Clinical Neuroembryology: Development and Developmental Disorders of The Human Central Nervous System Hans J. Ten Donkelaar

Clinical Neuroembryology:
Development and Developmental

Disorders of the Human Central
Nervous System Hans J. Ten Donkelaar
Visit to download the full and correct content document:
https://ebookmeta.com/product/clinical-neuroembryology-development-and-developm
ental-disorders-of-the-human-central-nervous-system-hans-j-ten-donkelaar/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...
The Human Brain during the First Trimester 40- to 42-mm

Crown-Rump Lengths: Atlas of Human Central Nervous
System Development 1st Edition Shirley A. Bayer
https://ebookmeta.com/product/the-human-brain-during-the-first-
trimester-40-to-42-mm-crown-rump-lengths-atlas-of-human-central-
nervous-system-development-1st-edition-shirley-a-bayer/
WHO Classification of Tumours Central Nervous System

Tumours 5th Edition Brat
https://ebookmeta.com/product/who-classification-of-tumours-
central-nervous-system-tumours-5th-edition-brat/
Therapeutic Development in the Absence of Predictive

Animal Models of Nervous System Disorders Proceedings
of a Workshop 1st Edition And Medicine Engineering
National Academies Of Sciences
https://ebookmeta.com/product/therapeutic-development-in-the-
absence-of-predictive-animal-models-of-nervous-system-disorders-
proceedings-of-a-workshop-1st-edition-and-medicine-engineering-
national-academies-of-sciences/
Financial Incentives to Encourage Development of

Therapies That Address Unmet Medical Needs for Nervous
System Disorders Workshop Summary 1st Edition Institute
Of Medicine
https://ebookmeta.com/product/financial-incentives-to-encourage-
development-of-therapies-that-address-unmet-medical-needs-for-
nervous-system-disorders-workshop-summary-1st-edition-institute-
Viral and Fungal Infections of the Central Nervous
System A Microbiological Perspective 1st Edition Hiba
Sami Safiya Firoze Parvez A Khan
https://ebookmeta.com/product/viral-and-fungal-infections-of-the-
central-nervous-system-a-microbiological-perspective-1st-edition-
hiba-sami-safiya-firoze-parvez-a-khan/
Harnessing Mobile Devices for Nervous System Disorders:

Proceedings of a Workshop 1st Edition And Medicine
Engineering National Academies Of Sciences
https://ebookmeta.com/product/harnessing-mobile-devices-for-
nervous-system-disorders-proceedings-of-a-workshop-1st-edition-
and-medicine-engineering-national-academies-of-sciences/
Diseases of the Nervous System, 2nd Edition Harald

Sontheimer
https://ebookmeta.com/product/diseases-of-the-nervous-system-2nd-
edition-harald-sontheimer/
Glycobiology of the Nervous System 2nd Edition Cara-

Lynne Schengrund
https://ebookmeta.com/product/glycobiology-of-the-nervous-
system-2nd-edition-cara-lynne-schengrund/
Primer on the Autonomic Nervous System Italo Biaggioni

(Editor)
https://ebookmeta.com/product/primer-on-the-autonomic-nervous-
system-italo-biaggioni-editor/
Hans J. ten Donkelaar
Martin Lammens
Akira Hori
Clinical
Neuroembryology
Development and Developmental Disorders of
the Human Central Nervous System
Third Edition
Clinical Neuroembryology
Hans J. ten Donkelaar • Martin Lammens • Akira Hori
Clinical
Neuroembryology
Development and Developmental Disorders
of the Human Central Nervous System
Third Edition
With Contributions by
Eleonora Aronica Willy O. Renier

Mireille N. Bekker Kohei Shiota
Marianna Bugiani Jeroen Smits
Andrew J. Copp Tetsuya Takakuwa
Johannes R. M. Cruysberg Paul A. Trainor
Wilfred F. A. den Dunnen Hans van Bokhoven
Bernd Fritzsch Ton van der Vliet
Kyoko Itoh Lana Vasung
Karin Kamphuis- van Ulzen Christl Vermeij-Keers
Irene M. J. Mathijssen Pieter Wesseling
Hajime Miyata Michèl Willemsen
Zoltán Molnár Shigehito Yamada
Ronald Pennings
Hans J. ten Donkelaar Martin Lammens
Department of Neurology and Donders Department of Pathology
Institute for Brain, Cognition and Behaviour University Hospital Antwerp
Radboud University Medical Centre and University of Antwerp
Radboud University Antwerp, Belgium
Nijmegen, The Netherlands
Akira Hori
Division of Neuropathology
Institute for Pathology
Hannover Medical School
Hannover, Germany
ISBN 978-3-031-26097-1 ISBN 978-3-031-26098-8 (eBook)

https://doi.org/10.1007/978-3-031-26098-8
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland
AG 2006, 2014, 2023
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the
whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustra-
tions, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or
information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar meth-
odology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors
or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Illustrations by Ad Gruter
Cover illustration by Ad Gruter (Nieuwegein, The Netherlands)
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
V
Preface
Apart from a general updating of the extensive literature on developmental neurobiol-

ogy, neurogenetics, imaging and developmental neuropathology between 2014 and
2022, in this third edition, more emphasis has been given to: (a) the developmental
ontology of the brain based on the prosomeric model; (b) imaging of the embryonic
brain (early prenatal diagnosis by ultrasound); (c) an expanded account of foetal brain
development and imaging by MRI, emphasizing the role of the subplate; (d) DTI stud-
ies on the development of major fibre connections such as the pyramidal tract, the
corpus callosum and the long association tracts, with examples in developmental dis-
orders; and (e) the impact of the next-generation sequencing techniques in research
and diagnosis. Moreover, new classifications of brain disorders have been implemented
for disorders of white matter and neurocristopathies. Throughout the book, several
new Clinical Cases have been added.
Several colleagues kindly contributed as new co-authors their expertise to this third
edition, including Marianna Bugiani (Amsterdam), Andrew Copp (London), Wilfred
den Dunnen (Groningen), Bernd Fritzsch (Iowa City), Hajime Miyata (Akita), Zoltán
Molnár (Oxford), Jeroen Smits (Utrecht), Tetsuya Takakuwa (Kyoto), Paul Trainor
(Kansas City) and Lana Vasung (Boston). They all contributed new Clinical Cases
and/or new illustrations. For other new Clinical Cases, we are grateful to Paul de Cock
(Leuven), Sophie Nambot and Christel Thauvin-Robinet (Dijon), Sung-Hee Park
(Jeonju), Cory Pfeifer (Dallas) and Ristsuko Pooh (Osaka). New illustrations were also
kindly provided by Filippo Arrigoni (Lecco), Trygve Bakken (Seattle), Sandeep Bhuta
(Southport), Lucas Boer (Nijmegen), Brenda Bohnsack (Chicago), Victor Borrell (Ali-
cante), Victor Chizhikov (Memphis), Gavin Clowry (Newcastle), Soma Dash and
Mark Miller (Kansas City), Jessica Dubois (Gif-sur-Yvette), Karen Elliott (Iowa City),
Joel Glover (Oslo), Anna Hoerder-Suabedissen (Oxford), Hao Huang (Philadelphia),
Camillo Jaimes (Boston), Ivica Kostović and Željka Krsnik (Zagreb), Yulia Markitan-
tova (Moscow), Evanthia Nikolopoulou (London), Cory Pfeifer (Dallas), Sung-Hee
Park (Jeonju), Ritsuko Pooh (Osaka), Luis Puelles and José Luis Ferran (Murcia),
Michael Skeide and Angela Friederici (Leipzig), Merina Varghese and Patrick Hof
(New York), Martijn van den Heuvel (Amsterdam), Jan Voogd (Oegstgeest), Charles
Watson (Perth), Mengqing Xiang (Piscataway), Zhengang Yang, Suijuan Zhong and
Xiaoqun Wang (Shanghai). As always, new illustrations were prepared by Ad Gruter
(Nieuwegein).

Martin Lammens
Antwerp, Belgium
Akira Hori
Hannover, Germany
Preface to the Second Edition
Apart from a general updating of the extensive literature on developmental neurobiol-

ogy, neurogenetics, imaging and developmental neuropathology between 2005 and
2013, more emphasis has been given to: (a) imaging of the embryonic brain (early
prenatal diagnosis by ultrasound); (b) imaging of the foetal brain by MRI; (c) DTI
studies on the development of major fibre connections such as the pyramidal tract and
the corpus callosum; and (d) the impact of newer genetic techniques such as whole
exome/genome sequencing. Moreover, new classifications of brain disorders have been
implemented such as a new classification of midbrain-hindbrain developmental disor-
ders and entire new families of disorders such as ciliopathies and dystroglycanopathies.
Throughout the book, several new Clinical Cases have been added. Several colleagues
kindly contributed as new co-authors their expertise to this second edition, including
Eleonora Aronica (Amsterdam), Mireille Bekker (Nijmegen), Kyoko Itoh (Kyoto),
Karin Kamphuis-van Ulzen (Nijmegen), Irene Mathijssen (Rotterdam), Ronald Pen-
nings and Hans van Bokhoven (Nijmegen), Patrick van der Voorn (Amsterdam) and
Shigehito Yamada (Kyoto). They also contributed new Clinical Cases. For other new
Clinical Cases, the help of Remke Dullemond (Rotterdam), Janet Eyre (Newcastle),
Floris Groenendaal (Utrecht), Gregor Kasprian (Vienna), Hajime Miyata (Akita),
Peter Nikkels (Utrecht), Tetsu Niwa (Yokohama), Andrea Poretti (Zurich), Ritsuko
Pooh (Osaka), Goran Simić (Zagreb) and Marjolein Willemsen (Nijmegen) is grate-
fully acknowledged. New illustrations were also kindly provided by Marco Catani and
Michel Thiebaut de Schotten (London), Cyrille Ferrier (Utrecht), Hao Huang (Dal-
las), Ole Kiehn (Stockholm), Grace Lai (New York), Anna Lavezzi (Milan) and Maria
Thom (London). A long weekend with Luis Puelles in Murcia greatly helped the first
author to implement new findings on the prosomeric model of the developing brain.

Martin Lammens
Edegem, Belgium
Akira Hori
Toyohashi, Japan
VII
Preface to the First Edition
The spectacular progress in developmental neurobiology, the tremendous advances in

(neuro) genetics and the high resolution of the modern imaging techniques applicable
to developmental disorders of the human brain and spinal cord have created a growing
interest in the developmental history of the central nervous system (CNS). This new
book provides a comprehensive overview of the development of the human CNS in the
context of its many developmental disorders due to genetic, environmental and
hypoxic/ischaemic causes. The book contains three general, introductory chapters in
which an overview of the development of the human brain and spinal cord, a summary
of mechanisms of development as obtained in experimental studies in various inverte-
brates and vertebrates, and an overview of the causes of congenital malformations
with some notes on prenatal diagnosis are presented. The developmental disorders of
the human brain and spinal cord are presented in a regional, more or less segmental
way, starting with neurulation and the neural tube defects, and ending with develop-
mental disorders of the cerebral cortex. These chapters are abundantly illustrated with
clinical case studies with imaging data and, when available, postmortem verification of
the developmental disorders involved. The book is intended for advanced medical stu-
dents, and all those clinicians working with children and adults with developmental
disorders of the CNS.
This book would not have been possible without the help of many colleagues in
the Netherlands and from abroad. Their help is gratefully acknowledged. Most of
the neuropathological material comes from the extensive collections of Drs. Akira
Hori and Martin Lammens. Many cases were kindly provided by Drs. Pieter Wes-
seling (Nijmegen), Gerard van Noort (Enschede) and Kohei Shiota (Kyoto). Pho-
tographical assistance was provided by Mrs. Roelie de Boer-van Huizen (Nijmegen),
Mrs. Chigako Uwabe (Kyoto) and Richard Rieksen (Enschede). Material for the
clinical case studies was provided by many clinical colleagues, including Drs. Ells-
worth C. Alvord Jr. (Seattle), Harm-Gerd Blaas (Trondheim), Cor Cremers and
Hans Cruysberg (Nijmegen), Mark D’hooghe (Bruges), Jennian Geddes (London),
Ben Hamel (Nijmegen), Frans Hoevenaars (Nijmegen), Nomdo Jansonius (Gron-
ingen), Akiyoshi Kakita (Niigata), Max Kros (Rotterdam), Hajime Miyata (Tot-
tori), Masashi Mizuguchi (Tokyo), Reinier Mullaart, Willy Renier and Jan Rotteveel
(Nijmegen), Harvey B. Sarnat (Calgary), Ben Semmekrot (Nijmegen), Waney
Squier (Oxford), Sachio Takashima (Fukuoka), Rudy van Coster and Caroline Van
den Broecke (Gent), Christl Vermeij-Keers (Rotterdam), Michel Willemsen (Nijme-
gen) and Mieko Yoshioka (Kobe). Imaging data were kindly provided by Drs.
Harm-Gerd Blaas (Trondheim), Berit Verbist (Leiden), John van Vugt and collabo-
rators (Amsterdam), Henk Thijssen and Ton van der Vliet (Nijmegen), and Guido
Wilms (Leuven). Several figures were contributed by Drs. Jo Curfs (Nijmegen),
Marieke de Heer and Jeannette Hoogeboom (Rotterdam), Raoul Hennekam
(Amsterdam), Jan E. Jirasek (Prague), Enrico Marani (Leiden), Loreta Medina
(Murcia), Zoltán Molnár (Oxford), Ronan O’Rahilly (Villars-sur-Glâne),
Annemieke Potters (Deventer), Kohei Shiota (Kyoto), Henny van Straaten (Maas-
tricht), Michiel Vaandrager (Rotterdam), Jan Voogd (Oegstgeest) and Shigehito
Yamada (Kyoto). Most of the drawings were made by Mrs. Marlu de Leeuw and
Mr. Ad Gruter. Financial support was generously provided by the “Stichting Neu-
rologie en Wetenschap” of the Department of Neurology (Head: Prof. Dr. George
VIII Preface to the First Edition
W.A.M. Padberg) and the Department of Pathology (Head: Prof. Dr. Han van
Krieken), both of the Radboud University Nijmegen Medical Centre, supporting
the costs of the drawings. The Japan Society for the Promotion of Science granted
the first author a short-term fellowship in May 2004 at the Congenital Anomaly
Research Centre (Head: Prof. Dr. Kohei Shiota) of Kyoto University.

