventricular layers in the prosen- lateral ventricle, separated from each other by a faint cephalon (from the intermediate zone of the devel- intereminential sulcus (or paleoneostriatal fissure, or oping cerebral cortex in the ferret), and (2) the neu- incorrectly striatocaudate sulcus). Exhaustion of their ral crest in the mesencephalon, rhombencephalon, matrix, which proceeds caudorostrally, does not begin and spinal cord, and (3) the monocyte-producing until trimester 2 (Sidman and Rakic, 1982). hematopoietic mesenchym. Glial growth factor, which Fasciculi, prosencephalic: Three chief bundles are de- is expressed by migrating cortical neurons, promotes scribed under this heading. The basal forebrain bun- their migration along radial glial fibers, and also aids dle (Fig. 19-23) contains descending fibers; it is “in in the maintenance and elongation of radial glial part related to the olfactory system but also includes cells. The chief types of glial cells are astroglia, oligo- presumably non-olfactory channels of the vegetative dendroglia, microglia, and ependymal, satellite, and nervous system present in macrosmatic, microsmatic, neurilemmal cells. Neurons and glial cells have the and anosmatic Mammals” and probably extends into same precursor. Glia boosts synaptic communication the mesencephalic tegmentum (Kuhlenbeck, 1977). and controls the number of synapses. Glial cells are The lateral forebrain bundle contains ascending as well about nine times more numerous than neurons. as descending fibers, and corresponds in large mea- Hippocampus (area hippocampi): The hippocampal pri- sure to the internal capsule (Fig. 19-23). The medial mordium appears (at stage 14) as an early marginal forebrain bundle (Fig. 19-23), which is predominantly layer (Fig. 16-11), followed by a ventricular thickening descending, is described as the main pathway for lon- in the dorsomedial wall of the cerebral hemisphere. Its gitudinal connections in the hypothalamus. C-shaped form is soon evident (by stage 18, Fig. 18-2). P1: JYS JWDD017-GLOSS JWDD017-ORahilly June 13, 2006 14:49 Char Count= 0

334 GLOSSARY

It consists mainly of large pyramidal cells that are con- Layer, external germinal (or external granular) of cere- centrated in a narrow band. The synapses per neuron bellum (Fig. 23-28B): A lamina on the surface of the are more than twice as numerous as elsewhere in the cerebellar primordium. It arises from the rhombic lip, cortex. See also Formation, hippocampal. mainly of the isthmic segment and of Rh. 1. A spe- Insula: The slight depression of the insula that becomes cial feature (at least in the rat) is that the migra- apparent in stage 23 is preceded by a flat area overlying tion of the cells in a lateromedial direction involves the lateral ventricular eminence at stages 18–22 (Fig. the use of axons as a substrate. It is frequently called 23-2). the external granular layer because the granule cells arise from it. The transformation and migration of the Isthmus rhombencephali: A term introduced by His for an cells of the external germinal layer as they become “independent part of the brain” (now acknowledged as granule cells have been studied (Sidman and Rakic, a neuromere) during development and in the adult. 1982). These cells are believed to be the origin of At the beginning of its appearance (in stages 13 and medulloblastoma. 14) this is a short, narrow part of the neural tube between the midbrain and the hindbrain (Fig. 13-3). Layer, primordial plexiform (Figs. 21-7 and 17-19): The It contains nuclei and intramural and commissural superficial stratum of the embryonic cerebral cortex. fibers of the trochlear nerves. Then it expands and par- This layer contains horizontal (Cajal–Retzius) cells, ticipates in the formation of the superior medullary unipolar as well as multipolar pluriform cells, tan- velum dorsally. Its basal portion contains cerebel- gentially arranged nerve fibers, horizontal branches lar tracts. The isthmus is believed to be a source of of corticipetal fibers, and vertical cytoplasmic prolon- morphogens. gations of the neuroepithelial cells. The long axes of the Cajal–Retzius cells run parallel to the cortical sur- Lamina reuniens (Schlussplatte): A term used by His face. Certain portions of the primordial plexiform layer (1904) for what is here called the embryonic lamina are considered to be functionally active in the human terminalis (q.v.). Its ventral part becomes the End- embryo by stage 20 (Mar´ın-Padilla and Mar´ın-Padilla, platte (lamina terminalis sensu stricto), which re- 1982). It has been proposed that “an initial PPL may be mains thin and forms the rostral wall of the telen- a universal feature of the developing central nervous cephalon medium. Its dorsal part is the Trapezplatte system” (Zecevic et al., 1999). or massa commissuralis (q.v.). The earliest synapses seen in the human brain Lamina terminalis, embryonic: The median wall of the are in the primordial plexiform layer (Larroche, 1981; telencephalon (Fig. 11-3) rostral to the chiasmatic Choi, 1988) at about stages 17 to 19. They are formed plate (future optic chiasma). The commissural plate by horizontal cells that correspond to those of Cajal– appears as a thickening in the embryonic lamina ter- Retzius (Larroche and Houcine, 1982). After the sub- minalis, and the remainder of the lamina then consti- division of the primordial plexiform layer into subpial tutes the adult lamina terminalis (Fig. 21-8) (Bossy, and subplate components, the synapses are present in 1966). those two layers, above and below the cortical plate but Laminae, alar and basal (Fig. 21-7): Terms used by His not within it (Molliver et al., 1973). Synapses have ap- for the dorsal and ventral zones of the neural tube, peared within the cortical plate by the end of trimester separated by the sulcus limitans. In the spinal cord, 2 (Molliver et al., 1973). the alar plate, which has a broader ventricular layer, is The primordial plexiform layer is thought to play essentially afferent, whereas the basal plate, which has a significant role in the structural organization of the a narrower ventricular layer but grows more rapidly, neocortex by determining the unique morphology of is fundamentally efferent (the “Bell–Magendie law”). its pyramidal cells. “However, the nature of layer I re- An alar/basal distinction continues into the rhomben- mains enigmatic” (Mar´ın-Padilla, 1992). cephalon and the mesencephalon, but not into the A useful scheme of the development of the neo- prosencephalon, where the sulcus limitans is absent. cortical layers has been proposed (Rakic, 1984, Fig. 3), This point was long disputed in the past. The laminae although the primordial plexiform layer was not in- express Pax genes (3 and 7 from the alar, 6 from the cluded. basal). Layer, subpial granular (of Brun): A lamina that appears Layer, dural limiting (Fig. 22-14B): A layer of condensed during trimester 2, and regresses and disappears cells appearing in the peripheral mesenchyme and during trimester 3 (Choi, 1988; Mar´ın-Padilla, 1995). forming the external boundary of the leptomeningeal It is formed from the subventricular layer of the olfac- primordium (O’Rahilly and Muller, ¨ 1986). See also tory bulb by chain-migration, does not show mitotic Meninx, primary. figures, and contains precursors of astrocytes that P1: JYS JWDD017-GLOSS JWDD017-ORahilly June 13, 2006 14:49 Char Count= 0

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later migrate into the gray matter of the insular LHRH neurons: Gonadotropin-producing cells that region. The layer acts as a precursor pool for reelin- contribute luteinizing-hormone-releasing hormone producing neurons that complement earlier- (LHRH, Schwanzel-Fukuda et al., 1996; Verney et al., generated cells during the cortical migration (Meyer 2002). They are derivatives of the olfactory neural et al., 1999 a). crest and develop from the medial parts of the nasal Layer, subventricular (Fig. 21-7): Present only after the pits (stage 16, Fig. 16-7A) and probably earlier from establishment of the cortical plate (at stage 21), this the nasal discs (stage 13). The cells are transported layer consists of cells at the interface between the (stage 19) by fibers of the vomeronasal nerve and ventricular and intermediate layers. These cells divide the nervus terminalis to the olfactory bulbs and without interkinetic nuclear migration, and the cel- to the forebrain septum (Fig. 19-11). The cells are lular production constitutes the secondary prolifera- accompanied by TH- positive neurons (Verney et al., tive phase. The subventricular layer of the neopallium 2002). remains active in the adult (mouse). Most glial cells Lip, rhombic: A proliferative area persisting in the dor- are produced in the subventricular and intermediate salmost part of the alar plate of the rhombencephalon, layers. including cells for the primordium of the cerebellum, and clearly defined at stage 17 (Fig. 17-3), when Layers, intermediate, marginal, and ventricular (Fig. 21- its mitotic figures are abundant and the remainder 6): The ventricular layer of the neural tube, which is of the basal plate has differentiated into marginal adjacent to the ventricular cavity, contains most of the and intermediate layers. The rhombic lip participates mitotic figures that generate neurons and glial cells. in the formation of the external germinal layer of Mitotic division therein is characterized by interki- the cerebellum (Fig. 23-28). Furthermore, it pro- netic nuclear migration (Fig. 9-6). Later the lamina duces three superficial streams: a pontine, a cochlear, becomes the ependymal layer. Mitotic figures, how- and the so-called olivo-arcuate migration of Essick ever, are not restricted to the ventricular layer but (1912). The last-mentioned layer (Fig. 20-19) is ill- can be found also more peripherally, in a subven- named because it has been shown (in the monkey) that tricular layer, where cells apparently divide without the olivary nuclei arise mainly from the ventricular movement of the nuclei during the mitotic cycle. It layer. is believed that a temporal pattern of heterogeneity The term “rhombic lip,” which should not be used exists in the matrix. In early cerebral development, as a synonym for the primordium of the cerebellum, more neurons (Cajal–Retzius cells, subplate cells, sec- was introduced by His, who distinguished primary and ondary matrix cells of the subventricular layer) than secondary types. His primary lip (1890), which would glial cells are produced. The development continues be expected to appear at about stages 16 and 17, was with the production of neurons for layers 6 and 5, and not found in the present series and was in all likelihood finally of neurons for layers 4, 3, and 2. As development artifactual, as pointed out by Hochstetter (1929) and proceeds, the percentage of glial cells versus neurons Kuhlenbeck (1973). Subsequent usage of the term is increases. twofold: (1) the junction between the thin roof plate The intermediate layer consists of several rows of and the much thicker alar lamina, i.e., more or less postmitotic cells that appear peripheral to the ven- equivalent to the taenia of the fourth ventricle; (2) tricular layer and it corresponds approximately to the functionally, as used in this book, the dorsolateral por- term mantle layer. The intermediate layer is poorly tion of the alar lamina, which (characterized by mitotic defined in routine histological sections, but very dis- figures from stage 16 on) acts as a proliferative zone tinct in Golgi preparations. It is composed mainly of (Figs. 20-20, 22-13, and 23-28). corticipetal and corticofugal fibers and their collater- als (Fig. 23-21) and is crossed by migrating neurons. Massa commissuralis (of Zuckerkandl): A bed through Because of its richness in fibers the layer was named which the fibers of two cerebral commissures pass: the embryonic white matter by Mar´ın-Padilla (1988a). It is commissura fomicis and the corpus callosum. It devel- the precursor of the internal white matter of the adult ops early in the fetal period from the commissural plate cerebral cortex. and also from proliferating cells of the mesenchyme The marginal layer is the cell-free peripheral zone between the medial hemispheric walls in the region of of the neural tube. It is seen in the spinal cord and the hippocampal primordium. in most parts of the brain. In the telencephalon it Matrix, extracellular (ECM): Occupying 15–20% of the may be considered to be present in the hippocampal volume of the brain and associated with neurons and primordium, whereas in the neopallium a primordial glia, the ECM preserves epithelial integrity and acts as plexiform layer (q.v.) is found. a substrate for cellular migration and as a guide for P1: JYS JWDD017-GLOSS JWDD017-ORahilly June 13, 2006 14:49 Char Count= 0