Martin Lammens
Akira Hori
Toyohashi, Japan
IX
Contents
1 Overview of the Development of the Human Brain and Spinal Cord...............1

Hans J. ten Donkelaar, Tetsuya Takakuwa, Lana Vasung, Shigehito Yamada,
Kohei Shiota, and Ton van der Vliet
1.1 Introduction................................................................................................................................................ 3
1.2 Major Stages in the Development of the Human Brain and Spinal Cord............................... 3
1.3 The First Three Weeks of Development............................................................................................. 12
1.3.1 Implantation.......................................................................................................................................................12
1.3.2 Gastrulation.........................................................................................................................................................13
1.3.3 Folding of the Embryo.....................................................................................................................................16
1.4 Neurulation................................................................................................................................................. 16
1.5 Development of the Spinal Cord.......................................................................................................... 19
1.6 Pattern Formation of the Brain............................................................................................................. 20
1.7 Early Development of the Brain........................................................................................................... 21
1.7.1 Imaging of the Embryonic Brain..................................................................................................................21
1.7.2 Neuromeres.........................................................................................................................................................22
1.7.3 The Ganglionic Eminences............................................................................................................................28
1.8 Foetal Development of the Brain......................................................................................................... 29
1.8.1 The Cerebellum..................................................................................................................................................30
1.8.2 The Cerebral Cortex..........................................................................................................................................36
1.8.3 Cerebral Commissures.....................................................................................................................................43
1.8.4 Imaging of the Foetal Brain...........................................................................................................................44
1.9 Development of the Meninges and Choroid Plexuses................................................................. 45
1.10 Development of the Blood Supply of the Brain.............................................................................. 48
1.11 Development of Fibre Tracts and Their Myelination..................................................................... 55
1.11.1 Development of Fibre Tracts.........................................................................................................................55
1.11.2 Development of Myelination........................................................................................................................58
1.11.3 Prenatal Motor Behaviour..............................................................................................................................61
1.12 The Foetal Connectome.......................................................................................................................... 63
References............................................................................................................................................................ 66
2 Mechanisms of Development.....................................................................................................77
Hans J. ten Donkelaar and Bernd Fritzsch
2.1 Introduction................................................................................................................................................ 79
2.2 Neural Induction........................................................................................................................................ 79
2.2.1 The Spemann-Mangold Organizer.............................................................................................................79
2.2.2 The Molecular Basis of Neural Induction..................................................................................................82
2.2.3 Polarity and the Establishment of the Neuraxis.....................................................................................82
2.2.4 Neural Induction in Amniote Embryos......................................................................................................83
2.2.5 Specific Pathways for Head Induction.......................................................................................................84
2.3 Cell Lineage Studies and Fate Mapping............................................................................................ 85
2.4 Pattern Formation..................................................................................................................................... 88
2.4.1 Regionalization of the Forebrain.................................................................................................................92
2.4.2 The Intrathalamic Limiting Zone.................................................................................................................93
2.4.3 The Midbrain-Hindbrain Boundary Organizer........................................................................................94
2.4.4 Segmentation of the Hindbrain...................................................................................................................96
2.5 Specification of Cell Fate......................................................................................................................... 99
2.5.1 Specification of Cell Fate in the Spinal Cord............................................................................................100
2.5.2 Specification of Cell Fate in the Hindbrain...............................................................................................102
2.5.3 Specification of Cell Fate in the Midbrain.................................................................................................110
2.5.4 Specification of Cell Fate in the Diencephalon.......................................................................................110
2.5.5 Specification of Cell Fate in the Hypothalamus.....................................................................................111
X Contents
2.5.6 Specification of Cell Fate in the Telencephalon......................................................................................112

2.5.7 The Transcriptomic Approach to the Developing Central Nervous System................................114
2.6 Neurogenesis, Gliogenesis and Migration........................................................................................ 115
2.6.1 Neurogenesis: Primary and Secondary Proliferative Compartments.............................................115
2.6.2 Gliogenesis..........................................................................................................................................................121
2.6.3 Migration..............................................................................................................................................................123
2.7 Axon Outgrowth and Guidance........................................................................................................... 125
2.7.1 Pioneer Fibres.....................................................................................................................................................125
2.7.2 The Guidance of Axons to Their Targets....................................................................................................126
2.7.3 Axon Guidance at Choice Points.................................................................................................................129
2.7.4 Commissure Formation..................................................................................................................................130
2.7.5 Formation of Thalamocortical and Corticofugal Projections............................................................131
2.7.6 Formation of Topographic Maps.................................................................................................................134
2.7.7 Genetic Approaches of Neural Circuits in Mice......................................................................................136
2.7.8 Human Disorders of Axon Guidance..........................................................................................................142
2.8 Programmed Cell Death.......................................................................................................................... 145
References............................................................................................................................................................ 147
3 Causes of Congenital Malformations.....................................................................................171

Martin Lammens, Mireille Bekker, Michèl Willemsen, Marianna Bugiani,
Hans van Bokhoven, Karin Kamphuis-van Ulzen, and Hans J. ten Donkelaar
3.1 Introduction................................................................................................................................................ 173
3.2 Causes of Congenital Malformations................................................................................................. 173
3.2.1 Genetic Disorders..............................................................................................................................................173
3.2.2 Environmental Causes.....................................................................................................................................183
3.3 Prenatal Diagnosis.................................................................................................................................... 190
3.3.1 Ultrasound and Magnetic Resonance Examination.............................................................................190
3.3.2 Invasive Tests......................................................................................................................................................196
3.3.3 Non-Invasive Tests............................................................................................................................................199
3.3.4 Laboratory Genetic Diagnosis......................................................................................................................199
3.4 Inborn Errors of Metabolism Affecting the CNS............................................................................. 203
3.4.1 Inborn Errors of Metabolism That Mainly Affect the CNS...................................................................203
3.4.2 Multisystem Disorders with CNS Involvement.......................................................................................204
3.5 Disorders of White Matter...................................................................................................................... 212
3.6 Vascular Disorders.................................................................................................................................... 222
3.7 Congenital Tumours................................................................................................................................. 236
3.8 Classifications of CNS Malformations................................................................................................. 239
References............................................................................................................................................................ 240
4 Neurulation and Neural Tube Defects...................................................................................249

Hans J. ten Donkelaar, Andrew J. Copp, Mireille Bekker, Willy O. Renier,
Akira Hori, and Kohei Shiota
4.1 Introduction................................................................................................................................................ 251
4.2 Primary Neurulation................................................................................................................................. 251
4.2.1 Primary Neurulation in Chick and Mammalian Embryos....................................................................251
4.2.2 Primary Neurulation in Human Embryos.................................................................................................255
4.3 Secondary Neurulation........................................................................................................................... 259
4.4 Causation of Neural Tube Defects....................................................................................................... 261
4.4.1 Isolated and Non-isolated Neural Tube Defects.....................................................................................261
4.4.2 Defined Genetic Causation of Neural Tube Defects.............................................................................261
4.4.3 Multifactorial Causation of Human Neural Tube Defects...................................................................264
4.4.4 Evidence from Genetic Mouse Models for Neural Tube Defects......................................................264
4.4.5 Genetic Loci Implicated in Human Neural Tube Defects....................................................................266
4.4.6 Environmental Factors in Neural Tube Defects......................................................................................268
4.4.7 Causation of NTD Subtypes...........................................................................................................................269
XI
Contents
4.4.8 Foetal Sex and Neural Tube Defects...........................................................................................................269

4.5 Prenatal Diagnosis and Foetal Therapy............................................................................................. 269
4.6 Cranial Neural Tube Defects.................................................................................................................. 272
4.6.1 Anencephaly.......................................................................................................................................................272
4.6.2 Encephaloceles and Cranial Meningoceles.............................................................................................277
4.7 Spinal Neural Tube Defects.................................................................................................................... 286
4.7.1 Myeloceles, Myelomeningoceles and Spinal Meningoceles.............................................................286
4.7.2 Spinal Lipomas...................................................................................................................................................290
4.7.3 Spina Bifida Occulta and Related Disorders............................................................................................293
4.7.4 The Tethered Spinal Cord Syndrome.........................................................................................................293
4.8 The Chiari Malformations....................................................................................................................... 295
4.9 Caudal Dysgenesis.................................................................................................................................... 299
References............................................................................................................................................................ 303
5 The Neural Crest and Craniofacial Malformations........................................................313

Christl Vermeij-Keers, Irene M. J. Mathijssen, Paul Trainor,
and Hans J. ten Donkelaar
5.1 Introduction................................................................................................................................................ 315
5.2 Induction and Epithelial-to-Mesenchymal Transition (EMT) of the Neural Crest................ 316
5.3 Derivatives of the Neural Crest............................................................................................................. 317
5.3.1 The Cranial Neural Crest.................................................................................................................................318
5.3.2 The Trunk Neural Crest....................................................................................................................................321
5.4 Craniofacial Development..................................................................................................................... 323
5.4.1 Early Development of the Face....................................................................................................................323
5.4.2 Development of the Pharyngeal Arches..................................................................................................327
5.4.3 Further Development of the Face...............................................................................................................328
5.4.4 Development of the Skull..............................................................................................................................334
5.5 Neurocristopathies................................................................................................................................... 337
5.5.1 Neurocristopathies Due to Defects in Cranial Neural Crest Cell Formation.................................339
5.5.2 Neurocristopathies Due to Defects in Cranial Neural Crest Cell Migration..................................342
5.5.3 Neurocristopathies Due to Defects in Cranial Neural Crest Cell Differentiation........................344
5.6 Retinoic Acid Syndrome.......................................................................................................................... 345
5.7 Cranial Ciliopathies................................................................................................................................... 346
5.8 Holoprosencephaly.................................................................................................................................. 346
5.9 Abnormal Development of the Skull with CNS Manifestations................................................ 352
5.9.1 The Craniosynostoses......................................................................................................................................352
5.9.2 Cranial Base Abnormalities............................................................................................................................362
References............................................................................................................................................................ 362
6 Development and Developmental Disorders of the Spinal Cord........................379

Hans J. ten Donkelaar, Kyoko Itoh, Hajime Miyata, and Akira Hori
6.1 Introduction................................................................................................................................................ 381
6.2 Gross Development of the Spinal Cord............................................................................................. 381
6.2.1 A Few Notes on the Development of the Vertebral Column.............................................................383
6.2.2 Ascensus Medullae...........................................................................................................................................384
6.3 Developmental Events in Spinal Neuronal Populations.............................................................. 385
6.4 The Specification of Cell Fates in the Spinal Cord.......................................................................... 387
6.4.1 Specification of Neuronal Fates in the Ventral Spinal Cord................................................................388
6.4.2 Patterning Cell Types in the Dorsal Spinal Cord.....................................................................................396
6.5 Development of Dorsal Root Projections......................................................................................... 397
6.6 Development of Spinal Ascending Projections.............................................................................. 400
6.7 Development of Descending Projections to the Spinal Cord.................................................... 402
6.7.1 Descending Projections from the Brain Stem.........................................................................................402
6.7.2 Development of the Pyramidal Tract in Rodents...................................................................................406
6.7.3 Development of the Pyramidal Tract in Macaque Monkeys..............................................................407
XII Contents
6.7.4 Development of the Human Pyramidal Tract.........................................................................................408

6.8 Developmental Anomalies of the Spinal Cord................................................................................ 416
6.8.1 Anomalies of Histogenesis............................................................................................................................416
6.8.2 Absence of Limbs..............................................................................................................................................416
6.8.3 Duplications of the Spinal Cord...................................................................................................................419
6.8.4 Neurenteric Cysts..............................................................................................................................................422
6.8.5 Syringomyelia.....................................................................................................................................................426
6.8.6 Abnormal Course or Absence of Fibre Tracts..........................................................................................426
References............................................................................................................................................................ 433
7 Development and Developmental Disorders of the Brain Stem.........................445

Hans J. ten Donkelaar, Bernd Fritzsch, Johannes R. M. Cruysberg,
Ronald J. E. Pennings, Jeroen J. Smits, and Martin Lammens
7.1 Introduction................................................................................................................................................ 447
7.2 Pattern Formation and Segmentation of the Brain Stem............................................................ 448
7.2.1 Pattern Formation of the Brain Stem.........................................................................................................448
7.2.2 Segmentation of the Brain Stem.................................................................................................................453
7.2.3 Progenitor Zones of the Brain Stem...........................................................................................................455
7.3 Development and Developmental Disorders of the Cranial Nerves....................................... 460
7.3.1 Development of the Cranial Nerves and Their Nuclei in Rodents...................................................461
7.3.2 Development of Cranial Nerve Ganglia in Rodents..............................................................................464
7.3.3 Development and Developmental Disorders of the Human Cranial Nerves..............................464
7.3.4 Congenital Cranial Dysinnervation Disorders........................................................................................466
7.3.5 Development of the Brain Stem Respiratory Circuit............................................................................474
7.4 Development of the Auditory System............................................................................................... 477
7.4.1 Development of the Ear..................................................................................................................................478
7.4.2 Development of the Auditory Projections...............................................................................................485
7.4.3 Molecular Basis of Inner Ear Development..............................................................................................486
7.4.4 Developmental Disorders of the Auditory System...............................................................................492
7.4.5 Genes Associations with Deafness.............................................................................................................501
References............................................................................................................................................................ 507
8 Development and Developmental Disorders of the Human Cerebellum......523

Hans J. ten Donkelaar, Wilfred F. A. den Dunnen, Martin Lammens,
Pieter Wesseling, Michèl Willemsen, and Akira Hori
8.1 Introduction................................................................................................................................................ 525
8.2 Some Notes on the Anatomy of the Cerebellum............................................................................ 525
8.2.1 Subdivision..........................................................................................................................................................525
8.2.2 Cerebellar Cell Types and Circuitry.............................................................................................................527
8.2.3 Compartmentalization....................................................................................................................................528
8.2.4 Major Fiber Connections................................................................................................................................528
8.2.5 Precerebellar Nuclei.........................................................................................................................................529
8.3 Morphogenesis of the Cerebellum...................................................................................................... 530
8.4 Four Basic Steps in the Histogenesis of the Cerebellum.............................................................. 532
8.4.1 Characterization of the Cerebellar Territory............................................................................................532
8.4.2 Formation of Two Proliferative Compartments......................................................................................541
8.4.3 Inward Migration of Granule Cells..............................................................................................................547
8.4.4 Differentiation of Cerebellar Neurons.......................................................................................................551
8.5 Development of the Precerebellar Nuclei......................................................................................... 555
8.5.1 Upper Precerebellar System..........................................................................................................................555
8.5.2 Lower Precerebellar System..........................................................................................................................555
8.5.3 Inferior Olivary Malformations.....................................................................................................................557
8.6 Mouse Mutants with Cerebellar Malformation............................................................................... 558
8.7 Developmental Disorders of the Cerebellum.................................................................................. 560
8.7.1 Midline or Vermis Malformations................................................................................................................562
XIII
Contents
8.7.2 Cerebellar Hypoplasia.....................................................................................................................................572

8.7.3 Pontocerebellar Hypoplasias........................................................................................................................572
8.7.4 Cortical Dysplasias............................................................................................................................................579
8.8 The Cerebellum and Cognition............................................................................................................. 580
References............................................................................................................................................................ 582
9 Development and Developmental Disorders of the Forebrain............................595

Hans J. ten Donkelaar, Martin Lammens, Johannes R. M. Cruysberg,
Karin Kamphuis-van Ulzen, Akira Hori, Kohei Shiota, Kyoko Itoh,
and Michèl Willemsen
9.1 Introduction................................................................................................................................................ 597
9.2 Prosomeres and Pattern Formation of the Forebrain................................................................... 598
9.3 Development of the Diencephalon..................................................................................................... 601
9.3.1 Development of the Thalamus.....................................................................................................................601
9.3.2 Development of the Prethalamus...............................................................................................................607
9.3.3 Development of Thalamocortical Projections........................................................................................607
9.4 Development of the Hypothalamus, the Preoptic Region and the Pituitary Gland........... 609
9.4.1 Development of the Hypothalamus and the Preoptic Region.........................................................609
9.4.2 Development of the Pituitary Gland..........................................................................................................612
9.4.3 Developmental Disorders of the Hypothalamus and the Pituitary Gland...................................614
9.5 Development of the Visual System..................................................................................................... 620
9.5.1 Development of the Eye.................................................................................................................................620
9.5.2 Congenital Malformations of the Eye........................................................................................................629
9.5.3 Development of the Visual Projections.....................................................................................................636
9.6 Overview of the Development of the Telencephalon................................................................... 639
9.6.1 Dorsoventral Regionalization of the Telencephalon............................................................................643
9.6.2 The Pallial-Subpallial Boundary...................................................................................................................646
9.6.3 Dorsal Telencephalic Patterning..................................................................................................................646
9.6.4 Ventral Telencephalic Patterning.................................................................................................................647
9.6.5 Radial and Tangential Migration in the Telencephalon.......................................................................649
9.7 Development of the Rhinencephalon................................................................................................ 650
9.7.1 Development of the Main Olfactory System...........................................................................................651
9.7.2 Development of the Accessory Olfactory System.................................................................................654
9.8 The Prosencephalies................................................................................................................................ 655
9.8.1 Aprosencephaly.................................................................................................................................................655
9.8.2 Holoprosencephaly..........................................................................................................................................659
9.8.3 Septo-Optic Dysplasia.....................................................................................................................................674
9.8.4 Isolated Arhinencephaly.................................................................................................................................675
9.9 Development and Developmental Disorders of the Basal Ganglia......................................... 677
9.9.1 Development of the Basal Ganglia.............................................................................................................677
9.9.2 Congenital and Acquired Disorders of the Basal Ganglia...................................................................685
9.10 Development and Developmental Disorders of the Amygdala................................................ 698
9.10.1 Development of the Amygdala....................................................................................................................698
9.10.2 Developmental Disorders of the Amygdala............................................................................................699
References............................................................................................................................................................ 701
10 Development and Developmental Disorders of the Cerebral Cortex..............725

Hans J. ten Donkelaar, Lana Vasung, Zoltán Molnár, Eleonora Aronica,
Martin Lammens, Hans van Bokhoven, Karin Kamphuis-van Ulzen,
and Akira Hori
10.1 Introduction................................................................................................................................................ 727
10.2 Overview of the Cerebral Cortex.......................................................................................................... 727
10.2.1 The Isocortex......................................................................................................................................................727
10.2.2 The Mesocortex.................................................................................................................................................731
10.2.3 The Allocortex....................................................................................................................................................731
XIV Contents
10.3 Overview of Main Cortical Connections............................................................................................ 733

10.3.1 Thalamocortical Projections..........................................................................................................................734
10.3.2 The Pyramidal Tract..........................................................................................................................................734
10.3.3 The Corpus Callosum and the Anterior Commissure...........................................................................735
10.3.4 Long Association Fibres..................................................................................................................................737
10.4 Development of the Isocortex.............................................................................................................. 739
10.4.1 Development of the Isocortex in Rodents...............................................................................................741
10.4.2 Transcriptomic Approach to the Developing Cerebral Cortex.........................................................752
10.4.3 Cortical Folding..................................................................................................................................................754
10.4.4 Development of the Human Isocortex......................................................................................................755
10.5 Development of the Hippocampal Formation................................................................................ 769
10.6 Development of the Main Cortical Connections............................................................................ 775
10.6.1 Development of Thalamocortical Projections........................................................................................775
10.6.2 Development of the Pyramidal Tract.........................................................................................................778
10.6.3 Development of the Corpus Callosum......................................................................................................779
10.6.4 Development of Long Association Fibres................................................................................................784
10.7 Malformations of Cortical Development.......................................................................................... 785
10.7.1 Malformations Due to Abnormal Neuronal/Glial Proliferation/Apoptosis...................................788
10.7.2 Malformations Due to Abnormal Cortical Migration...........................................................................798
10.7.3 Malformations Due to Abnormal Cortical Organization and Late Migration..............................816
10.7.4 Disorders of Cortical Development and Epilepsy..................................................................................818
10.7.5 Vascular Disorders.............................................................................................................................................830
10.7.6 Disorders of Cortical Connectivity..............................................................................................................832
10.7.7 Intellectual Disability.......................................................................................................................................839
10.7.8 Neurobehavioural Disorders.........................................................................................................................848
10.8 Development of Language and Congenital Language Disorders............................................ 853
10.8.1 Anatomical and Functional Differences Between the Cerebral Hemispheres............................853
10.8.2 Language and the Brain.................................................................................................................................854
10.8.3 Language Pathways.........................................................................................................................................855
10.8.4 Ontogeny of Language...................................................................................................................................859
10.8.5 Congenital Language Disorders..................................................................................................................860
References............................................................................................................................................................ 862
Supplementary Information
Index................................................................................................................................................ 895
XV
Contributors
Eleonora Aronica, M.D., Ph.D. Department of Pathology, Amsterdam UMC, Amsterdam,

The Netherlands
Mireille Bekker, M.D., Ph.D. Department of Obstetrics, University Medical Centre Utrecht,
Utrecht, The Netherlands
Marianna Bugiani, M.D., Ph.D. Department of Pathology, Amsterdam UMC, Amsterdam,

The Netherlands
Andrew J. Copp, Ph.D. Division of Biosciences, Great Ormond Street Institute of Child
Health, University College London, London, UK
Johannes R. M. Cruysberg, M.D., Ph.D. Department of Ophthalmology, Radboud University

Medical Centre, Nijmegen, The Netherlands
Wilfred F. A. den Dunnen, M.D., Ph.D. Department of Pathology and Medical Biology, Univer-
sity Medical Centre Groningen, Groningen, The Netherlands
Bernd Fritzsch, Ph.D. Departments of Biology and Otolaryngology, University of Iowa, Iowa,
IA, USA
Akira Hori, M.D., Ph.D. Department of Neuropathology, Medizinische Hochschule Hannover,

Hannover, Germany
Kyoko Itoh, M.D., Ph.D. Department of Pathology and Applied Neurobiology, Kyoto Prefec-
tural University of Medicine, Kyoto, Japan
Karin Kamphuis-van Ulzen, M.D. Department of Radiology and Nuclear Medicine, Radboud
University Medical Centre, Nijmegen, The Netherlands
Martin Lammens, M.D., Ph.D. Department of Pathology, University Hospital Antwerp, Ant-
werp, Belgium
Irene M. J. Mathijssen, M.D., Ph.D. Department of Plastic & Reconstructive & Hand Surgery,
Erasmus MC, Rotterdam, The Netherlands
Hajime Miyata, M.D., Ph.D. Department of Neuropathology, Research Institute for Brain and
Blood Vessels, Akita Cerebrospinal and Cardiovascular Centre, Akita City, Japan
Zoltán Molnár, M.D., Ph.D. Department of Physiology, Anatomy and Genetics, University of
Oxford, Oxford, UK
Ronald J. E. Pennings, M.D., Ph.D. Department of Otorhinolaryngology, Radboud University

Medical Centre, Nijmegen, The Netherlands
Willy O. Renier, M.D., Ph.D. Kortrijk, Belgium
Kohei Shiota, M.D., Ph.D. Kyoto University Graduate School of Medicine and Shiga Univer-
sity of Medical Science, Kyoto and Shiga, Japan
Jeroen J. Smits, M.D., Ph.D. Department of Clinical Genetics, University Medical Centre
Utrecht, Utrecht, The Netherlands
XVI Contributors
Tetsuya Takakuwa, M.D., Ph.D. Human Health Science, Graduate School of Medicine, Kyoto
University, Kyoto, Japan
Hans J. ten Donkelaar, M.D., Ph.D. Department of Neurology, Radboud University Medical
Centre, Nijmegen, The Netherlands
Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
Paul Trainor, Ph.D. Stowers Institute for Medical Research and Department of Anatomy and
Cell Biology, University of Kansas Medical Centre, Kansas City, MO, USA
Ton van der Vliet, M.D. Department of Radiology, University Medical Centre Groningen,
Groningen, The Netherlands
Hans van Bokhoven, Ph.D. Department of Human Genetics, Radboud University Medical
Lana Vasung, M.D., Ph.D. Harvard Medical School, Boston Children’s Hospital, Fetal Neona-
tal Neuroimaging and Developmental Science Centre, Boston, MA, USA
Christl Vermeij-Keers, M.D., Ph.D. Department of Plastic & Reconstructive & Hand Surgery,
Erasmus MC, Rotterdam, The Netherlands
Pieter Wesseling, M.D., Ph.D. Department of Pathology, VU Medical Centre, Amsterdam,