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axonal extension. Fibronectin and laminin in the ma- Neopallium: The cerebral cortex derived from the areas trix facilitate migration, whereas chondroitin sulfate that possess a cortical plate, which latter begins to proteoglycans inhibit it. appear in stage 21 (Fig. 21-7) Meninx, primary: The loose mesenchyme (meninx prim- Nerve, vomeronasal (Fig. 18-13): Nonmyelinated fibers itiva of Salvi) adjacent to the brain (Fig. 14-5) from the vomeronasal organ (q.v.). The fibers enter and spinal cord. From stage 17 onwards the lep- the rostromedial wall of the olfactory bulb. tomeningeal meshwork contains fluid that is believed Nervus terminalis (Fig. 20-13): Fibers that enter the ol- to be derived from the adjacent blood vessels. Its pe- factory tubercle at stage 18 and that are probably au- ripheral border is represented by the dural limiting tonomic. These fibers arise in the nasal mucosa and layer (q.v.). (O’Rahilly and Muller, ¨ 1986). will later traverse the cribriform plate. Midline: An undesirable term for the median plane (q.v.) (O’Rahilly, 1996). Neuroectoderm: See Ectoderm, neural. Migration: Several types are described. Neuroglia: See Glia. Neuromeres: Morphologically identifiable transverse sub- (1) Non-radial migration. Neurons that do not use radial divisions perpendicular to the longitudinal axis of the glia, as a migratory substrate have to glide across one embryonic brain and extending onto both sides of the glial fiber to another (O’Rourke et al., 1995). body (Muller ¨ and O’Rahilly, 1997b). The larger (pri- (2) Radial migration, mediated by radial glial cells, is mary) neuromeres appear early in the open neural prominent in the development of the telencephalic folds (at stage 9), and the smaller (secondary) neu- cortex (Sidman and Rakic, 1973). Cells within a given romeres are found both before and after closure of the radial column share the same birthplace and migrate neural tube. The full complement of 16 neuromeres is along a common pathway towards the pia mater. The present at stage 14 (Table 10-1). Neuromeres are par- number of radial columns determines the extent of the ticularly clear in the hindbrain (Fig. 10-3), where they cortical surface, whereas the number of cells within are termed rhombomeres (q.v.). In some instances the columns determines cortical thickness. the neuromeres are coextensive with domains of gene (3) Tangential migration involves clonally related cells expression, whereas in others the domains cross in- that are dispersed in a direction parallel to the pia terneuromeric boundaries. mater. Tangential migration occurs in the cerebral cor- Neuropores: Temporary rostral (stage 11, Fig. 11-7) and tex (Zecevic and Milosevic, 1997; Meyer and Wahle, caudal (stages 11 and 12) openings that represent the 1999; Marin et al., 2001; Ulfig et al., 2001) and in the remains of the neural groove before the fusion of the rhombencephalon (Fig. 18-18). neural folds has been completed at each end. The neu- (4) Combined radial and tangential migration. In the ropores close during stages 11 and 12, respectively. cerebral cortex GABA-positive cells use both directions The rostral (or cephalic) neuropore has been studied for dispersing from the ventricular zone: radial migra- particulary (O’Rahilly and Muller, ¨ 1989a, 2002). tion towards the pia, tangential migration parallel to Neurulation: The formation of the neural tube in the em- the pia. The tangential “may be guided by glial fibers” bryo (Fig. 9-5). Primary neurulation is the folding of (Ulfig, 2002). In the cerebellum radial migration is the neural plate to form successively the neural groove from the ventricular zone, tangential from the rhom- and the neural tube. Secondary neurulation, which oc- bic lip (Fig. 18-18). curs without direct involvement of the ectoderm and (5) “Chain migration” by elongated neurons that are without the intermediate phase of a neural plate, is closely apposed and connected by membrane special- the continuing formation of the spinal cord from the isations, and ensheathed by a protective layer of glial caudal eminence, which develops a neural cord (q.v.) cells. It provides “a steady supply of new GABAergic (Muller ¨ and O’Rahilly, 2004a). neurons destined for the olfactory bulb” and originat- ing in the subventricular layer of the cortex (Verney et Nuclei: The term is used here in the restricted meaning of al., 2002). areas of lower cellular density and slightly larger cellular size. As Dekaban (1954) pointed out, early and later Myelination: The process by which glial cells ensheath the neurons “group themselves into ‘centers’ or ‘nuclei,’ axons of neurons in layers of myelin. Rapid conduction which will constitute functional systems or parts of the of electrical impulses is thereby ensured. Both oligo- systems.” Rakic (1974), on the other hand, in delim- dendrocytes and astrocytes participate. The number of iting diencephalic nuclei, maintains that subdivisions coverings is determined by the axon. Myelin accounts into discrete nuclear groups “appears to be based ini- for approximately 70% of the dry weight of the mam- tially on the establishment of boundaries by fascicles malian CNS. of nerve fibers.” P1: JYS JWDD017-GLOSS JWDD017-ORahilly June 13, 2006 14:49 Char Count= 0

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Nuclei, amygdaloid: These dopaminergic nuclei are orig- the roof of the aqueduct, beneath the posterior com- inally in a diencephalic position mostly in the medial missure); and (8) the area postrema (at the junction ventricular eminence (Fig. 18-6), but later become te- of the fourth ventricle and the central canal), which lencephalic (Figs. 19-8 and 19-9). resembles the subfornical organ but differs from the Nuclei, basal (Fig. 19-6): An arbitrary group that gener- strictly circumventricular organs in being related to ally includes the corpus striatum (q.v.), the amygdaloid the fourth rather than the third ventricule and in being complex, and the claustrum. To these are added, from bilateral. a clinical point of view, the subthalamic nucleus and Paleopallium: The cerebral cortex of the piriform area, the substantia nigra, to complete the basal structures including the surface of the medial ventricular em- affected pathologically in socalled extrapyramidal mo- inence with the amygdaloid complex. The piriform tor diseases. The region of the future basal nuclei, cortex is the transitional region between paleopallium which becomes compartmentalized into two entities and neopallium. It becomes apparent when the corti- by stage 19, extends to the preoptic sulcus caudally cal plate appears in stage 21 (Fig. 21-10). and to the prosencephalic septal area rostrally. The Paraphysis: A telencephalic formation appearing first as two compartments are, in order of appearance: (1) the a knob (stage 18, Fig. 18-8) and later developing one medial ventricular eminence, and (2) the lateral ven- or more evaginations, which are in communication tricular eminence (Fig. 19-7). From the lateral em- with the ventricle of the telencephalon medium and inence arise the caudate nucleus and the putamen; are lined by a single layer of ciliated cells. Further from the medial the amygdaloid complex; and from details: Ariëns Kappers (1955); O’Rahilly and Muller ¨ a basal thickening, the nucleus accumbens. The con- (1990). stituent cells of the basal nuclei are derived from the Parencephalon (Table 10-1): A part of the diencephalon subventricular zone. These cells proliferate through- (neuromere D2) which, together with the synen- out the entire prenatal period (Kahle, 1969; Sidman cephalon (q.v.), becomes discernible at stage 13. Two and Rakic, 1982) by a special mode of division (inves- portions can be distinguished at stage 14: the rostral tigated by Smart in the mouse). The basal nuclei are parencephalon (including the infundibular region and not ganglia, which, by definition, occur only in the the ventral thalamus) and the caudal parencephalon peripheral nervous system. (containing the mamillary region and the dorsal tha- Organ, vomeronasal: Epithelial pockets that appear bilat- lamus). erally in the nasal septum in stage 17. They enlarge Plane, median: This is considered to be a special region during the embryonic and fetal periods and are gen- that is subject to a variety of anomalies, such as holo- erally said to involute postnatally, although this has prosencephaly and agenesis of the corpus callosum. been queried (Smith et al., 1997, 2002). See also Nerve, The median features of the developing brain are shown vomeronasal. in Figures 17-5 and 24-32. Organs, circumventricular: Specialized ependymal re- Plate, callosal commissural: See Massa commissuralis. gions in (chiefly) the third ventricle. They are prac- Plate, cerebellar: A term used when the cerebellar pri- tically all median in position and (with the exception mordium becomes coronally oriented and more or less of the subcommissural organ) are highly vascular and at a right angle to the remainder of the rhomben- lack a blood–brain barrier. They vary in prominence cephalon (Fig. 18-1). See also Cerebellum and and in structure with age, and some are difficult to Swellings, cerebellar. find in the adult or may even disappear. Functions include secretion of substances (e.g., neuropeptides) Plate, chiasmatic (or torus opticus): A bridge between the into the cerebrospinal fluid, and transport of neuro- optic primordia across the median plane (Fig. 10-3). chemicals in both directions between neurons, glia, Its rostral end corresponds to the tip of the former and blood cells and the CSF. The main structures neural plate. The fibers of the preoptico-hypothalamic that are generally included are (1) the median emi- tract cross in its caudal part at stage 18 (Fig. 18-2) and nence of the tuber cinereum (around the base of the the optic fibers in its rostral portion at stage 19 (Figs. infundibulum); (2) the neurohypophysis; (3) the or- 19-3 and 20-2). ganum vasculosum of the lamina terminalis (OVLT; Plate, commissural (Fig, 12-3): A thickening in the em- supraoptic crest; intercolumnar tubercle); (4) the sub- bryonic lamina terminalis (q.v.) at the situs neuro- fornical organ (at the level of the interventricular poricus (q.v.). It is considered by some to be the bed foramina); (5) the (telencephalic) paraphysis (a tem- through which commissural fibers of the anterior porary ependymal thickening rostral to the velum commissure, corpus callosum, and commissura forni- transversum in trimester 1); (6) the epiphysis cerebri; cis pass (Streeter, 1912; Hochstetter, 1929; Bartelmez (7) the subcommissural organ (modified ependyma in and Dekaban, 1962). Others (e.g., His, 1904; Rakic and P1: JYS JWDD017-GLOSS JWDD017-ORahilly June 13, 2006 14:49 Char Count= 0