The Netherlands
Michèl Willemsen, M.D., Ph.D. Department of Child Neurology, Radboud University Medical
Shigehito Yamada, M.D., Ph.D. Congenital Anomaly Research Center, Graduate School of
Medicine, Kyoto University, Kyoto, Japan
1 1
Overview of the Development

of the Human Brain and Spinal
Cord
Hans J. ten Donkelaar, Tetsuya Takakuwa, Lana Vasung,
Shigehito Yamada, Kohei Shiota, and Ton van der Vliet
Corner’s ten-somite embryo
Contents
1.1 Introduction – 3
1.2 ajor Stages in the Development of the Human

M
Brain and Spinal Cord – 3
1.3 The First Three Weeks of Development – 12

1.3.1 I mplantation – 12
1.3.2 Gastrulation – 13
1.3.3 Folding of the Embryo – 16
1.4 Neurulation – 16
1.5 Development of the Spinal Cord – 19
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023

H. J. ten Donkelaar et al., Clinical Neuroembryology, https://doi.org/10.1007/978-3-031-26098-8_1
1.6 Pattern Formation of the Brain – 20
1.7 Early Development of the Brain – 21

1.7.1 I maging of the Embryonic Brain – 21
1.7.2 Neuromeres – 22
1.7.3 The Ganglionic Eminences – 28
1.8 Foetal Development of the Brain – 29

1.8.1 T he Cerebellum – 30
1.8.2 The Cerebral Cortex – 36
1.8.3 Cerebral Commissures – 43
1.8.4 Imaging of the Foetal Brain – 44
1.9 Development of the Meninges and Choroid Plexuses – 45
1.10 Development of the Blood Supply of the Brain – 48
1.11 Development of Fibre Tracts and Their Myelination – 55

1.11.1 evelopment of Fibre Tracts – 55
D
1.11.2 Development of Myelination – 58
1.11.3 Prenatal Motor Behaviour – 61
1.12 The Foetal Connectome – 63
References – 66
1.2 · Major Stages in the Development of the Human Brain and Spinal Cord
3 1
1.1 Introduction 1.2 ajor Stages in the Development
M
of the Human Brain and Spinal Cord
The development of the human brain and spinal cord
may be divided into several phases, each of which is The human embryonic period, i.e. the first 8 weeks of
characterized by particular developmental disorders development, can be divided into 23 stages, the Carnegie
(Volpe 1987; van der Knaap and Valk 1988; Aicardi stages (CS; O’Rahilly and Müller 1987), originally
1992; . Table 1.3). After implantation, formation and described as developmental horizons (XI–XXIII) by
separation of the germ layers occur, followed by dorsal Streeter (1951), and completed by Heuser and Corner
and ventral induction phases, and phases of neurogene- (1957; developmental horizon X) and O’Rahilly (1973;
sis, migration, organization and myelination. With the developmental stages 1–9). Some of the reconstructed
transvaginal ultrasound technique, a detailed descrip- models and drawings of the extensive Carnegie Collec-
tion of the living embryo and foetus has become possi- tion are now archived in the Human Developmental
ble (Pooh and Kurjak 2009; Rama Murthy 2019). With Anatomy Center in Washington, DC (7 http://nmhm.
magnetic resonance imaging (MRI), foetal development washingtondc.museum/collections/hdac/index.h tm).
of the brain can now be studied in detail from about the Important contributions to the description of human
beginning of the second half of pregnancy (Garel 2004; embryos were also made by Nishimura et al. (1977),
Prayer 2011). Much progress has been made in elucidat- Jirásek (1983, 2001, 2004) and from the Zagreb Collec-
ing the mechanisms by which the central nervous system tion of Human Brains by Ivica Kostović and colleagues
(CNS) develops, and also in our understanding of its (see Judaš et al. 2011; Kostović and Vasung 2009;
major developmental disorders, such as neural tube Kostović et al. 2019a, b). Examples of human embryos,
defects, holoprosencephaly, microcephaly and neuronal taken from the famous Kyoto Collection (see Shiota
migration disorders. Molecular genetic data, that explain 2018; Yamaguchi and Yamada 2018), are shown in
programming of development aetiologically, can now be . Figs. 1.1 and 1.2. In the embryonic period, postfertil-
incorporated (Flores-Sarnat and Sarnat 2008; Barkovich ization or postconceptional age is estimated by assigning
et al. 2001, 2009, 2012; Desikan and Barkovich 2016; an embryo to a developmental stage using a table of
Barkovich and Raybaud 2018). In this chapter, an over- norms, going back to the first Normentafeln by Keibel
view is presented of (1) major stages in the development and Elze (1908). The term gestational age is commonly
of the human CNS, (2) the first three weeks of develop- used in clinical practice, beginning with the first day of
ment, (3) neurulation, (4) pattern formation, (5) early the last menstrual period. Usually, the number of men-
development of the brain, (6) foetal development of the strual or gestational weeks (GWs) exceeds the number
brain, (7) the development of the blood supply of the of postfertilization weeks by 2. During week 1 (CS 2–4)
brain, (8) the development of major fibre tracts and (9) the blastocyst is formed, during week 2 (CS 5 and 6)
the foetal connectome. Mechanisms of development are implantation occurs and the primitive streak is formed,
discussed in 7 Chap. 2, and an overview of the causes followed by the formation of the notochordal process
of developmental malformations and their molecular and the beginning of neurulation (CS 7–10). Somites
genetic basis is presented in 7 Chap. 3. In the second, first appear at stage 9. The neural folds begin to fuse at
specialized part of this book the development of the CS 10, and the rostral and caudal neuropores close at
CNS and its disorders are discussed in more detail. In CS 11 and 12, respectively. Gradually, the pharyngeal
this book, the developmental ontology based on the bars, the optic and otic vesicles, and the limb buds
prosomeric model developed by Luis Puelles and John appear. The main external and internal features of
Rubenstein is applied (Puelles and Rubenstein 2003; human embryos are summarized in . Table 1.1. The
Puelles 2013, 2019, 2021; Puelles et al. 2012, 2013). It is first four embryonic weeks are also described as the
a reasonable framework to encompass the current state period of blastogenesis, and the fifth to eighth weeks as
of knowledge of this fluid topic. The model is ‘merely an the period of organogenesis (Opitz 1993; Opitz et al.
epistemic instrument; it should be retained only as long 1997). The foetal period cannot be divided into a series
as it proves capable of dealing straightforwardly with of morphologically defined stages. It is the period of
the available data, and which could in due course be phenogenesis (Opitz 1993; Opitz et al. 1997). In the clin-
modified or be replaced’ (Puelles 2013). Throughout the ical literature, a subdivision of the prenatal period into 3
book, the terminology used follows the second edition trimesters of 13 weeks each is commonly used. At the
of the Terminologia Embryologica (TE2 2017) and the junction of the trimesters 1 and 2, the foetus of about 90
Terminologia Neuroanatomica (TNA 2017; ten days has a greatest length of 90 mm, whereas at the junc-
Donkelaar et al. 2017, 2018). tion of the trimesters 2 and 3, the foetus is about 250 mm
4 Chapter 1 · Overview of the Development of the Human Brain and Spinal Cord
. Fig. 1.1 Dorsal views of staged early human embryos (Carnegie stages 6, 7, 9–11). (From the Kyoto Collection of Human Embryos;
kindly provided by Kohei Shiota, Kyoto)
in length and weighs approximately 1000 g (O’Rahilly whole viscerocranium and part of the neurocranium are
and Müller 2001; . Table 1.2). The newborn brain formed from the neural crest (Le Douarin and Kalcheim
weighs 300–400 g at full term. Male brains weigh slightly 1999; Wilkie and Morriss-Kay 2001; Francis-West et al.
more than those of females but, in either case, the brain 2003; Morriss- Kay and Wilkie 2005; Trainor 2014;
constitutes 10% of the body weight (Crelin 1973). 7 Chap. 5).
The brain and the spinal cord arise from an area of Remarkable progress has been made in non-
the ectoderm known as the neural plate. The folding of destructive imaging technologies, more in particularly
the neural plate, leading to successively the neural MRI. By using a super-parallel magnetic resonance
groove and the neural tube, is called primary neurula- (MR) microscope (Matsuda et al. 2007), over 1400
tion. The caudal part of the neural tube does not arise human embryonic specimens have been imaged in the
by fusion of the neural folds but develops from the so- Kyoto Human Embryo Visualization Project (Yamada
called caudal eminence. This process is called secondary et al. 2006, 2010; Shiota et al. 2007; Takakuwa 2018;
neurulation (7 Chap. 4). Before and after the surface . Fig. 1.3). Selective images from the database can be
ectoderm of the two sides fuses, the fusing neuroecto- viewed on the web (7 http://bird.cac.med.kyoto-u.
dermal cells of the neural folds give off the neural crest ac.jp/index_e.html). Episcopic fluorescence image cap-
cells. The neural crest is a transient structure and gives ture is another novel method that can provide registered
rise to the spinal and cranial ganglia. Moreover, the two-dimensional (2D) image stacks suitable for rapid
5 1
three-dimensional (3D) rendering (Weninger and and Jovanov-Milošević 2006; Kostović and Vasung
Mohun 2002). This technique has been used in a devel- 2009; 7 Chap. 10). More recently, Kostović et al. (2019a)
opmental atlas of the early first-trimester embryo from distinguished five developmental phases: (1) an early
CS 13 to 23 (Yamada et al. 2010). Another 3D atlas of foetal phase (9–13 postconceptional weeks or PCWs)
human embryos is based on the Carnegie Collection of with prominent proliferative zones, a trilaminar cerebral
Human Embryos (de Bakker et al. 2012, 2016). Shiraishi wall and with initial formation of the low MRI signal
et al. (2015) created 3D reconstructions of the human intensity subplate, known as the presubplate (see 7 Sect.
brain from CS 14 till CS 23 with MR imaging data from 1.8); during PCW 13–15, the subplate is formed; (2) a
101 samples from the Kyoto Collection (. Fig. 1.4). midfoetal phase (PCW 15–23) with transient foetal cel-
The growth rate of the rhombencephalon exceeded that lular zones fully developed, a synapse-rich subplate
of the prosencephalon until CS 19. With the emergence dominating on MRI and thalamocortical axons accu-
of the cerebral hemispheres, after CS 20 the growth of mulating below the cortical plate; (3) a late foetal or
the forebrain becomes much greater. The rapid growth early preterm phase (PCW 24–28), characterized by the
of the cerebral hemispheres is largely responsible for the subsequent development of gyri and sulci, thalamocor-
exponential growth of the brain during the foetal tical fibres penetrating the cortical plate, persistence of
period. the subplate, vulnerable periventricular axonal cross-
The embryonic period includes three in time overlap- roads and poorly myelinated fibre systems; (4) a late pre-
ping phases: formation and separation of the germ lay- term phase (PCW 29–36), during which secondary gyri
ers, and dorsal and ventral induction phases and the volume of the cerebral wall develop rapidly,
(. Table 1.3). During the first phase, the neural plate is with a decline in the ventricular and subventricular pro-
formed. In the dorsal induction phase, the neural tube is liferative zones and the subplate reaching its peak vol-
formed and closed, and the three primary divisions or ume and thickness at PCW 30 (Vasung et al. 2016); and
neuromeres of the brain (the prosencephalon, mesen- (5) a near-term phase (PCW 36–41) with gradual disap-
cephalon and rhombencephalon) appear. In the ventral pearance of transient foetal zones.
induction phase, the cerebral hemispheres, the eye vesi- Each of the developmental phases of the brain is
cles, the olfactory bulbs and tracts, the pituitary gland characterized by particular developmental disorders
and part of the face are formed. In the sixth week of (. Table 1.3). During the separation of the germ layers,
development strong proliferation of the ventral walls of enterogenous cysts and fistulae may occur. In the dorsal
the telencephalic vesicles gives rise to the ganglionic or induction phase, neural tube defects (7 Chap. 4) occur.
ventricular eminences. These elevations do not only Developmental disorders in the ventral induction phase,
form the basal ganglia but also give rise to many neu- in which the prosencephalon is normally divided into
rons that migrate tangentially to the cerebral cortex. the diencephalon and the two cerebral hemispheres, are
Neurogenesis starts in the spinal cord and the brain characterized by a single, incompletely divided forebrain
stem. Neurogenesis in the cerebellum and the cerebral (holoprosencephaly; 7 Chap. 9). This very heteroge-
cortex occurs largely in the foetal period. The human neous disorder may be due to disorders of ventralization
foetal period extends from the ninth week of develop- of the neural tube (Flores-Sarnat and Sarnat 2008) such
ment to the time of birth. With regard to the prenatal as underexpression of the strong ventralizing gene Sonic
ontogenesis of the cerebral cortex, Marín-Padilla (1990) hedgehog (SHH). During neurogenesis of the forebrain,
suggested to divide this long developmental period into malformations due to abnormal neuronal proliferation
two separate ones: (1) the foetal period proper (GW or apoptosis may occur, leading to microcephaly or
9–24), characterized by the formation of the cortical megalocephaly. During the migration of the cortical
plate; and (2) the perinatal period, extending from GW neurons, malformations due to abnormal neuronal
24 to the time of birth. This period is characterized by migration may appear, varying from classic lissenceph-
neuronal maturation. The separation between these two aly (‘smooth brain’), several types of neuronal heteroto-
periods at GW 24 is somewhat arbitrary but may be pia, and polymicrogyria to minor cortical dysplasias.
clinically relevant. GW 24 approximates roughly the For many of these malformations, disorders of secre-
lower limit for possible survival of the prematurely born tory molecules and genes that mediate migration have
infant. Disorders of migration are more likely to occur been found (7 Chap. 10). Many of these malformations
in the foetal period, whereas abnormalities affecting the are characterized by the presence of intellectual disabil-
architectonic organization of the cerebral cortex are ity and epilepsy. Cerebellar disorders are more difficult
more likely to occur in the perinatal period (7 Chap. to fit into this scheme. The Dandy-Walker malformation
10). Kostović suggested a further subdivision of the foe- is thought to arise late in the embryonic period, whereas
tal period into four developmental phases and corre- cerebellar hypoplasia presumably occurs in the foetal
lated histogenetic events with structural MRI (Kostović period (see 7 Chap. 8).
. Fig. 1.2 Lateral views of staged human embryos (Carnegie stages 12–23). (From the Kyoto Collection of Human Embryos; kindly pro-
vided by Kohei Shiota, Kyoto)
7 1
. Fig. 1.2 (continued)