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Yakovlev, 1968) have maintained that the commissur- Preplate: A term that is sometimes used (e.g., by Bystron ation is preceded by the development of a massa com- et al., 2005) for the early marginal zone of the cortical missuralis (q.v.), which implies some fusion of the me- primordium. dial hemispheric walls at the level of the hippocampal Prosomeres: The neuromeres of the prosencephalon. primordium. Recess, isthmic (Fovea isthmi): The ventral limit of the Plate, cortical (Fig. 21-7): A neopallial feature first found mes-metencephalic sulcus (Fig. 17-5) (Bartelmez and in the embryo at stage 21 (Fig. 21-9). It consists of Dekaban, 1962). three to five rows of cells that have migrated radially from the ventricular layer and are arranged vertically. Recess, postoptic: The site where the optic sulci meet in It increases in thickness and persists for long into the the median plane (Fig. 10-3). This is the caudal limit fetal period. Although formerly it was thought that of the chiasmatic plate. only layers 2 to 5 develop from the cortical plate, it Recess, preoptic: In later stages this depression indicates is now generally believed that layer 6 is also derived the rostral limit of the chiasmatic plate (Fig. 14-2). from the plate (Mrzijak et al., 1988). The migrating Rhombomeres: The transverse swellings in the neural neurons that accumulate within the primordial plex- tube, known as neuromeres, are termed rhombomeres iform layer are arranged in an outside–inside order. in the developing rhombencephalon, where they are Synapses develop relatively late within the cortical clearly visible up to stage 17 (Muller ¨ and O’Rahilly, plate, at about 23 weeks (Molliver et al., 1973), whereas 2003 b). They are originally four in number (Fig. 9-2C) they are already present in the primordial plexiform and are termed A, B, C, and D. They increase in number layer at stages 17–19. by subdivision during stage 10 and are numbered 1, 2, 3 Plate, neural (Fig. 8-2): The neural primordium that first (from A), 4 (corresponding to B), 5, 6, 7 (from C), and 8 becomes visible during stage 8 and is present in cau- (corresponding to D and related to somites 1–4). Eight dal areas up to stage 10. At the time of its first appear- rhombomeres are generally identifiable from stage 11 ance it is slightly vaulted on each side of the neural to stage 17; in addition, the isthmus rhombencephali groove. The prenotochordal part of the neural plate is (q.v.) becomes apparent from stage 13 onwards. They the diencephalic region (neuromere D1 and the future are believed to result from transverse bands of high mi- rostral parencephalon). The epinotochordal portion of totic activity and they are maintained by cytoskeletal the neural plate (that overlying the notochord) devel- components, although their significance is still dis- ops a floor plate (q.v.). puted. Cranial nerves 5 to 10 have a clear relationship Plate, optic: The median region that unites the optic pri- to specific rhombomeres; the otic vesicle (Fig. 12-2 mordia of the two sides (Fig. 10-3). It represents the and 12-6), however, changes its position with regard rostral end of the neural plate, and it participates in to the rhombomeres, shifting from Rh.4 (in stage 10) the formation of neuromere D1. to Rh.6 (in stages 14–17). Plate, prechordal: A multilayered accumulation of Roof plate: The plate consists of the dorsomedial cells of mesendodermal cells in close contact with the me- the neural tube (Fig. 21-7). It is believed to be induced dian part of the future prosencephalon in the human by a morphogenic protein of ectodermal origin, and embryo (Figs. 8-3 and 8-6). The plate differs apprecia- it may be important in causing differentiation of the bly in the mouse and in the chick embryo. It has been dorsal part of the spinal cord. unequivocally found first at stage 7, and is usually de- Septum, prosencephalic: The septum verum (Andy and tectable at stage 8. The plate lacks a clearly visible, Stephan, 1968) is the basal part of the medial wall complete underlying sheet of endoderm. At stages 9 of the cerebral hemispheres. Hence it is formed at the and 10 the plate is related to neuromere D1 (Muller ¨ time when the hemispheres expand beyond the lamina and O’Rahilly, 2003a). terminalis, beginning at stage 17. It is the area between Plates, alar and basal: See Laminae, alar and basal. the olfactory bulb and the commissural plate (Fig. 18- Plexuses, choroid: Intraventricular invaginations at 2). The nuclei arising in it during the embryonic period stages 18–20 of choroidal (as distinct from ventric- are the medial septal nucleus, the caudal nucleus of ular) ependyma derived from the ventricular layer of the diagonal band, and the nucleus accumbens. the neural tube and characterized by tight junctions Sexual differentiation and brain development: All em- and tela choroidea (vascular pia mater). The plexuses bryos are exposed to maternal estrogen, and male are relatively very large in the embryo (Fig. 23-16). fetuses additionally to their own testosterone; the hy- They produce cerebrospinal fluid (in contrast to the pothalamus is especially involved. Later, these hor- ependymal fluid of earlier stages) and probably a vari- mones play a “housekeeping” role in the growth and ety of growth factors. maintenance of cells of the brain in both sexes. P1: JYS JWDD017-GLOSS JWDD017-ORahilly June 13, 2006 14:49 Char Count= 0

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Situs neuroporicus (Fig. 12-7): The site of final closure of the original components of the primordial plexiform the rostral neuropore. It corresponds later to an area layer are believed neither to decrease nor to disappear, within the commissural plate (O’Rahilly and Muller, ¨ but rather to undergo a significant and progressive di- 1989a, 2002). lution (Mar´ın-Padilla, 1988a). The early subplate cells Stalk, hemispheric: The original connection undergo regressive changes and they are progressively (Streifenhugelstiel, ¨ Hemisphärenstiel: His, 1904) replaced by new projection neurons (Mar´ın-Padilla, between the diencephalon and the telencephalon, 1988a). which becomes a stalk from about stage 17. It becomes Sulcus, hypothalamic (Table 20-1): An internal groove be- greatly enlarged by fibers and tracts, especially by tween the thalamus sensu lato (comprising the dorsal the continuation of the internal capsule (Figs. 21-6, and ventral thalami) and the hypothalamus sensu 22-10, and 22-11), namely the lateral prosencephalic lato (comprising the subthalamus and hypothalamus fasciculus (q.v.). See Sharp (1959) and Richter (1965). sensu stricto). It begins and ends in the diencephalon Stammbundel¨ : The term used by His for the fibers (lateral (Fig. 17-4 inset). prosencephalic fasciculus, q.v.) connecting the dorsal Sulcus, intereminential: A term used by the present au- thalamus and telencephalon and continuing also to thors for the slight groove that appears at stage 18 the epithalamus and to the mesencephalon. between the lateral and medial ventricular eminences Stem cells, neural: The pluripotential stem cells of the (Fig. 22-6A). mammalian brain develop in the ventricular layer of Sulcus limitans (Fig. 21-7 and 21-8): An internal groove the embryo and fetus, as well as from the neural crest. found bilaterally in the developing mesencephalon, These cells develop into both neurons and glia. Neu- rhombencephalon, and spinal cord. It is present at ronal stem cells persist in the adult mammalian cen- stage 12 and is the boundary between the alar and tral nervous system (e.g., in the ependyma) and partic- basal laminae (q.v.). In the human embryo the sul- ipate in plasticity and regeneration, but they have the cus limitans ends rostrally near the rostral end of the immunocytochemical markers of glia. The only site mesencephalon (Fig. 17-4). This point was long disin the adult peripheral nervous system where produc- puted in the past (Fig. 21-8). See also Laminae, alar and tion of neural stem cells is documented is the olfactory basal. neuroepithelium. A pool of progenitor cells within the human dentate gyrus continues to produce new gran- Swellings, cerebellar: Bulges that are parts of the cerebellar plate, i.e., the alar lamina of the isthmic seg- ule cells throughout life. Adult glial progenitors develop into oligodendrocytes and astrocytes (Comptson ment together with that of rhombomere 1. The earlier et al., 1997). However, studies of embryonic and adult appearing internal cerebellar swelling (innerer Klein- hirnwulst of Hochstetter, 1929) is inside the fourth stem cells still contain “red herrings” (Quesenberry et al., 2005) and much further work remains to be ventricle (Fig. 17-4). The external cerebellar swelling done. (ausserer¨ Kleinhirnwulst) forms as an expansion at the site of the rhombic lip (Fig. 17-3). It is delimited Subplate (Figs. 21-7 and 23-22): A derivative of the pri- by a groove that corresponds to the later posterolat- mordial plexiform layer (q.v.), which may participate eral fissure of the cerebellum. The internal and ex- in the specification of the cortical plate (q.v.). It has ternal cerebellar swellings are sometimes referred to, been termed a waiting compartment for incoming af- respectively, as the intraventricular and extraventric- ferent axons (Rakic). Catecholamine axons enter the ular portions of the developing cerebellum. telencephalic wall and occupy the subplate and (although more sparsely) the marginal (subpial) layer Synencephalon (Fig. 13-8): The caudalmost part of the during the embryonic period (Verney et al. 2002). It diencephalon, the portion that gives rise to the pre- is possible, therefore, that an initial contact between rubrum and the pretectum. It is delineated ros- catecholaminergic fibers and GABA-positive neurons trally by the habenulo-interpeduncular tract (fascicu- is established early (Zecevic and Milosevic, 1997; Ver- lus retroflexus) and caudally by the di-mesencephalic ney et al. 2002). However, several classes of afferent borderline passing between the two constituents of the fibers wait for weeks before penetrating the cortical posterior commissure. plate, and the role they play in the transitory synaptic Telencephalon medium or impar: The first part of the te- organization of the subplate is still unclear. lencephalon to appear (at stage 10, Fig. 10-3) is lateral A clear anatomical separation does not exist be- in position. Only later (stage 14) do the lateral walls tween the subplate and the intermediate layer; both become domed and form the future cerebral hemi- are characterized by an abundance of fibers (Figs. 23- spheres (Muller ¨ and O’Rahilly, 1985). The median part 21 and 23-22). The subplate gradually disappears dur- of the telencephalon persists throughout life, so that ing early infancy (Kostović and Rakic, 1990). However, a portion of the third ventricle remains telencephalic. P1: JYS JWDD017-GLOSS JWDD017-ORahilly June 13, 2006 14:49 Char Count= 0