1 . Table 1.1 Developmental stages and features of human embryos
Carnegie Length (mm) Age (days) External features Internal features (with emphasis on the
stages nervous system)
1 1 Fertilization
2 2–3 From 2 to about 16 cells

3 4–5 Free blastocyst Inner cell mass and trophoblast
4 6 Attaching blastocyst Cytotrophoblast and syncytiotrophoblast
distinguishable
5 0.1–0.2 7–12 Implantation; embryonic disc circular Amniotic cavity; primary yolk sac; extra-
embryonic mesoderm
6 0.2 17 Embryonic disk elongated Chorionic villi; primitive streak and node;
prechordal plate appears; secondary yolk sac
7 0.4 19 Embryonic disk oval Notochordal process visible; haematopoiesis
starts
8 1.0–1.5 23 Primitive pit appears; neural folds may Notochordal and neurenteric canals
begin to form detectable
9 1.5–2.5 25 First somites appear; mesencephalic Neural groove evident; 3 major subdivisions
flexure begins; otic disc forms of brain distinguishable; heart begins to
develop
10 2–3.5 28 Neural folds begin to fuse; otic pit Optic primordium begins to develop; cardiac
develops; 4–12 somites; pharyngeal arches loop appears; intermediate mesoderm
1 and 2 visible
11 2.5–4.5 29 Rostral neuropore closes; 13–20 somites Optic vesicles develop
12 3–5 30 Caudal neuropore closes; 21–29 somites; 4 Secondary neurulation starts
pharyngeal arches visible; upper limb buds
appearing
13 4–6 32 Otic vesicle closed; lens disc not yet Retinal and lens discs develop; primordium
indented; 30 or more somites; 4 limb buds of cerebellum
visible
14 5–7 33 Lens pit appears; upper limb buds Future cerebral hemispheres; pontine flexure;
elongated optic cup develops; adenohypophysial pouch
defined
15 7–9 36 Lens pit closed; nasal pit appearing; hand Future cerebral hemispheres become defined;
plate forming retinal pigment visible
16 8–11 38 Retinal pigment visible; nasal sacs face Pineal gland develops; neurohypophysial
ventrally; auricular hillocks beginning; evagination; olfactory tubercle
foot plate appears
17 11–14 41 Head relatively larger; trunk straighter; Internal and external cerebellar swellings;
auricular hillocks distinct; finger rays chondrification begins in humerus, radius
and some vertebral centra
18 13–17 44 Body more cuboidal; elbow region and toe Oronasal membrane develops; 1–3 semicircu-
rays appearing lar ducts in internal ear
19 16–18 46 Trunk elongating and straightening Olfactory bulb develops; cartilaginous otic
capsule; choroid plexus of fourth ventricle
20 18–22 49 Upper limbs longer and bent at elbows Optic fibres reach optic chiasm; choroid
plexus of lateral ventricle
21 22–24 51 Fingers longer; hands approach each Cortical plate becomes visible; optic tract
other, feet likewise and lateral geniculate body
9 1
.. Table 1.1 (continued)
Carnegie Length (mm) Age (days) External features Internal features (with emphasis on the
stages nervous system)
22 23–28 53 Eyelids and external ear more developed Olfactory tract; internal capsule; adenohypo-
physial stalk incomplete
23 27–31 56 Head more rounded; limbs longer and Insula indented; caudate nucleus and putamen
more developed recognizable; humerus presents all cartilagi-
nous stages
After O’Rahilly and Müller (1987, 2001)
. Table 1.2 Criteria for estimating age during the foetal period
Age (postcon- Average Average foot Average Main external characteristics

ceptional crown-rump length (mm) weight (g)
weeks) length (mm)
Previable foetuses
9 50 7 8 Eyes closing or closed; head large and more rounded; external
genital not distinguishable as male or female; intestines in
proximal part of umbilical cord; low-set ears
10 61 9 14 Intestines returned to abdomen; early fingernail development
12 87 14 45 Sex distinguishable externally; well-defined neck
14 120 20 110 Head erect; eyes face anteriorly; ears close to their definitive
position; lower limbs well developed; early toenail development
16 140 27 200 External ears stand out from head
18 160 33 320 Vernix caseosa covers skin; quickening felt by mother
20 190 39 460 Head and body hair (lanugo) visible
Viable foetuses
22 210 45 630 Skin wrinkled, translucent, pink to red colour
24 230 50 820 Fingernails present; lean body
26 250 55 1000 Eyes partially open; eyelashes present
28 270 59 1300 Eyes wide open; good head of hair may be present; skin slightly
wrinkled
30 280 63 1700 Toenails present; body filling out; testes descending
32 300 68 2100 Fingernails reach finger tips; skin pink and smooth
36 340 79 2900 Body usually plump; lanugo hairs almost absent; toenails reach
toe tips; flexed limbs; firm grasp
38 360 83 3400 Prominent chest; breasts protrude; testes in scrotum or palpable in
inguinal canals; fingernails extend beyond finger tips
After Moore et al. (2000)

a b c
1
d e f
g h i
j k l
11 1
. Fig. 1.4 3D reconstructions of the brain at Carnegie stages 14, (From Shiraishi et al. 2015, with permission; courtesy Tetsuya
17, 20 and 23: a lateral view of the brain at same scale; b morphology Takakuwa, Kyoto)
of the ventricles observed through a transparent brain at same scale.
. Fig. 1.3 Magnetic resonance (MR) microscopy of human abdominal cavity, the midgut (Mg) is invested in the umbilical cord
embryos at different developmental stages. Human embryos at Carn- (UC). At CS 18 g–i, anlagen for the digits are evident in the forelimb
egie stages (CS) 13, 16, 18 and 22 were imaged by MR microscopy. a, g, h. In the thoracic cavity, the heart and the lung (Lg) are clearly seen
d, g, j Photographs of the embryos; b, e, h, k Three-dimensional (3D) (i). At CS 22 j–l craniofacial and eye developments have advanced
reconstructions of the same embryos using MR images; c, f, i, l Two- considerably and the digits in the fore- and hindlimbs are well devel-
dimensional (2D) MR images in the sagittal plane. At CS 13 a–c, limb oped l. At this stage of development, most of the abdominal cavity is
buds are present and the prosencephalon (P), mesencephalon (M) occupied by the liver (Li) and physiological midgut herniation is pres-
and rhombencephalon (R) with rhombomeres can be seen. Also nota- ent (arrowhead in l). CF cervical flexure, D diencephalon, PF pontine
ble is the looped heart tube (Ht). At CS 16 d–f, the eye primordia and flexure, T telencephalon, Tn tongue; bars: 1 mm. (From Yamada et al.
upper and lower limb buds with limb paddles are observed (E). In the 2010, with permission; courtesy Shigehito Yamada, Kyoto)
1 . Table 1.3 Major stages of human CNS development
Stage Time of occurrence Major morphological events in brain Main corresponding disorders
(weeks)
Embryonic period
Formation and 2 Neural plate Enterogenous cysts and fistulas;
separation of germ split notochord syndrome
layers
Dorsal induction: 3–4 Neural tube, neural crest and derivatives; closure of Anencephaly, encephalocele,
primary neurula- rostral and caudal neuropores; paired alar plates myeloschisis; myelomeningo-
tion cele, Chiari malformations
Ventral induction: 4–6 Development of forebrain and face; formation of Holoprosencephaly; Dandy-
telencephalization cerebral vesicles; optic and olfactory placodes; Walker malformation;
rhombic lips appear; ‘fusion’ of cerebellar plates craniosynostosis
Foetal period
Neuronal and glial 6–16 Cellular proliferation in ventricular and subventricu- Microcephaly, megalencephaly
proliferation lar zones; early differentiation of neuroblasts and
glioblasts; cellular death (apoptosis); migration of
Purkinje cells and external granular layer in cerebel-
lum
Migration 12–24 Migration of cortical neurons; formation of corpus Neuronal migration disorders
callosum (lissencephalies, polymicrogy-
ria, schizencephaly, heterotopia)
Perinatal period
Organization 24 to postnatal Late migration; organization and maturation of Minor cortical dysplasias
cerebral cortex; synaptogenesis; formation of internal
granular layer in cerebellum
Myelination 24–2 years Myelination disorders,
postnatally destructive lesions (secondarily
acquired injury of normally
formed structures)
Based on Aicardi (1992)
1.3 The First Three Weeks of Development ferentiated and is known as the epiblast. Duplication of
the inner cell mass is probably the basis for most cases of
During the first three weeks of development, the three monozygotic twinning. Possibly, such divisions arise
germ layers (ectoderm, mesoderm and endoderm), the during ‘hatching’, the emergence of the blastocyst from
basis of the various organs and systems of the body, are the zona pellucida (O’Rahilly and Müller 2001). At
established. During the first week of development (CS approximately six days (CS 4b), the blastocyst becomes
2–4), the embryo develops from a solid mass of totipo- attached to the endometrium of the uterus.
tent cells or blastomeres (the morula) into the blasto-
cyst. This occurs when 16–32 cells are present. The
blastocyst is composed of an inner cell mass or embryo- 1.3.1 Implantation
blast, giving rise to the embryo, and the trophoblast, the
peripherally situated cells, surrounding the blastocystic The second week is characterized by implantation (CS
cavity and forming the developmental adnexa 5) and the formation of the primitive streak (CS 6).
(. Fig. 1.5). Embryoblast cells adjacent to this cavity The trophoblast differentiates into the cytotrophoblast
form a new layer of flat cells, the hypoblast. This cell and the more peripherally situated syncytiotrophoblast
layer covers the blastocystic cavity from inside that is that invades the endometrium. Blood-filled spaces, the
now called the primitive umbilical vesicle or yolk sac. lacunae, soon develop within the syncytiotrophoblast
The rest of the inner cell mass remains relatively undif- and communicate with endometrial vessels, laying the
1.3 · The First Three Weeks of Development
13 1
a b c
d e
. Fig. 1.5 Implantation and the formation of the bilaminar and maternal blood in lacunae is shown in red. AC amniotic cavity,
embryo: a 107-cell blastocyst; b–e blastocysts of approximately 4.5, ChC chorionic cavity, eem extra-embryonic mesoderm, lc lacuna, pv
9, 12 and 13 days, respectively. The trophoblast and the cytotropho- primary villi, PUV primary umbilical vesicle, SUV secondary umbil-
blast are indicated in light red, the syncytiotrophoblast is stippled ical vesicle (yolk sac), us umbilical stalk. (After Langman 1963)
basis for the placental circulation. Between the epiblast 1.3.2 Gastrulation
and the cytotrophoblast, the amniotic cavity appears.
The embryonic disc is now known as the bilaminar During CS 6, in the slightly elongated embryonic disc
embryo. Only the cylindric epiblast cells adjacent to the caudally situated cells of the epiblast migrate ventral-
hypoblast form the embryo. The remaining flattened wards along the median plane, and form the primitive
epithelial cells participate in the formation of the streak (. Fig. 1.6). It probably appears between days
amnion (. Fig. 1.5). The amniotic cavity is bounded 12 and 17 (Jirásek 1983, 2001; Moore et al. 2000;
ventrally by the epiblast and dorsally by a layer of O’Rahilly and Müller 2001). The rostral, usually dis-
amniotic ectoderm. tinct, part of the primitive streak is known as the primi-
the prechordal plate. Caudally, the epiblast is closely

1 related to the endoderm, giving rise to the cloacal mem-
brane (. Fig. 1.6). The primitive streak is the first clear-
cut indication of bilaterality, so the embryo now, apart
from rostral and caudal ends, also has right and left
sides. Genetic mutations expressed in the primitive
streak may lead to duplication of the neural tube
(7 Chap. 6) or its partial or complete agenesis (Flores-
Sarnat and Sarnat 2008).
The extra-embryonic mesoderm soon covers the tro-
phoblast, the amniotic ectoderm and the yolk sac
(. Fig. 1.5). Extra-embryonic mesoderm at the caudal
part of the embryo forms the connecting or umbilical
stalk that anchors the embryo to the chorion. The cho-
rion is composed of the trophoblast and the covering
extra-embryonic mesoderm. Hypoblast cells and this
extra-embryonic mesoderm form the wall of the yolk
sac, whereas the amniotic epithelium and its mesoder-
mal layer form the amnion. The secondary umbilical
vesicle or yolk sac develops from the primary one, prob-
ably by collapse and disintegration of the latter (Luckett
1978). The yolk sac is involved in active and passive
transport to the embryo, and is possibly associated with
the relationship between metabolic disorders such as
diabetes mellitus and congenital malformations
(O’Rahilly and Müller 2001). The chorion encloses the
chorionic cavity, in which the embryonic disc, now a tri-
laminar embryo, is located.
During the third and the fourth weeks, the somites,
the heart, the neural folds, the three major divisions of
. Fig. 1.6 Dorsal (top) and medial (bottom) views of a stage 7 the brain, the neural crest and the beginnings of the
embryo. The ectoderm is indicated in red, the notochordal process in inner ear and the eye develop. At approximately 19 days
light red and the endoderm in grey. AC amniotic cavity, all allantois, (CS 7), rostral to the primitive streak, a prolongation
mclo membrana cloacalis, nchpr notochordal process, pchpl pre-
below the ectoderm, the notochordal process, arises
chordal plate, PN primitive node, PS primitive streak, SUV second-
ary umbilical vesicle (yolk sac), us umbilical stalk. (After O’Rahilly from the primitive node, and extends rostrally as far as
1973) the prechordal plate (. Fig. 1.6). The floor of the noto-
chordal process breaks down at CS 8, giving rise to the
tive node of Hensen. The primitive streak is a way of notochordal plate. The embryonic disc is now broader
entrance whereby cells invaginate, proliferate and rostrally, and a shallow neural groove appears, which is
migrate to subsequently form the extra-embryonic the first morphological indication of the nervous system
mesoderm, the endoderm and the intra-embryonic (O’Rahilly 1973; O’Rahilly and Gardner 1979; O’Rahilly
mesoderm. Remnants of the primitive streak may give and Müller 1981; Jirásek 2001, 2004). The primitive
rise to sacrococcygeal teratomas (7 Chap. 4). The endo- node may be hollowed by a primitive pit, which extends
derm replaces the hypoblast. The remaining part of the into the notochordal process as the notochordal canal
epiblast is the ectoderm. For this process the term gas- (O’Rahilly 1973). The channel becomes intercalated in
trulation is frequently used. Originally, the term referred the endoderm, and its floor begins to disintegrate at
to the invagination of a monolayered blastula to form a once, allowing temporary communication between the
bilayered gastrula, containing an endoderm-lined arch- amniotic cavity and the umbilical vesicle. The remnant
enteron as found in amphibians (7 Chap. 2). Nowadays, of the notochordal canal at the level of the primitive pit
the term gastrulation is more generally used to delimit is known as the neurenteric canal (. Fig. 1.7a). It may
the phase of development from the end of cleavage until be involved in the pathogenesis of enterogenous cysts
the formation of an embryo possessing a defined axial (7 Chap. 6). The prechordal plate is wider than the
structure (Collins and Billett 1995). Rostral to the prim- notochordal process, and is in close contact with the
itive node, the endoderm appears thicker and is called floor of the future forebrain. The prechordal plate is
1.3 · The First Three Weeks of Development
15 1
a d
b e
c f
. Fig. 1.7 The folding of the embryo: a, d Carnegie stage (CS) 8; b, e mesonephros, moph membrana oropharyngealis, nch notochord, ncr
CS 10; c, f CS 11/12. The ectoderm (ec) and its derivates are indicated neural crest, neur neurenteric canal, ng neural groove, p paraxial meso-
in red, derivates of the mesoderm (mes) in light red and the endoderm derm, PCC pericardiac cavity, pchpl prechordal plate, pros prosen-
(en) in grey. AC amniotic cavity, all allantois, cem caudal eminence, cephalon, rhomb rhombencephalon, sc spinal cord, sompl
dmt dermamyotome, fg foregut, hf head fold, hg hindgut, i intermedi- somatopleure, spchpl splanchnopleure, sptr septum transversum, SUV
ate mesoderm, IEC intra-embryonic coelom, l lateral plate of meso- secondary umbilical vesicle (yolk sac), tf tail fold, ur umbilical ring, us
derm, mclo membrana cloacalis, mes mesencephalon, mg midgut, mnp umbilical stalk. (After Streeter 1951; Hamilton and Mossman 1972)
derived from the prechordal mesendoderm (de Souza the most caudal part of the spinal cord (O’Rahilly and
1 and Niehrs 2000) and it is essential for the induction of Müller 2001). Malformations in this region may lead to
the forebrain (7 Chap. 9). The prechordal plate is usu- the still poorly understood caudal regression syndrome
ally defined as mesendodermal tissue underlying the that is discussed in 7 Chap. 4. Rostrally, the ectoderm
medial aspect of the anterior neural plate just anterior and the endoderm come together as the oropharyngeal
to the rostral end of the notochord. membrane, which temporarily separates the gut from the
amniotic cavity. Pharyngeal arches, clefts and pouches
become visible. The pharyngeal arches are separated by
1.3.3 Folding of the Embryo the pharyngeal clefts, and appear ventrolaterally on the
head and neck between four and five weeks. Four pairs
At approximately 25 days (CS 9), folding of the embryo are visible at CS 13 (. Fig. 1.2). More caudally, no
becomes evident. Rostral or cephalic and caudal folds clear-cut arrangement is found, but it is customary to
overlie the beginning foregut and hindgut, respectively distinguish a fifth and a sixth arch. The externally situ-
(. Fig. 1.7). Caudal to the cloacal membrane, the allan- ated clefts have internal counterparts, the pharyngeal
tois arises as a dorsal diverticle of the umbilical vesicle. pouches. The development of the pharyngeal arches is
On each side the mesoderm is arranged as three compo- closely related to that of the rhombomeres and the neu-
nents (. Fig. 1.7e): (1) a longitudinal, paraxial band ral crest, and is controlled by Hox genes (Favier and
adjacent to the notochord, forming the somites; (2) Dollé 1997; Rijli et al. 1998). Each pharyngeal arch is
intermediate mesoderm, giving rise to the urogenital characterized by a unique combination of Hox genes.
system; and (3) a lateral plate, giving rise to two layers Rostral to the somites, the paraxial mesoderm forms the
covering the body wall and the viscera, respectively. The somitomeres from which the external eye musculature
first layer is known as the somatopleure, the other as the and the muscles of the pharyngeal bars arise (Noden
splanchnopleure. In the Anglo-Saxon literature, how- 1991; Noden and Trainor 2005; Trainor 2014; see
ever, the terms somatopleure and splanchnopleure 7 Chap. 5). The sense organs of the head develop from
include the covering ectoderm and endoderm, respec- interactions of the neural tube with a series of epider-
tively (O’Rahilly and Müller 2001). The space between mal thickenings called the cranial ectodermal placodes.
the somatopleure and the splanchnopleure is the coe- The olfactory placode forms the olfactory epithelium,
lom. At first it is found outside the embryo (the extra- the trigeminal placode forms the trigeminal ganglion,
embryonic coelom), later also within the embryo. This is the otic placode forms the inner ear and the epibranchial
the intra-embryonic coelom or body cavity, which devel- placodes form the distal ganglia of the VIIth, IXth and
ops in the lateral plate mesoderm (. Fig. 1.7e, f). For a Xth nerves (7 Chap. 7). The lens placode forms the lens
discussion of body wall closure and its relevance to gas- and induces the overlying ectoderm to form the trans-
troschisis and other ventral body wall defects, see Sadler parent cornea (7 Chap. 9).
and Feldkamp (2008) and Hunter and Stevenson (2008).
Somites arise at CS 9 in longitudinal rows on each
side of the neural groove. The first four pairs of somites 1.4 Neurulation
belong to the occipital region. Within the next 10 days
subsequently 8 cervical, 12 thoracic, 5 lumbar, 5 sacral The first indication of the neural plate in human embryos
and some 3–6 coccygeal somites are formed, but they are is a median sulcus around 23 days of development. At
never visible together at one stage of development. Each approximately 25 days (CS 9), this neural groove is
somite divides into a ventromedial sclerotome, partici- deeper and longer. Its rostral half represents the fore-
pating in the formation of the vertebral column (7 Chap. brain, its caudal half mainly the hindbrain (. Fig. 1.8).
6), and a dorsolateral dermamyotome that forms a myo- The neural folds of the forebrain are conspicuous. The
tome and the overlying dermis (dermatome). Each myo- mesencephalic flexure appears, and allows a first
tome divides into two parts: (1) a dorsal epimere, giving subdivision of the brain into three major divisions in the
rise to the erector spinae muscle, and (2) a ventral still unfused neural folds (O’Rahilly 1973; O’Rahilly and
hypomere, from which the ventral vertebral muscles Gardner 1979; Müller and O’Rahilly 1983, 1997; Jirásek
(epaxial muscles), the muscles of the lateral and ventral 2001, 2004): the forebrain or prosencephalon, the mid-
body wall (hypaxial muscles) and the muscles of the brain or mesencephalon, and the hindbrain or rhomben-
extremities arise. The derivatives of the epimeres become cephalon (. Fig. 1.9). The otic placodes, the first
innervated by the dorsal rami of the spinal nerves, those indication of the internal ears, can also be recognized.
of the hypomeres by the ventral rami (7 Chap. 6). At CS 10, the two subdivisions of the forebrain, the tel-
The primitive streak becomes confined to a region encephalon and the diencephalon, become evident
known as the caudal eminence, or end-bud, which gives (Müller and O’Rahilly 1985). An optic sulcus is the first
rise to the hindgut, adjacent notochord and somites, and indication of the developing eye. Closure of the neural
1.4 · Neurulation
17 1
a b c d
. Fig. 1.8 The formation of the neural tube and neural crest. Dorsal views and transverse sections are shown for human embryos of CS 8
a, CS 9 b, CS 10 (c, seven somites) and CS 10 (d, ten somites). ec ectoderm, ncr neural crest, np neural plate
groove begins near the junction between the future brain nial and autonomic ganglia, (2) the enteric nervous sys-
and the spinal cord. Rostrally and caudally, the cavity of tem, (3) the medulla of the adrenal gland, (4) the
the developing neural tube communicates via the rostral melanocytes, the pigment-containing cells of the epider-
and caudal neuropores with the amniotic cavity. The ros- mis, and (5) many of the skeletal and connective tissue
tral neuropore closes at about 30 days (CS 11), and the of the head. The final phase of primary neurulation is
caudal neuropore about one day later (CS 12). The site the separation of neural and surface ectoderm by mes-
of final closure of the rostral neuropore is at the site of enchyme. Failure to do so may lead to an encephalocele,
the embryonic lamina terminalis (O’Rahilly and Müller at least in rats (O’Rahilly and Müller 2001).
1999). The closure of the neural tube in human embryos Malformations of the neural crest (neurocristopathies)
is generally described as a continuous process that may be accompanied by developmental disorders of the
begins at the level of the future cervical region, and pro- CNS (7 Chap. 5).
ceeds both rostrally and caudally (O’Rahilly and Müller Detailed fate map studies are available for amphibi-
1999, 2001; de Bakker et al. 2017). Nakatsu et al. (2000), ans and birds (7 Chap. 2). The organization of verte-
however, provided evidence that neural tube closure in brate neural plates appears to be highly conserved. This
humans may initiate at multiple sites as in mice and conservation probably extends to mammals, for which
other animals (see also Bassuk and Kibar 2009; Pyrgaki detailed fate maps are more difficult to obtain.
et al. 2010; Rifat et al. 2010; Massarwa and Niswander Nevertheless, available data (Rubenstein and Beachy
2013). Neural tube defects are among the most common 1998; Rubenstein et al. 1998; Inoue et al. 2000; Puelles
malformations (7 Chap. 4). et al. 2012; Puelles 2013) showed that in mice ventral
When the surface ectodermal cells of both sides fuse, parts of the forebrain such as the hypothalamus and the