340 GLOSSARY

Torus hemisphericus: A ridge at the ventricular surface Ventricle, optic: At ﬁrst (stage 13), the cavity of the op- between the telencephalon and the diencephalon, and tic vesicle, which is a prolongation of that of the di- along which the cerebral hemispheres are evaginated encephalon. Later it becomes the intraretinal slit be- (Fig. 14-2). An external di-telencephalic sulcus devel- tween the external and internal strata of the optic cup, ops and accompanies it. and ultimately the potential space (along which so- called detachment of the retina occurs) between layer Torus opticus: See Plate, chiasmatic. 1 and layers 2–10 of the retina (Fig. 23-13). Velum transversum: A transverse ridge in the roof of the Zona limitans intrathalamica: A zone that parallels the forebrain marking the limit between telencephalon marginal ridge and sulcus medius between the dor- and diencephalon (Fig. 14-2). sal and ventral thalami and is ﬁrst recognizable as a thicker marginal layer at this site. Fibers of the zona Ventricle, olfactory (Fig. 22-12): A prolongation of the are visible at stage 19 (Fig. 19-22). The zona is be- lateral ventricle into the growing olfactory bulb at lieved to form later the lamina medullaris externa. The approximately stages 19 to 23, and also in the fetal marginal ridge, sulcus medius, and zona limitans in- period. trathalamica are seen in Figure 21-14. P1: FAW/FAW P2: FAW JWDD017-APP-1 JWDD017-ORahilly June 13, 2006 14:58 Char Count= 0

APPENDIX1 CHANGING LENGTHS OF THE BRAIN AND ITS SUBDIVISIONS FROM 31/ TO 51/ WEEKS (STAGES2 9–16)2

Figure A–1. (A) The actual lengths in mm, based on the authors’ studies of 25 embryos.

Stage 9 10111213141516

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1 1 342 Appendix 1: CHANGING LENGTHS OF THE BRAIN AND ITS SUBDIVISIONS FROM 3/2 TO 5 /2 WEEKS (STAGES 9–16)

Figure A–1. (B) Changes in length given as percentages of the total length of the brain, based on the authors’ studies of 91 embryos. The vertical rectangles in the rhombencephalon show the level of the otic primordia (Ot.) A-D, early (primary) neuromeres. 1-8, rhombomeres. P1: FAW/FAW P2: FAW JWDD017-APP-2 JWDD017-ORahilly June 13, 2006 13:45 Char Count= 0

APPENDIX2 COMPUTER RANKING OF THE SEQUENCE OF APPEARANCE OF FEATURES OF THE BRAIN

Stage 7 8 9 10 11 12 13 14 15 Total

Total number 7 32 3 21 24 36 44 56 40 263 Good quality 7 21 3 12 18 22 20 36 26 165 Silver-treated 0 0 0 01255518 Greatest length (mm) 0.3−0.7 0.4−1.5 1.4±0.52.1±0.23.4±0.23.6±0.14.9±0.16.6±0.27.4±0.3 1 1 Age (weeks) 3 3 2 442 5 1. Neural groove 5/19 +++++++ 2. Otic disc/groove/pit 1/21 +++++++ 3. Neural groove closes 9/12 +++++ 4. Optic sulcus 6/12 +++++ 5. Optic vesicle 16/18 ++++ 6. Entire notochord 5/18 17/17 +++ 7. Rostral neuropore closes 4/18 ++++ 8. Otocyst 19/22 +++ 9. Adenohypophysial pocket 18/21 +++ 10. Ganglia of 5 and 7 are 15/19 +++ compact 11. Rhombencephalic marginal 15/16 +++ layer 12. Root of fourth ventricle is thin 1/18 16/19 +++ 13. Caudal neuropore closes 0/17 13/22 +++ 14. Hypoglossal roots appear 3/22 +++ 15. Lens disc +++ 16. Intramedullary roots 5 and 7 13/13 35/35 + 17. Intramedullary roots 9–11 12/12 34/34 + 18. Nucleus of lateral + 35/35 + longitudinal fasciculus 19. Nucleus of 3 19/20 35/35 +

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344 Appendix 2: COMPUTER RANKING OF THE SEQUENCE OF APPEARANCE OF FEATURES OF THE BRAIN

Stage 7 8 9 10 11 12 13 14 15 Total

Total number 7 32 3 21 24 36 44 56 40 263 Good quality 7 21 3 12 18 22 20 36 26 165 Silver-treated 0 0 0 0 1 255518 Greatest length (mm) 0.3−0.7 0.4−1.5 1.4±0.52.1±0.23.4±0.23.6±0.14.9±0.16.6±0.27.4±0.3 1 1 Age (weeks) 3 3 2 442 5 20. Nucleus of 4 15/19 34/35 + 21. Vestibular ganglion 12/19 33/35 25/25 22. Endolymphatic 11/20 33/35 + appendage 23. Ventral longitudinal 7/12 32/35 + fasciculus 24. Lateral longitudinal 4/4 4/4 22/22 fasciculus 25. Terminal-vomeronasal +++ crest 26. Mesencephalic marginal +++ layer 27. Migration in alar plate of 18/20 35/35 + rhombomere 1 28. Loose cells in chiasmatic 9/13 25/27 + plate 29. Hypothalamic cell cord 9/20 ++ 30. Fibers in vestibular 8/16 35/35 + ganglion 31. Occipital dermatomes 12/18 28/33 + disappear 32. Rhombencephalic ventral 6/17 25/27 + commissure 33. Optic cup 5/20 34/36 + 34. Spinal tract of 5 4/14 31/34 + 35. Spinal tract of 7 and 8 3/13 30/34 + 36. Medial longitudinal 7/15 27/36 + fasciculus 37. Area of epiphysis cerebri 3/19 30/32 + 38. Superior 5/20 28/34 + glossopharyngeal ganglion is compact 39. Migration in marginal 3/20 28/33 + layer of retina 40. Lamina terminalis is thin 1/20 30/35 25/25 41. Perinotochordal 31/36 + mesenchyme is dense 42. Loose cells in tectum 29/34 25/25 mesencephali 43. Cervical dorsal funiculus 27/33 + 44. Hypoglossal roots are 23/34 25/25 united 45. Terminal-vomeronasal 5/17 20/35 24/26 crest reaches telencephalon 46. Dorsal funiculus reaches 20/31 25/25 C2 47. Marginal layer in 1/19 14/27 19/19 hippocampus 48. Intra-isthmic root of 4 11/24 25/25 49. Oculomotor ﬁbers leave 1/20 16/33 25/25 mesencephalon

1 The period covered is from stage 8 (probably about 23 days) to stage 19 (6 2 weeks). Based on 467 embryos. Corrected and modiﬁed from O’Rahilly, M¨uller, Hutchins, and Moore (1984, 1987, 1988). The ages are postfertilizational. Cranial nerves are indicated by Arabic numerals. P1: FAW/FAW P2: FAW JWDD017-APP-2 JWDD017-ORahilly June 13, 2006 13:45 Char Count= 0