the similarly fusing neuroectodermal cells of the neural eye vesicles arise from the medial part of the rostral or
folds give off neural crest cells (. Fig. 1.8). These cells prosencephalic part of the neural plate (. Fig. 1.11c).
arise at the neurosomatic junction. The neural crest cells Pallial as well as subpallial parts of the telencephalon
migrate extensively to generate a large diversity of dif- arise from the lateral parts of the prosencephalic neural
ferentiated cell types (Le Douarin and Kalcheim 1999; plate. The lateral border of this part of the neural plate
Trainor 2014; 7 Chap. 5), including (1) the spinal cra- forms the dorsal, septal roof of the telencephalon. The
1 a b
. Fig. 1.9 Corner’s ten-somite embryo a. b A median section, RhA-RhD primary rhombomeres, T telencephalic neuromere, 1–10
showing the subdivision of the brain into the primary neuromeres. first ten somites. (a, illustration by James Didusch, from Corner
all allantois, CE caudal eminence, D1, D2 diencephalic neuromeres, 1929, with permission; b, after O’Rahilly and Müller 1987)
M mesomere, mclo membrana cloacalis, nch notochord, ot otocyst,
most rostral, median part of the neural plate gives rise to astrocytes (7 Chap. 2). The neurons send axons into an
the commissural plate from which the anterior commis- outer layer, the marginal zone. The mantle layer, con-
sure and the corpus callosum arise. taining the cell bodies, becomes the grey matter, and the
Initially, the wall of the neural tube consists of a axonal, marginal layer forms the white matter. In the
single layer of neuroepithelial cells, the germinal neuro- spinal cord, this three-zone pattern is retained through-
epithelium or matrix layer. As this layer thickens, it grad- out development.
ually acquires the configuration of a pseudostratified Secondary proliferative compartments are found else-
epithelium. Its nuclei become arranged in more and where in the brain. The external germinal or granular
more layers, but all elements remain in contact with the layer is confined to the cerebellum. It develops from the
external and internal surface. Mitosis occurs on the ventricular zone of the rostral part of the rhombic lip, a
internal, ventricular side of the cell layer only (7 Chap. thickened germinal zone in the rhombencephalic alar
2), and migrating cells form a second layer around the plate, and gives rise to the granule cells of the cerebel-
original neural tube. This layer, the mantle layer or inter- lum. The subventricular zone is found in the lateral and
mediate zone, becomes progressively thicker as more basal walls of the telencephalon. This zone gives rise to
cells are added to it from the germinal neuroepithelium a large population of glial cells and to the granule cells
that is now called the ventricular zone. The cells of the of the olfactory bulb. A special role for the outer subven-
intermediate zone differentiate into neurons and glial tricular zone as a proliferative compartment for neurons
cells. Radial glial cells are present during early stages of has been demonstrated (Kriegstein and Alvarez-Buylla
neurogenesis. Most radial glial cells transform into 2009; Lui et al. 2011; 7 Chaps. 2 and 10).
1.5 · Development of the Spinal Cord
19 1
1.5 Development of the Spinal Cord genes in the ventral half of the spinal cord. Many other
genes are involved in the specification of the various
After neurulation, the spinal cord can be divided into progenitor zones and the types of neurons derived from
dorsal alar plates derived from lateral parts of the neural them in the spinal cord (7 Chap. 6). Motoneurons are
plate, and ventral basal plates derived from its medial the first neurons to develop (Windle and Fitzgerald
parts (. Fig. 1.10). The alar and basal plates are sepa- 1937; Bayer and Altman 2002). They appear in the
rated by the limiting sulcus (sulcus limitans) of His (His uppermost spinal segments at approximately embryonic
1880). The alar plates are united by a small roof plate, day 27 (about CS 13/14). At this time of development
and the basal plates by a thin floor plate. The alar plates also dorsal root ganglion cells are present. Dorsal root
and incoming dorsal roots form the afferent or sensory fibres enter the spinal grey matter very early in develop-
part of the spinal cord, whereas the basal plate and its ment (Windle and Fitzgerald 1937; Konstantinidou
exiting ventral root form the efferent or motor part. The et al. 1995; 7 Chap. 6). The first synapses between pri-
spinal ganglia arise from the neural crest. The develop- mary afferent fibres and spinal motoneurons were found
ment of the alar and basal plates is induced by extracel- in a CS 17 embryo (Okado et al. 1979; Okado 1981).
lular signalling molecules, secreted by the notochord and Ascending fibres in the dorsal funiculus have reached
the adjacent ectoderm (. Fig. 1.10). The protein SHH the brain stem at CS 16, i.e. at about 37 postovulatory
of the SHH gene in the notochord induces the forma- days (Müller and O’Rahilly 1989). The first descending
tion of the floor plate. In its turn, the floor plate induces supraspinal fibres from the brain stem have extended
the formation of motoneurons in the basal plate. Bone into the spinal cord at CS 14 (Müller and O’Rahilly
morphogenetic proteins (BMPs) from the ectoderm 1988b). Even the late developing pyramidal tract extends
induce the formation of the alar and roof plates and of as far caudally as the spinomedullary junction at the end
the neural crest. BMP4 and BMP7 induce the expres- of the embryonic period (Müller and O’Rahilly 1990c;
sion of the transcription factor ‘Slug’ in the neural crest ten Donkelaar 2000). The spinal cord then still reaches
and the expression of certain Pax transcription factors the end of the vertebral canal. During the foetal period,
in the alar plates. SHH suppresses these dorsal Pax it ‘ascends’ to lumbar levels (7 Chap. 6).
a c
. Fig. 1.10 The development of the spinal cord and the dorsaliz- crest (ncr) and support the expression of Pax3 and Pax7 in the dorsal
ing (bone morphogenetic proteins, BMPs) and ventralizing (Sonic part of the spinal cord. SHH suppresses the expression of these tran-
hedgehog, SHH) factors involved. a SHH in the notochord (nch, red) scription factors. ap alar plate, bp basal plate, mn motoneurons, np
induces the formation of the floor plate (fp), after which SHH in the neural plate, rp roof plate, slH sulcus limitans of His. (After Carlson
floor plate induces the formation of motoneurons b, c. BMP4 and 1999)
BMP7 (light red) from the ectoderm (ec) induce Slug in the neural
1.6 Pattern Formation of the Brain anterior mesoderm and the chordamesoderm initiate
1 neural development by inducing neural tissue of an ante-
Prospective subdivisions of the brain are specified rior type, i.e. forebrain and midbrain, in the overlying
through pattern formation, which takes place in two ectoderm along its entire anteroposterior length. A sec-
directions: from medial to lateral, and from rostral to ond signal from chordamesoderm alone converts the
caudal (Lumsden and Krumlauf 1996; Rubenstein and overlying neuroectoderm induced by the first signal into
Beachy 1998; . Fig. 1.11). Mediolateral or ventrodorsal a posterior type of neural tissue, i.e. hindbrain and spinal
pattern formation generates longitudinal areas such as cord (7 Chap. 2). Endodermal signalling molecules also
the alar and basal plates, and rostrocaudal pattern for- play an important role in the induction of the rostral
mation generates transverse zones (one or more neuro- part of the CNS (de Souza and Niehrs 2000).
meres). Most likely, the rostrocaudal regionalization of Developmental gene-expression studies show that
the neural plate is induced already during gastrulation the vertebrate CNS can be divided into three regions.
(Nieuwkoop and Albers 1990). In amphibians, the first The anterior region comprises the forebrain and the
mesoderm to ingress gives rise to the anterior head meso- midbrain, and is characterized by expression of the
derm. The mesoderm that follows will form the chorda- homeobox genes Emx and Otx. The middle division
mesoderm and more lateral mesodermal structures. The comprises the isthmic rhombomere (rhombomere 0 or
anterior mesoderm differs from the chordamesoderm r0; see 7 Sect. 1.7.2) and the first rhombomere (r1). It is
also in the genes that it expresses. Signals from both the known as the midbrain–hindbrain boundary (MHB) or
a
c
. Fig. 1.11 Bauplan and pattern formation of the mouse brain. a indicated in light red, the medializing (M) or ventralizing (V) factor
The dorsal view of the rostral part of the neural plate (np) shows the SHH in red, the fibroblast growth factor 8 (FGF8) in dark grey and
approximate locations of the prosencephalon (pros), mesencephalon brain factor 1 (Foxg1) in grey. Medial signals induce the basal plate
(mes) and rhombencephalon (rhomb), and b the transverse section (bp), whereas lateral signals induce the alar plate (ap). anr anterior
shows the structures involved. The expression of some genes involved neural ridge, cb cerebellum, cho chiasma opticum, ec ectoderm, en
in the patterning of the brain is shown in a dorsal view of the neural endoderm, ev eye vesicle, hy hypothalamus, is isthmus, m mesenceph-
plate of an E8 mouse c and in a median section through the neural alon, nch notochord, nr neural ridge, pchpl prechordal plate, p1, p6
tube at E10.5 d. The arrows indicate the morphogenetic processes prosomeres, Rthp Rathke’s pouch, r1–r7 rhombomeres, tel telen-
involved in the closure of the neural tube. The expression of lateral- cephalon. (After Rubenstein and Beachy 1998; Rubenstein et al.
izing (L) or dorsalizing (D) signalling molecules such as BMPs is 1998)
1.7 · Early Development of the Brain
21 1
isthmocerebellar region. The third region comprises Although much of our insight into these patterning
most of the rhombencephalon (r2–r11) and the spinal mechanisms relies on studies in mice, humans are sub-
cord, and is characterized by Hox gene expression. ject to a wide variety of naturally occurring mutations
Longitudinal patterning centres are present along the (7 Chap. 9).
ventral (notochord and prechordal plate, and later the
floor plate) and dorsal (epidermal–neuroectodermal
junction, and later the roof plate) aspects of the neural 1.7 Early Development of the Brain
plate and early neural tube. Medial, i.e. ventralizing, sig-
nals such as SHH play an important role during the for- Lateral and medial views of the developing brain are
mation of the primordia of the basal plate. SHH induces shown in . Figs. 1.12 and 1.13. The neural tube becomes
the formation of motoneurons in the spinal cord and bent by three flexures: (1) the mesencephalic flexure at
brain stem (7 Chaps. 6 and 7). Lateral, i.e. dorsalizing, the midbrain level, already evident before fusion of the
signals such as BMPs from the adjacent ectoderm induce neural folds; (2) the cervical flexure, situated at the junc-
the formation of the alar plate and the dorsal part of the tion between the rhombencephalon and the spinal cord;
forebrain. SHH is not only responsible for dorsoventral and (3) the pontine flexure in the hindbrain. The three
patterning in the CNS, but also plays a role during the main divisions of the brain (the forebrain or prosen-
specification of oligodendrocytes, the proliferation of cephalon, the midbrain or mesencephalon and the hind-
neural precursors and the control of axon growth (Marti brain or rhombencephalon) can already be recognized
and Bovolenta 2002). The BMPs also have a variety of when the neural tube is not yet closed. The forebrain
functions (Mehler et al. 1997). Holoprosencephaly, a soon divides into an end portion, the telencephalon, and
defect in brain patterning, is the most common struc- the diencephalon, and the optic vesicles can be identified
tural anomaly of the developing forebrain (Golden (. Fig. 1.13). With the development of the cerebellum,
1998; Muenke and Beachy 2000; Sarnat and Flores- the division of the hindbrain into a rostral part, the ros-
Sarnat 2001; Monuki and Golden 2018; 7 Chap. 9). tral hindbrain, colloquially called the ‘pons’, and a cau-
Specialized, transverse patterning centres are present dal part, the caudal hindbrain (medulla oblongata or
at specific anteroposterior locations of the neural plate myelencephalon), becomes evident. The junction between
such as the anterior neural ridge, the intrathalamic limit- the hindbrain and midbrain is relatively narrow and is
ing zone and the already mentioned MHB (. Fig. 1.11). known as the rhombencephalic isthmus (isthmus rhomb-
They provide a source of secreted factors that establish encephali). The first part of the telencephalon that can
the regional identity in adjacent domains of the neural be recognized is the telencephalon medium or impar. By
tube. The posterior limit of Otx2 expression marks the CS 15, the future cerebral hemispheres can be recog-
anterior limit of the MHB, whereas the anterior limit of nized. The cerebral hemispheres enlarge rapidly so that
Gbx2 expression marks its posterior limit. In Otx2 by the end of the embryonic period they completely
knockout mice, the rostral neuroectoderm is not formed, cover the diencephalon. Frontal, temporal and occipital