COMPUTER RANKING OF THE SEQUENCE OF APPEARANCE OF FEATURES OF THE BRAIN 345

Stage 13 14 15 16 17 Total

Total number 40 56 44 140 Good quality 26 39 32 97 Silver-treated 5 3 5 13 Greatest length (mm) 7.4 ± 0.39.3 ± 1.512.6 ± 1.2 1 Age (weeks) 5 5 2 6 50. Amygdaloid part of basal nuclei 14/27 21/22 + 51. Lens vesicle separated from surface ectoderm 13/36 +++ 52. Fibers of 8 (vestibular) to otic vesicle 11/27 24/24 ++ 53. Preoptico-hypothalamic tract 13/25 23/24 ++ 54. 6 leaves rhombencephalon 10/34 24/25 ++ 55. Common afferent tract 0/14 6/34 25/26 ++ 56. Future cerebral hemispheres 11/28 25/26 ++ 57. Habenular nucleus 24/25 37/37 + 58. Primordial plexiform layer in future cerebral 23/24 ++ hemispheres 59. Dorsal roots ofCN1and2contain nerve fibers 0/17 11/30 24/26 ++ 60. Dorsolateral nucleus of 5 9/29 22/24 ++ 61. Retinal pigment 20/23 ++ 62. Utriculo-endolymphatic fold 21/25 ++ 63. Ventral roots ofCN1and2contain nerve fibers 1/15 14/34 21/26 ++ 64. Decussation of mesencephalic root of 5 8/11 24/24 + 65. Preoptic sulcus 12/16 6/12 17/17 + 66. Decussation of 4 2/34 21/24 37/39 + 67. Nasal pit 2/35 20/26 ++ 68. Fibers in amygdaloid part of basal nuclei 11/15 35/35 + 69. Nerve fibers in habenular nucleus 19/24 31/33 + 70. Ventral thalamus and subthalamus are loose peripherally 10/18 36/36 + 71. Trochlear fibers leave isthmus rhombencephali 0/34 9/13 35/37 + 72. Zona limitans intrathalamica 7/12 17/17 + 73. Mesencephalic root of 5 9/21 27/28 + 74. Basilar artery 2/26 13/18 28/34 + 75. Basement membranes (adenohypophysis and 13/20 15/30 8/25 ++ hypo-thalamus) are in contact 76. Interpeduncular nucleus 11/16 25/31 24/25 77. Decussation of superior colliculi 0/32 7/15 30/35 21/21 78. Nucleus of mamillary body 16/24 28/36 + 79. Dorsolateral nucleus of 9 3/23 9/26 29/35 + 80. Rostral olfactory elevation 7/19 4/4 29/30 81. Caudal olfactory elevation 0/16 34/34 30/30 82. Cells of cochlear ganglion are different from those 0/34 10/20 25/30 21/28 of vestibular ganglion 83. Rostrolateral groove of vestibular pouch 3/9 14/21 + 84. Hypothalamotegmental tract 2/34 4/13 12/22 26/27 85. Supramamillary commissure 6/13 13/27 22/24 86. Medial forebrain bundle 3/10 10/13 23/23 87. Basal nuclei protrude into ventricle 36/37 + 88. Caudolateral groove of vestibular pouch 2/9 21/25 + 89. Crossed tectobulbar tract 29/31 28/28 90. Sulcus limitans hippocampi 3/16 25/34 23/24 91. Area epithelialis 6/20 22/33 26/27 92. Ventrolateral and dorsolateral nuclei of 10 30/32 28/28 93. Tractus solitarius separates from common afferent tract 4/24 24/37 + 94. Hippocampal thickening 2/16 23/33 31/31 95. Common afferent tract reaches more rostrally than 29/29 + entrance of 5 96. Atrial fossa of otic vesicle 2/14 16/30 31/31 97. Olfactory fibers enter telencephalon 3/16 17/32 + P1: FAW/FAW P2: FAW JWDD017-APP-2 JWDD017-ORahilly June 13, 2006 13:45 Char Count= 0

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Stage 13 14 15 16 17 Total

Total number 40 56 44 140 Good quality 26 39 32 97 Silver-treated 5 3 5 13 Greatest length (mm) 7.4 ± 0.39.3 ± 1.512.6 ± 1.2 1 Age (weeks) 5 5 2 6 98. Mamillotegmental tract 11/23 13/31 28/31 99. Dorsolateral nucleus of 7 0/24 4/26 22/36 28/28 100. Fibers in alar plate of rhombomere 1 9/20 21/32 19/27 101. Migrating cells in hippocampus 21/31 + 102. Neurohypophysial evagination 2/23 16/37 30/31 103. Mesenchyme between lens vesicle and surface ectoderm 14/35 32/32 104. Hypothalamo-thalamic tract 3/23 4/12 2/8 8/12 105. Posterior commissure 6/14 6/34 30/31

Stage 15 16 17 18 19 Total

Total number 40 56 44 48 36 224 Good quality 26 39 32 35 23 155 Silver-treated 5 3 5 7 7 27 Greatest length (mm) 7.4 ± 0.39.3 ± 1.512.6 ± 1.215± 1.518.4 ± 1.5 1 1 Age (weeks) 5 5 2 662 106. Cell islands in olfactory tubercle 13/31 28/31 35/35 23/23 107. Mesenchymal skeleton in pharyngeal arch 2 7/37 29/31 35/35 23/23 108. Blind nasal sac 4/39 31/32 35/35 23/23 109. Primary lens fibers 5/35 27/31 35/35 23/23 110. Crescentic lens cavity 29/31 35/35 23/23 111. Fibers from olfactory field to amygdaloid body 5/10 9/23 35/35 23/23 112. Habenulo-interpeduncular tract 4/16 14/24 35/35 23/23 113. Intermediate layer in tectum mesencephali 22/31 35/35 23/23 114. Cortical nucleus in amygdaloid body 22/31 35/35 23/23 115. Definitive special visceral nucleus of 5 18/31 35/35 23/23 116. Capillaries between adenohypophysis and 15/32 34/35 23/23 hypothalamus 117. Dorsal thalamus with intermediate layer 9/28 35/35 23/23 118. Commissure of nerve 3 4/32 35/35 23/23 119. Tractus solitarius separated 3/32 35/35 23/23 120. Olfactory bulb and fibers from bulb to 3/25 25/26 23/23 olfactory tubercle 121. First signs of choroid plexus of lateral ventricle 2/32 34/35 23/23 122. First signs of choroid plexus of fourth ventricle 2/32 31/35 23/23 123. Follicles in epiphysis cerebri 3/32 25/31 20/21 124. Adenohypophysis separated from pharynx 1/39 1/32 27/35 23/23 125. Nerve fibers in retina 2/29 18/33 23/23 126. Supraoptic commissure 2/32 15/32 22/23 127. Vomeronasal ganglion 35/35 23/23 128. Nucleus isthmi sends fibers to cerebellum 34/34 23/23 129. Primordium of stapes surrounds stapedial a. 35/35 23/23 130. Sensory nucleus of 5 32/32 23/23 131. Internal cerebellar swelling 35/35 23/23 P1: FAW/FAW P2: FAW JWDD017-APP-2 JWDD017-ORahilly June 13, 2006 13:45 Char Count= 0

COMPUTER RANKING OF THE SEQUENCE OF APPEARANCE OF FEATURES OF THE BRAIN 347

Stage 15 16 17 18 19 Total

Total number 40 56 44 48 36 224 Good quality 26 39 32 35 23 155 Silver-treated 5 3 5 7 7 27 Greatest length (mm) 7.4 ± 0.39.3 ± 1.512.6 ± 1.215± 1.518.4 ± 1.5 1 1 Age (weeks) 5 5 2 662 132. Dentate nucleus 33/33 23/23 133. Bucconasal membrane 34/35 23/23 134. Medial ventricular elevation extends to 32/33 23/23 preoptic sulcus 135. Vomeronasal organ 33/35 23/23 136. Mesenchymal nasal septum is condensed 33/35 23/23 137. Nasolacrimal duct 33/35 23/23 138. External cerebellar swelling and posterolateral 28/32 23/23 ﬁssure 139. Walls of neurohypophysis are folded 34/35 19/23 140. At least two semicircular ducts have become 2/31 29/35 23/23 individualized 141. Medial ventricular elevation reaches septal 25/30 22/23 area 142. Olfactory bulb shows ventricular recess 22/34 20/23 143. Cell migration in area dentata 24/30 12/23 144. Plexus of fourth ventricle contains villi 14/35 23/23 145. Cavity of lens vesicle slitlike or disappeared 18/35 17/23 146. Mamillothalamic tract 11/32 19/22 147. Choana 7/35 19/23 148. Styloid process is cartilaginous 5/35 19/23 149. Globus pallidus externus 2/25 22/23 150. Area of nucleus accumbens projects into 16/16 ventricle 151. Nuclei of forebrain septum 22/23 152. Subcommissural organ 16/17 153. Cochlear nuclei 22/23 154. Ganglion of nervus terminalis 20/23 155. Orbital wing of sphenoid is cartilaginous 19/23 156. Stria medullaris thalami 5/35 13/23 157. Plexus of lateral ventricle possesses villi 1/35 16/23 158. Cochlear duct turned “upward” 2/35 13/22 159. Paraphysis is present as a button 16/22 160. Mandible begins to ossify 15/23 161. Thalamostriatal ﬁbers 1/35 13/23 162. Medial accessory olivary nucleus 13/23 163. Fibers in optic chiasma 7/18 164. Paraphysis with opening to ventricular cavity 8/22 165. Maxilla is ossifying 5/23 166. Stapedial artery is regressing 4/23 167. Habenular commissure 2/17 P1: FAW/FAW P2: FAW JWDD017-APP-2 JWDD017-ORahilly June 13, 2006 13:45 Char Count= 0

348 Appendix 2: COMPUTER RANKING OF THE SEQUENCE OF APPEARANCE OF FEATURES OF THE BRAIN

Appendix 2. Continued. Main Features from 7 to 8 Postfertilizational Weeks, Beyond the Study by Computer Ranking

Approximate Stage age (days)

20 47 Crossing fibers in optic chiasma Medial septal nucleus Nucleus of diagonal band Cuneate and gracile decussating fibers Olivo-arcuate migration 21 50 Lateral olfactory tract Cortical plate in cerebral hemispheres Pyramidal cells in hippocampus Globus pallidus internus (future entopeduncular nucleus) Cranial nerves with glial (olfactory and optic) and neuri-lemmal cells between nerve fibers Ventral part of lateral geniculate body Area of future dentate gyrus Dentate nucleus of cerebellum 22 52 Internal capsule present and three outlets forming Nerve fibers between neopallial subplate and internal capsule Claustrum Intereminential sulcus between medial and lateral ventricular eminences Roof of ventricle 3 becoming folded Intradural veins (dural sinuses) present 23 56 Hippocampus reaches temporal pole Insula Caudate nucleus and putamen Beginning of anterior commissure Optic tract reaches ventral part of lateral geniculate body Cerebellar commissures Principal nucleus of inferior olivary nuclei Olivocerebellar fibers Cells of area membranaceae cuboidal Pyramidal decussation Falx cerebri Most cisterns present Lateral parts of tentorium cerebelli No apertures in roof of ventricle 4 P1: FAW/FAW P2: FAW JWDD017-APP-3 JWDD017-ORahilly June 13, 2006 14:57 Char Count= 0

APPENDIX3 SEQUENCE AND STAGE OF APPEARANCE OF MEDIAN FEATURES OF THE BRAIN

Preoptic recess (rostral end of neural plate) (stage 14)

Neuromere Dorsocaudally Stage Ventrocaudally Stage

T Lamina terminalis Embryonic 11 Adult 15 Commissural plate (situs neuroporicus) 12 Velum transversum 14 ⎧ D1 ⎨Chiasmatic plate 10 ⎩Supraoptic commissure 17 Postoptic recess 14 Par. r. ⎧Infundibular region 13 Par. c. ⎨Inframamillary recess 17 ⎩Mamillary region 13 Supramamillary recess 17 (termination of sulcus limitans) Syn. Epiphysis cerebri 16 Supramamillary commissure 15 Posterior commissure 17 M1 Commissure of superior colliculi 15 M2 Oculomotor decussation 17 Isth. Trochlear decussation 15 Isthmic recess 16

Abbreviations: D1, Diencephalon. Isth., Isthmus. M1, M2, Mesencephalon. Par. c. & r., Parencephalon caudalis & rostralis. Syn., Synencephalon. T, Telencephalon.

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APPENDIX4 SEQUENCE AND STAGE OF APPEARANCE OF TRACTS OF THE BRAIN

Tract Stage Tract Stage

Lateral longitudinal 12 Crossed tectobulbar 16 Ventral longitudinal 13 Fibers from olfactory tubercle 16, 17 Common afferent1 13 to amygdaloid body Medial longitudinal∗ 13 Habenulo-interpeduncular∗ 16, 17 Dorsal funiculus 14 Fibers from olfactory bulb to 17 Preoptico-hypothalamic2 14 olfactory tubercle4 Hypothalamotegmental 14, 15 Mamillothalamic 18 Mamillotegmental 15 Stria medullaris thalami∗ 18, 19 Medial forebrain bundle∗ 15, 16 Lateral lemniscus 18, 19 Tractus solitarius separates 15, 16 Thalamostriatal5 19 from common afferent tract Tract of zona limitans 19 Hypothalamo-thalamic3 15, 16 intra thalamica Tract of posterior commissure 15, 16 Central tegmental∗6 19

1Containing ﬁbers of the future tractus solitarius. 2Part of the basal forebrain bundle. 3Containing striatosubthalamic ﬁbers. 4Part of the basal forebrain bundle. 5Synonyms: lateral forebrain bundle, Stammbundel ¨ (of His). 6Zecevic and Verney (1995). ∗Pathways concerned with the transportation of monoamines.

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APPENDIX5 SEQUENCE AND STAGE OF APPEARANCE OF FEATURES ASSOCIATED WITH THE RHOMBENCEPHALON

Age Stage (weeks) Neural Discs Neural Crest Ganglia Nuclei Nerve Fibers

1 932 9 (otic) 10 4 10 (arch 4) 5, 7, 9, 10(−11?) 11 7–8 5, 7–8 11–12 (5, 7, 9, 10–11, 12 eff.)∗ 12 9 superior & 5, 7, 9, 11 SVE; 10 superior 12 GSE 12–13 7, 9, 9 inferior & 3, 4, eff. 5, 7 eff. (arches 2 & 3) 10 inferior 5, 7 GVA 1 13 4 2 5 (arch 1) 3 GSE 13–14 6eff. 14 4 GSE; 5 mesenc. root; 8v eff. 9, 10–11 aff. 14–15 5 6 GSE 15–16 Sup. & inf. salivatory 1 16 5 2 8c 17 6 5 motor 18 5 main sensory 1 19 6 2 8c ventral & dorsal 20 7 10 dorsal eff. 21 8v lateral 1 22 7 2 8v superior

∗Provisional location. Abbreviations: aff., afferent; eff., efferent; GSE, general somatic efferent; GVA, general visceral afferent; SVE, special visceral efferent; 8c, 8v, cochlear and vestibular parts of cranial nerve 8, respectively. Source: All the data are based on the authors’ studies.

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Index

Items in this index are generally listed under nouns rather than adjectives. For example, pontine ﬂexure under Flexure. Similarly rostral neuropore under Neuropore, fourth ventricle under Ventricle. Malformations and syndromes named after people, however, are listed under the names of these people. T, Table.

A newborn, 319 Canal Adenohypophysis, 47, 49, 50, 81, 100, 105, 119, otic, 112, 204 central, 293 121T, 122, 143, 163, 287 staged, 107, 112T, 203, 252, 253 neurenteric, 26, 28, 34, 35, 37, 38, 331 Adhesion, intrathalamic, 298 trigeminal, 112, 204 notochordal, 21, 29, 331 Age, 13, 15–17 Astrocytes, 175 Capsule Agenesis Asymmetry, cerebral, 103, 297 external, 273, 284 cerebellar, 82 internal, 167, 208, 210, 236–238, 243, 273, corpus callosum, 300 284, 287, 294 B hypoglossal nerve, 74 Cavum septi pellucidi, 311 Basicranium, see Chondrocranium sacral, 74 Cebocephaly, 82, 84 Bell–Magendie, law of, 258, 332 Albinism, 74 Cell(s) Blindsack, mesencephalic, 135, 170, 206, 244, Alveus, 303 Cajal-Retzius, 129, 331 247 Amygdala. See Complex, amygdaloid catecholaminergic, 169, 331 Blood vessels (See also, Arteries and Veins), 85, Anencephaly, 82, 83, 218 cholinergic, 177 98, 99 Angle of forebrain, 263, 295 dopaminergic, 177, 230 Body Ansa cervicalis, 98, 106, 123, embryonic stem, 21 lateral geniculate, 190, 198, 268, 289 Aorta, 59,70 ependymal, 172 mamillary, 77, 95, 269 Apertures of fourth ventricle, 244 hippocampal stem, 300 medial geniculate, 289 Aplasia, caudal, 74 olfactory, 159 paraterminal, 156 Apoptosis, 329 piriform (Purkinje), 281 pineal (See also Epiphysis), 104, 118 Aqueduct of midbrain, 101, 111, 293 TH-IR, 126 Brain Arachnoid, 217 Center(s) (See also Neurons) functional aspects, 170, 248, 309 Arch(es) dopaminergic, 177, 332 growth of, 319 aortic, 68–70 monaminergic, 126T, 331 measurements of, 317, 341 neural, 145, 228 Cerebellum, 330 newborn, 308, 310, 312, 313 pharyngeal, 40, 65, 69, 70 agenesis, 82 ventricles. See Ventricles Archicerebellum, 279 appearance at stages 13 to 17, 75 “vesicles”, 1, 31 Archipallium, 108, 331 corpus, 146, 200 weight of, 10, 317 Archistriatum, 108, 149T, 155, 156t embryonic development, 78T, 108T Brain stem, 291, 292, 305, Area eversion, 279 median views, 291, 292, 318, 319 dentate, 135, 190, 200, 242, 278, 331 extraventricular, 117, 134, 145, 151 Bulb, olfactory, 123, 131, 137, 140, 152, 159, epithelialis, 135, 173, 177, 190, 200, 242, 331 external germinal layer, 144, 216, 239, 179, 232, 276, 295 (rotation), 304 hippocampi, 96, 331 245–247, 281, 334 Bundle (See also Fasciculus) membranacea, 119, 244, 331 fetal, 258T, 279–280 basal forebrain, 166, 331 reuniens, 331 ﬁssuration, 279, 280 lateral forebrain, 98, 139, 166, 167, 199, 267, septal, 177, 178 ﬂocculus, 145, 201, 212, 239, 245, 246, 279 333 ventral tegmental, 175–177 folia, 279, 280 medial forebrain, 98, 106, 123, 137, 157, 166, Arhinencephaly, 82 fusion, 245, 247, 258, 266, 279 167, 333 Arnold–Chiari malformation, 102 hemispheres, 171, 247, 279 vestibulocerebellar, 106 Artery(-ies) to brain, 257, 297, 313 histological differentiation, 280, 281 basilar, 107, 119, 122, 153 intraventricular, 118, 144, 145, 151, 201, circulus arteriorus, 107, 204, 296 C 212, 245 hypoglossal, 80, 112, 204 C-shaped structures, 269T, 269 neo (ponto) cerebellum, 279 internal carotid, 59, 224, 235, 308, 309 Cajal-Retzius, cells of, 129, 331 nodule, 246, 279

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INDEX 355

Cerebellum (continued) neural, 23T, 33, 36, 37T, 39. 42–44, 47, 49T, Epithalamus, 148, 152, 159, 286 paleocerebellum, 272, 279, 53, 62, 332 Exencephaly, 218 peduncle(s) optic, 33, 57, 62–67 Eye, 62, 64–67, 104, 232, 233 inferior, 144, 165, 181, 201,239, 248, 249, otic, 43, 49 optic primordia, 50 282 rhombencephalic, 43, 44 superior, 144, 223 spinal, 43, 49T F spinocerebellum, 279 terminal-vomeronasal, 43, 77 Falx cerebri, 16T, 230, 232, 276 staged, 101, 144–146, 223, 245–247 Crus cerebri, 297, 306 Fasciculus subdivisions, 272T Cuneus, 307 cuneatus, 248 vermis, 246, 247, 279 Cup, optic, 64, 79, 91, 99, 104, 114, 189 gracilis, 248 herniation of, 102 Cyclopia, 49, 50, 114 lateral longitudinal, 88, 98 Cerebrum, 332 Cyst, enteric, 38 medial longitudinal, 75, 88, 98, 147, 166, Chiari malformation, 102 211, 249 Chiasma, optic, 100, 166, 189, 207, 235, D prosencephalic, 98, 139, 166, 167, 199, 267 291–291 Dandy–Walker syndrome, 132 retroﬂexus. See Tract, Chondrocranium, 149, 153, 163, 191, 209, 225, Decussation, 332 habenulo-interpeduncular 228, 229, 234, 235, 267, 282 cuneate, 171, 248, 250 ventral longitudinal, 63, 88, 98 basicranium, 153, 226, 228, 267, 282 gracile, 171, 248, 250 Fimbria, 269, 302, 303 Chorda tympani, 123, 224, 266 lemniscal, 152, 171, 223, 250 Fissure(s), 331 Choroid plexus optic, 166, 189 choroid of brain, 157, 172, 190, 222, 238, 4th ventricle, 203, 215 pyramidal, 223, 250, 251 278, 308 lateral ventricle, 157, 172, 203, 211, 236, of superior cerebellar peduncles, 223 choroid of eye, 94, 104 237, 269 of superior colliculi, 98, 105, 106, 118, 130, longitudinal, 115, 117, 127, 137 ultrasound images, 16 177 posterolateral, 134, 144, 206, 245 Circulus arteriosus, 107, 204, 288, 296, 313 trochlear, 98, 118, 245, 246 retinal, 91, 94, 104 Cistern(s), 153, 190, 196, 226, 231, 234 Diastematomyelia, 38 transverse, 308 Claustrum, 155, 214, 236, 273 Diencephalon, 41, 93, 95, 122, 128T, 186T, 222, Flexure(s), 221, 263 Colliculus, colliculi 268 cervical, 221 facial, 267 Disc(s) See also Plate) mesencephalic, 62, 96,136, 221, 254 inferior, 211, 225 epipharyngeal, 23, 39, 49T, 69 pontine, 87, 102, 164, 221 superior, 119 lens, 76, 232 Flocculus, 201, 212, 239, 245, 246 Commissure(s), 160, 332 nasal, 57 Floor plate, 333 anterior, 125, 291–294 otic, 33, 34, 48 Fluid cerebellar, 222, 223 retinal, 76, 232 cerebrospinal, 244 of fornix, 294 Dopaminergic innervation, 237 ependymal, 77 habenular, 161, 171, 189, 207, 222 Duct(s) Fold(s) of oculomotor nerve, 118, 171 endolymphatic, 94 choroid, posterior, 106, 118, 222 semicircular, 149, 188, 250 rhombencephalic, 135, 152 of superior colliculi, 98, 105, 106, 118, 130, Dura mater, 217, 230 telencephalic, 157 177 limiting layer, 119, 173, 217, 230, 231, 334 neural, 27, 33, 36 supramamillary, 98, 118 subdural space, 153 Folia of cerebellum, 280 supraoptic, 118, 137, 156, 166, 189, 207, 252 spinal, 153 Foramen, interventricular, 105, 118, 127, 152, trochlear, 98, 118, 245, 246 Dysraphia 236 Complex cerebral, 82 Forebrain. See Prosencephalon amygdaloid, 88, 98, 123, 125, 138, 166, 331 spinal, 185 Formation, hippocampal, 300–303, 301T, 333 Cord Fornix, 238, 269, 294, 299, 308 hypoglossal cell, , 62, 332 E Funiculus hypothalamic cell, 87, 90 Ectoderm, neural, 23T, 333 cuneatus, 248 neural, 72, 73, 332 Ectopia, neural, 132 dorsal, 143, 165, 201 spinal, 31, 154, 184, 193, 259, 265, 332 Eminence(s), 333 gracilis, 248 Corpus caudal, 31, 34, 40, 46, 72, 333 lateral, 165 callosum, 238, 271, 289–294, 297, 307, 308 lateral and medial, 108, 118, 135, 152, 156T, ventral, 88 agenesis of, 300 333 Fusion striatum, 155T, 156T, 210, 237, 332 medial, 95, 333 cerebellar hemispheres, 247, 279 Cortex, cerebral, 193 ventricular, 87, 333 cerebral hemispheres, 205, 207, 265 neopallium, 238, 271 Encephalocele, 60 di-telencephalic, 205, 210, 219 piriform, 196 Encephalomeningocele, 60 neural folds, 39T, 40 vascularization, 170 Endplatte. See Lamina reuniens Cranior(h)achischisis, 60, 218 Ependyma, 215 G Cranium (See also Chondrocranium) choroidal, 172, 215 Ganglion, ganglia, 98, 106 craniovertebral region, 209, 226, 227 ventricular, 172 cervical, 98 Crest, Epiblast, 21, 29, 35, 46, 47 cranial, 62–65, 69, 98, 106, 123, 165, 224, cranial, 23T, 49T, 332 Epiphysis cerebri, 104, 105, 109, 118, 121T, 266, facial, 43, 45 137, 142, 161, 162, 291, 292 facio-vestibulocochlear, 45, 64, 68, 80, 134, mesencephalic, 43, 44 Hinterlappen, 161 165, 333 nasal, 43, 158, 174 Vorderlappen, 120, 161 parasympathetic, 165 P1: FAW/FAW P2: FAW JWDD017-IND JWDD017-ORahilly July 5, 2006 21:19 Char Count= 0

356 INDEX

trigeminal, 64, 92, 128, 134, intermediate, 37, 335 glossopharyngeal, 88, 89 vomeronasal, 141 159 internal granular, 281 hypoglossal, 62, 71, 80, 88, 92, 98, 106, 224 spinal, 154, 184 mantle, 91, 108, 335 oculomotor, 88, 98, 123, 176, 224 sympathetic, 154 marginal, 37, 335 olfactory, 108, 123, 125, 131, 140, 160 Genes, 98, 167, 257T, 300 piriform, 281 optic, 223, 252 Glia, 175, 195, 239, 331 primordial plexiform, 88, 108, 129, 173, 193, dysgenesis, 132 Glioma, nasal, 60 240, 241, 334 spinal, 154, 209, 227 Globus pallidus subpial, 195 superior laryngeal, 224 externus, 171, 190, 192, 199, 236, 243 subventricular, 173, 195, 335 terminalis, 160, 177, G7 internus (See also Nucleus, entopeduncular) transient subpial granular layer, 214, 276, trigeminal, 88, 224, 249 190, 198 334 trochlear, 94, 98, 106, 224 Groove (See also Fossa) ventricular, 37, 335 vagus, 83, 98, 106 interpeduncular, 176, 239 Lemniscus, medial, 249 vestibular, 98 isthmic, 152, 171 Leptomeninx, 217 vomeronasal, 141, 159, 336 neural, 25, 27, 29, 33, 34, 36, 48, 59 Lip Neural tube defects, 258 primitive, 25, 28, 29, 34 dorsal of rostral neuropore, 56, 57, 71, 81, Neurobiotaxis, 180 Gyrus, gyri, 306T, 311, 312 83 Neuroectoderm, 23T, 333 cingulate, 269 rhombic, 117, 146, 201, 215, 245, 335 Neuroglia, See Glia. dentate, 300, 302 terminal of rostral neuropore, 56, 71, 83 Neurohypophysis, 50, 81, 105, 121T, 122, 163 Lissencephaly, 218 Neuromeres, 42, 45T, 81, 90, 101, 130, 336 H Lobe, ﬂocculonodular, 279 staged, 42, 81, 90, 130, 131 13, 81 Hemisphärenstiel (See also Stalk), 339 Locus caeruleus, 95, 100, 123 Neurons Hemisphere(s) catecholaminergic, 166, 169 cerebellar, 246, 279, 280 M cholinergic, 177 cerebral, 88, 295, 308, 309 Massa cellularis reuniens, 192 GABA-expressing, 187, 156, 187 Hindbrain. See Rhombencephalon Massa commissuralis, 225 LHRH, 335 Hinterlappen of epiphysis, 161 Median sections of brain, 153, 191, 226, 282, Neuropores, 39, 53–57, 71, 73, 336 Hippocampus (See also Formation, 291, 292 Neuroschisis, 74 hippocampal) 108, 110, 118, 125, 131, Medulloblastoma, 258 Neurulation, 23, 30, 72, 73, 336 135, 173, 190, 200, 222, 242, 269, 275, Meningocele, 259 primary and secondary, 23, 30, 73 302, 303, 333 Meninx, meninges, 78, 89, 184, 217 secondary, 71, 72 Holoprosencephaly, 113, 114, 257T Mesencephalon, 42, 130, 136, 175–177, 306, Node, primitive, 27, 29, 33, 34, 47 Hypoblast, 21, 46, 47 309 Nodule of cerebellum, 246 Hypophysis cerebri (See also Adenohypophysis Mesocoel, 244, 245 Notochord, 36, 58, 63, 87, 95, 107, 122 and Neurohypophysis), 105, 120, 121T, Mesocortex, 242 split syndrome, 38 122, 143, 162, 163, 304 Microglia, 105, 175 Nucleus, nuclei, 123, 336 Hypothalamus, 89, 95, 99, 100, 105, 110, 139, Migration abducent, 147, 165 287 interkinetic nuclear, 37 accumbens, 156, 210, 234 neural crest, 43, 44 afferent, 181 I neurons, 146 ambiguus, 147, 248, 249 Indusium griseum, 269, 308 olfactory, 213, 276 amygdaloid, 108, 126, 138, 139, 155, 157, 337 Infundibulum, 122 olivo-arcuate, 181, 219, 248, 266 anterior olfactory, 276 Insula, 137, 188, 210, 211, 221, 236, 263, 298, pontine, 248 basal, 149, 155, 219, 220, 276, 337 334 rhombencephalic, 215 caudate, 155, 210, 237, 243, 269, 284 Isthmus rhombencephali , 77, 78, 81, 87, 99, telencephalic, 174 cochlear, 147, 165, 248, 249 101, 130, 247, 334 telo-diencephalic, 272 common efferent, 91 Isthmushöcker, 134, 174 Midbrain. See Mesencephalon cuneate, 248, 286 Mittelhirnblindsack. See Blindsack dentate, 135, 201, 239, 249 K Mittelhirnpolster, 87, 107 of diagonal band, 157, 177, 196 Kappenkern, 248 Möbius, sequence of, 82 diencephalic, 190, 268 Kleinhirnwulst, 134, 170, 339 Myelination, 175, 297, 319–321 dorsal efferent of vagus, 181, 248, 249 Myelomeningocele, 259 entopeduncular, 190, 198 L Myeloschisis, 259 facial, 165, 180 Labyrinth, membranous, 188, 309, 277 funiculi teretis, 248 Lamina N gracilis, 248, 286 afﬁxa, 190, 192, 274, 278 Neocerebellum (pontocerebellum), 279 habenular, 125, 159, 166, 268 alar and basal, 36, 119, 193, 334 Neopallium, 108, 110, 238 hypoglossal, 80, 147, 181, 248, 249 epithelialis, 275 Neostriatum, 155, 156T, 210 intercalatus, 181, 248, 249 reuniens, 334 Neoteny, 319 interpeduncular, 146, 175–177, 191, 268 terminalis, 77, 109, 156, 293, 320, 334 Nerve(s) interstitial, 89, 123 Law abducent, 83, 88, 165 isthmic, 160 Bell-Magendie, 258, 334 accessory, 88, 223 lentiform, 155T biogenetic, 108 cochlear, 164, 165 mamillary, 190, 197, 268 Layer(s) cranial, 98, 106, 123, 151, 164, 223, 224, 248, medial accessory olivary, 152, 153, 181, 268 dural limiting. See Dura 249, 266 medial septal, 177, 178 external germinal, 239, 245, 281, 334 facial, 83, 98, 106, 180, 224 motor, 91 P1: FAW/FAW P2: FAW JWDD017-IND JWDD017-ORahilly July 5, 2006 21:19 Char Count= 0

INDEX 357

Nucleus, nuclei (continued) neural, 21, 26, 28, 30, 37, 338 Spina biﬁda, niger, 306 notochordal, 23, 33, 36, 37, 47, 58 aperta and cystica, 24 oculomotor, 147, 175 optic, 338 normal, 209, 228 olivary, inferior, 249, 268, 286 otic, 32, 48, 59 occulta, , 24, 184, 185 olivary, superior, 147, 248, 249 prechordal, 22, 26, 27, 29, 44, 50 Splenium , 290, 307 oval, 166 roof, 36, 58, 193, 338 Stalk of posterior commissure, 123 somitic, 72 hemispheric, 118, 192 243, 272, 339 raphe, 180, 248 Plexus, choroid, 157, 215, 338 hypophysial, 304 red, 147, 306 Pons, 293, 320 optic, 99, 128, 131, 139 rhombencephalic, 248, 249, 310 Pouch, adenohypophysial (Rathke), 100 Stammbündel, 167, 192, 199, 208, 339 septal, 164, 165, 229, 231 Precuneus, 307 Stem cells, 21, 337 solitarius, 181, 249 Preplate (See also Layer, primordial plexiform), Streak, primitive, 23T, 26, 28, 29, 31, 33–35, 46 subthalamic, 123, 190, 197, 199 193, 241, 338 Streifenhügelstiel. See Stalk, hemispheric superior salivatory, 147 Presubiculum, 242, 303 Stria(e) taeniae. See Oval nucleus Process acoustic, 248 thalamic, 268 neural, of vertebra, 184 medullaris thalami, 157, 159, 166, 200, 210, trigeminal, 248 notochordal, 21, 25, 27, 28T, 47 268, 275 trochlear, 147 Prosomeres, 338 olfactory, 125, 196, 224, 266, 276, 304 tuberalis, 268 Pulvinar, 272 terminalis, 125, 208, 225, 273, 308 vestibular, 143, 165, 248, 249 Putamen, 155, 210, 236, 243 Striatum, 330 Subiculum, 242, 303 O Subplate, 193, 195, 240, 241, 265, 297, 305, 339 R Obex, 244 Subthalamus, 110, 139, 287, 297, 306T, 311, “Recapitulation,” 108 Olfactory bulb. See Bulb, olfactory 312 Recesses Olfactory nerve. See Nerve, olfactory Sulcus, sulci inframamillary, 270 Operculum (-a), 298, 309 central, 307, 311, 312 infundibular, 270 Organ circularis, 140, 177, 276 isthmic, 191, 270, 338 circumventricular, 337 di-telencephalic, 88, 138, 199, 205 lateral of fourth ventricle, 152, 200, 224, 244, subcommissural, 189, 337 hippocampi, 274 247 vomeronasal, 141, 337 hypothalamic, 95, 96, 104, 109, 110, 287, 339 mamillary, 62,197 Otocyst (otic vesicle), 65, 69 intereminential, 135, 155, 210, 333, 339 mesocelic, 291 isthmic, 171, 207 olfactory, 270 P limitans, 77, 104, 194, 339 pineal, 156, 161, 207, 222, 270, 293 Pain, 336, 265 medius, 90, 139, 198, 287 postoptic, , 41, 100, 120, 338 Paleocerebellum (spinocerebellum), 272 optic, 41, 44, 55, 57 preoptic, 41, 120, 338 Paleopallium, 108, 337 parieto-occipital, 307, 311 supramamillary, 270 Paleostriatum, 108, 155T preoptic, 156 suprapineal, 222, 293 Pallidum, 155T preotic and postotic, 32 Reconstruction(s), 5, 6 Paraphysis, 140, 152, 177, 189, 207, 337 terminalis, 192, 211, 212, 275 Retina, 79, 233 Parencephalon, 42, 43, 90, 337 transversus rhombencephali, 191 Rhombencephalon, 40, 41, 42, 54, 101, 111, Parkinson disease, 175 Synapses, 129, 241, 258, 271, 297, 305 248, 310, 353 Peduncle(s) Synencephalon, 86, 87, 89, 90, 95, 106, 131, 339 Rhombomeres, 54, 101, 111, 338 cerebral, 176, 306 Synophthalmia, 50, 114 Ridge, marginal, 104, 109, 118, 128, 139, 171, inferior cerebellar, 144, 165, 181, 201, 239, 207, 222 248, 249, 282 T superior cerebellar, 144, 223 Taenia, rhombencephalic, 246 Pia mater, 129, 173, 217 S “Tail,” 93 Pineal. See Epiphysis Sac, nasal, 127, 140, 141, 158 Tectum, 306 Pit Schlussplatte, 332 Tegmentum, 146, 306 lens, 79 Sclerotomes, 119 Tela choroidea, 172, 215 nasal, 99 Septum Telencephalon, medium (impar), 39, 41, 62, 63, otic, 52 forebrain (prosencephalic), 125, 135, 152, 77, 95, 127, 339 primitive, 28, 34 156, 276, 338 Tentorium cerebelli, 100, 107, 128, 200, 212, Pituitary. See Adenohypophysis and medullae rhombencephali, 153, 171, 143, 231, 320 Neurohypophysis 171, 180 Thalamus, 95, 167, 268, 278 Placode (See also Disc and Plate) nasal, 153, 228 dorsal and ventral, 81, 90, 95, 128, 130, epipharyngeal (disc), 23, 39, 49T, 69 pellucidum, 308, 311 135,158, 191, 282 Plate (See also Disc) verum, 135, 336 Torus alar (lamina), 36, 72, 73 Sexual differentiation of the brain, 307, hemisphericus, 95, 96, 99, 105, 340 basal (lamina), 36 338 opticus, 41 cerebellar, 117, 144, 337 Situs neuroporicus, 55, 65, 67, 194, 339 Tract(s), 88, 98, 106, 123, 166, 268, 351 chiasmatic, 44, 52, 64, 95, 337 Skull. See Chondrocranium and Cranium accessory optic, 268 commissural, 77, 179, 337 Somites, 33, 34, 36, 40,71, 74, 83 amygdalo-habenular, 166 cortical, 192, 193, 195, 210, 240, 338 Space common afferent, 88, 106, 123 ﬂoor, 28T, 36, 58,180, 193 subarachnoid, 119, 128, 140, 153, 173, 217 corticospinal, 251 nasal, 57, 65, 84 subdural, 153 corticothalamic, 265 P1: FAW/FAW P2: FAW JWDD017-IND JWDD017-ORahilly July 5, 2006 21:19 Char Count= 0

358 INDEX

cuneatus, 248, 251 staged, 88, 98, 106, 123, 166, 248, 249 Ventricle(s), 202, 244, 270 cuneocerebellar, 248 striatothalamic, 267 fourth, 87, 95, 225, 244 dentatorubral, 171 tectobulbar, 98, 249 lateral, 96, 211, 244, 269, 270, 298, diencephalic, 268 thalamocortical, 265, 286 299 Tract(s) thalamostriatal, 166, 267 olfactory, 160, 191, 244, 276, 340 gracilis, 248, 251 trigeminocerebellar, 98 optic, 62, 67, 91, 89, 192, 232, 340 habenulo-interpeduncular, 98, 106, 123, 137, trigeminospinal, 164, 249 third, 88, 99, 187, 244, 259, 267 159, 166, 177, 197, 286 ventral longitudinal, 63, 98 Vermis, 247, 279 hypothalamo-thalamic, 166 vestibulocerebellar, 106 Vertebra(e), 24, 154, 209, 226, 227 lateral longitudinal, 88 vestibulospinal, 248, 249 Vesicle(s) lateral olfactory, 304 Tube, neural, 36, 37, 40, 73, 74, 175, 193 lens, 79 mamillotegmental, 166, 286 Tubercle optic, 50, 57, 62–64 mamillothalamic, 166, 197 interpeduncular, 134, 170 otic, 53, 64 medial longitudinal, 75, 88, 98, 106 olfactory, 103,118, 123, 137, 140, 157, 276 umbilical, 22, 35, 150, 188 medial tectobulbar, 123 Vorderlappen of epiphysis, 120, 161 mesencephalic of trigeminal nerve, 88, 98, V 106, 123, 164, 249 Vein(s) W olfactory, 276 capital, 59 Waardenburg syndrome, 257 olivocerebellar, 268 cardinal, 59, 70 Weight of brain, 305 optic, 192, 199, 223 omphalo-enteric, 59 Willis. See Circulus arteriosus preopticohypothalamic, 88, 106, 123, 166 staged, 59, 70, 183 preopticohypothalamo-tegmental, 88, 98, umbilical, 32, 54, 59, 70 106, 137 Velum Z pyramidal, 249 interpositum, 308 Zona limitans intrathalamica (See also Ridge, solitarius, 123, 164, 165, 215, 248, 249 superior medullary, 101, 119, 149, 246 marginal, and Sulcus medius, 131, 139, spinothalamic, 181 transversum, 87, 95, 119, 340 166, 191, 198, 340