leading to the absence of the prosencephalon and the poles and the insula become recognizable (. Fig. 1.12),
midbrain (Acampora et al. 2001; Wurst and Bally-Cuif whereas an olfactory bulb becomes visible on the ventral
2001). In Gbx2 knockouts, all structures arising from the surface. Nakashima et al. (2011) used MR microscopic
first two rhombomeres (r0, r1), such as the cerebellum, imaging for a morphometric analysis of the brain vesi-
are absent. Cells in the MHB (the isthmic organizer) cles during the embryonic period.
secrete fibroblast growth factors (FGFs) and Wnt pro-
teins, which are required for the differentiation and pat-
terning of the midbrain and hindbrain (Rhinn and 1.7.1 Imaging of the Embryonic Brain
Brand 2001). The intrathalamic limiting zone (zona limi-
tans intrathalamica) of Rendahl (1924) is important for The introduction of the ultrasound method has opened
the establishment of regional identity in the diencepha- new possibilities for studying the human embryonic
lon (Kiecker and Lumsden 2012). It separates the (dor- brain. The use of the transvaginal route has so greatly
sal) thalamus from the ventral thalamus or prethalamus improved the image quality that a detailed description of
(7 Chaps. 2 and 9). Signals from the anterior neural the living embryo and early foetus has become possible
ridge including FGF8 regulate the expression of Foxg1 (. Fig. 1.14). Ultrasound data show agreement with the
(earlier known as brain factor 1, BF1), a transcription developmental time schedule described in the Carnegie
factor that is required for normal telencephalic and cor- staging (CS) system (Blaas et al. 1994, 1995a, b; Blaas
tical morphogenesis (Rubenstein and Beachy 1998; and Eik-Nes 1996, 2009; van Zalen-Sprock et al. 1996;
Monuki and Walsh 2001). For structural brain anoma- Blaas 1999; Pooh 2009; Pooh et al. 2003, 2011). Human
lies in patients with FOXG1 syndrome and in Foxg1+/– development and possible maldevelopment can be fol-
mice, see Pringsheim et al. (2019) and 7 Chap. 10. lowed in time. Three-dimensional (3D) ultrasound tech-
. Fig. 1.12 Lateral views of the developing brain in CS 12, 13, 15, trigeminal ganglion, mes mesencephalon, n pl nasal placode, o occip-
17 and 23. The mesencephalon is indicated in light red. cb cerebel- ital lobe, pros prosencephalon, t temporal lobe, tel telencephalon.
lum, di diencephalon, ep epiphysis, ev eye vesicle, f frontal lobe, f ce (After O’Rahilly and Müller 1999)
flexura cervicalis, f cr flexura cranialis, f po flexura pontina, gV, V
niques have made it possible to reconstruct the shape of to that of Hox genes in mice (Vieille-Grosjean et al.
the brain ventricles and to measure their volumes (Blaas 1997). Each rhombomere is characterized by a unique
et al. 1995a, b; Blaas 1999; Blaas and Eik-Nes 2002). combination of Hox genes, its Hox code. The timing and
Anomalies of the ventricular system such as diverticula sequence of appearance of neuromeres and their deriva-
are rare (Hori et al. 1983, 1984a). Accessory ventricles of tives were studied in staged human embryos (Müller and
the posterior horn are relatively common and develop O’Rahilly 1997; . Fig. 1.16). In the human brain, they
postnatally (Hori et al. 1984b; Tsuboi et al. 1984). are usually abbreviated with a capital (M1, P1, Rh1), in
all other vertebrates without (m1, p1, r1). The neuro-
meres of the forebrain, midbrain and hindbrain were
1.7.2 Neuromeres determined morphologically on the basis of sulci,
mitotic activity in the walls and fibre tracts. Six primary
Morphological segments or neuromeres of the brain neuromeres appear already at CS 9 when the neural folds
were already known to von Baer (1828), and described are not fused (. Fig. 1.8b): prosencephalon, mesen-
for the human brain by Bartelmez (1923) and Bergquist cephalon and four rhombomeres (A–D). Sixteen second-
(1952), and for many other vertebrates (Nieuwenhuys ary neuromeres can be recognized from about CS 11.
1998). Neuromeres are segmentally arranged transverse They gradually fade after CS 15 (. Fig. 1.13). Eight
bulges along the neural tube, particularly evident in the rhombomeres (Rh1–8), an isthmic neuromere (I), two
hindbrain (. Fig. 1.15). Only more recently, interest in mesomeres (M1, M2) of the midbrain, two diencephalic
neuromeres was greatly renewed owing to the advent of neuromeres (D1, D2) and one telencephalic neuromere
gene-expression studies on development, starting with (T) have been distinguished. The diencephalic neuro-
the homeobox genes. The expression of HOX genes in mere D2 can be further subdivided into the synencepha-
the developing human brain stem is directly comparable lon, the caudal parencephalon and the rostral
23 1
. Fig. 1.13 Medial views of the developing brain in CS stages 10–13, geminal ganglion, gVII facial ganglion, hy hypothalamus, is isthmus,
15 and 17. The mesomeres (M, M1, M2) and the mesencephalon (mes) Lc locus coeruleus, lge lateral ganglionic eminence, lterm lamina ter-
are indicated in light red. Asterisks indicate the spinomedullary junc- minalis, mge medial ganglionic eminence, np cran cranial neuropore,
tion. ap alar plate, bp basal plate, cbi internal cerebellar bulge, cho chi- nIV nervus trochlearis, ov otic vesicle, 1–8 rhombomeres, slH sulcus
asma opticum, comm pl commissural plate, D1, D2 diencephalic limitans of His, syn synencephalon, telm telencephalon medium, vth
neuromeres, dth dorsal thalamus, ep epiphysis, ev eye vesicle, gV tri- ventral thalamus. (After O’Rahilly and Müller 1999)
parencephalon. Neuromere D1 was suggested to give rise In fact, the human prosomeres D1 and T together form
to the optic vesicles and the medial ganglionic eminences the secondary prosencephalon. Consequently, the medial
(Müller and O’Rahilly 1997; O’Rahilly and Müller ganglionic eminence and the hypothalamus arise from
2008). It should be emphasized, however, that Müller the secondary prosencephalon. A recent version of the
and O’Rahilly’s subdivision of the prosencephalon is prosomeric model is shown in . Fig. 1.18.
rather arbitrary. The prosomere D1 is defined as a far Each neuromere has alar (dorsal) and basal (ven-
too large neuromere extending to the rostral border of tral) components. In the developing spinal cord and
the chiasmatic plate. It seems more likely that the proso- brain stem, the limiting sulcus of His divides the prolif-
meric model developed by Puelles and Rubenstein (2003) erative compartments into alar and basal plates. The
can also be applied to human embryos. In this model, mesencephalic part of the sulcus is not continuous with
the primary prosencephalon becomes divided into the a more rostral, diencephalic sulcus (Keyser 1972;
caudal prosencephalon, giving rise to the prosomeres P1– Gribnau and Geijsberts 1985; Müller and O’Rahilly
P3 (the diencephalon), and the secondary prosencephalon, 1997; . Fig. 1.13). Studies in mice (Bulfone et al. 1993;
giving rise to the hypothalamus, the eye vesicles, the neu- Puelles and Rubenstein 1993; Shimamura et al. 1995;
rohypophysis and the entire telencephalon including the Rubenstein et al. 1998; Martínez et al. 2012; Medina
medial and lateral ganglionic eminences (. Fig. 1.17). and Abellán 2012; Puelles et al. 2012) showed that some
a b c
d e f
g h i
. Fig. 1.14 Ultrasound images in human embryos of seven a–f and nal sections in d–f. In the lower set of figures g–i, silhouette ultra-
seven to eight gestational weeks (GW; g–i). In the upper set of fig- sound images at GW 7–8; crown-rump length: 19.3 mm (g), 22.3 mm
ures a–f, surface rendering image a and silhouette ultrasound image (h) and 23.9mm (i). These ultrasound images show the rapid devel-
b showing forebrain, midbrain and hindbrain. In c–f, tomographic opment of the telencephalon (arrows). These images were kindly pro-
ultrasound images, a sagittal section c showing the level of the coro- vided by Ritsuko Pooh (Osaka)
genes are expressed in the alar plate only, others only in In mice (7 Chap. 2), the prosencephalon has been
the basal plate (. Fig. 1.11). One gene, Nkx2.2, is divided into six prosomeres, numbered p1–p6 from cau-
expressed along the longitudinal axis of the brain, end- dal to rostral. Prosomeres p1–p3 form the diencephalon.
ing in the chiasmatic region. Based on these findings, in The prosomeres p4–p6, together known as a protoseg-
all murine prosomeres alar and basal parts are distin- ment, form the secondary prosencephalon (Rubenstein
guished (Rubenstein et al. 1998; Puelles et al. 2000; et al. 1998; Puelles et al. 2000, 2012, 2013; Puelles and
Puelles and Rubenstein 2003; Martínez et al. 2012; Rubenstein 2003; Martínez et al. 2012; Puelles 2013,
Puelles 2013; . Fig. 1.18). Puelles and Verney (1998) 2019), from which the hypothalamus, both eye vesicles,
applied the prosomeric subdivision to the human fore- the neurohypophysis and the telencephalon arise. The
brain. The prosomeric model of the vertebrate fore- basal part of the secondary prosencephalon gives rise to
brain was implemented in the HUDSEN Atlas the basal part of the hypothalamus, whereas from the
(7 http://www.hudsen.org), a three-dimensional spatial alar part, the alar part of the hypothalamus and the
framework for studying gene expression in the develop- entire telencephalon, i.e. the cerebral cortex and the sub-
ing human brain (Kerwin et al. 2010). cortical centres, such as the basal ganglia, arise. The eye
25 1
the diencephalon: p1 is the synencephalon, p2 the caudal
parencephalon and p3 the rostral parencephalon. These
three segmental units contain in their alar domains
(. Fig. 1.18; Puelles et al. 2008; Puelles et al. 2012, 2013;
Puelles 2019), from caudal to rostral, the pretectum with
the pretectal nuclei and the posterior commissure (p1), the
epithalamus with the habenular nuclei, and the thalamus
(p2), and the prethalamus with the prethalamic reticular
nucleus and the zona incerta, and the eminentia prethal-
ami (p3). The diencephalic basal plate contains the dien-
cephalic part of the substantia nigra–ventral tegmental
area (VTA) complex, the interstitial nucleus of Cajal and
related nuclei and the fields of Forel, collectively described
as the prerubral or diencephalic tegmentum (TNA 2017).
In several aspects, the diencephalic basal region shares
characteristics with the midbrain, so ‘mesodiencephalic’
may also be a useful descriptor. The entire hypothalamus
arises from the alar and basal components of the second-
ary prosencephalon. The secondary prosencephalon is
currently divided into three parts: (1) the hypothalamic
and telencephalic prosomere 1 (hp1), from which the cau-
dal or peduncular hypothalamus derives; (2) the hypotha-
lamic and telencephalic prosomere 2 (hp2), from which the
rostral or terminal hypothalamus derives; and (3) the
acroterminal region, from which the eye vesicle and the
neurohypophysis derive (. Fig. 1.18). The entire telen-
cephalon, pallium and subpallium derive from the alar
components of the secondary prosencephalon.
A relatively small set of genes is sufficient to establish
the rostrocaudal general plan of the CNS (Puelles 2013,
2019; Watson et al. 2019). Those vital to brain stem
development include the Pax group, Otx2, Wnt1, Gbx2,
Fgf8, Shh and the family of the Hox genes. Pax6 estab-
lishes the boundary between the diencephalon and the
midbrain; Otx2 is expressed in the forebrain and mid-
brain, but not in the hindbrain; Gbx2 is expressed in the
. Fig. 1.15 Dorsal view of a malformed embryo (CS 14) showing
the bulging of several rhombomeres. (Kindly provided by Kohei
most rostral part of the hindbrain (isthmus and r1);
Shiota, Kyoto) Fgf8 is selectively expressed in the isthmus; and the Hox
genes are expressed from r2 to the end of the spinal
vesicles and the neurohypophysis arise from the most cord. Since the cerebellum is a developmental dorsal
rostral part of the secondary prosencephalon, i.e. the alar derivative of the isthmus and the first rhombomere,
acroterminal region. More recently, Puelles et al. (2012) it is also an intrinsic part of the hindbrain. There is now
subdivided the secondary prosencephalon into two need to harmonize the parts of the neuromeric hind-
hypothalamic ‘prosomeres’ (hp2 and hp1) and the acro- brain with the older subdivision into pons and medulla
terminal region (. Fig. 1.18; 7 Chaps. 2 and 9). oblongata. Watson et al. (2019) proposed to group the
The diencephalon in its classic, columnar view (Herrick region from the isthmus to the sixth rhombomere as the
1910; Droogleever Fortuyn 1912) was divided into four rostral hindbrain and rhombomeres 7–11 as the caudal
dorsoventrally arranged columns separated by ventricular hindbrain. As a consequence, several structures tradi-
sulci, i.e. the epithalamus, the dorsal thalamus, the ventral tionally included within the caudal mesencephalon in
thalamus and the hypothalamus. Extensive embryological fact arise from the isthmic rhombomere and should be
studies by the Swedish school of neuroembryologists included within the isthmic region of the prepontine teg-
(Bergquist and Källén 1954) and a more recent Spanish mentum (. Fig. 1.19). Based on the distribution of the
school initiated by Luis Puelles (1995) made it clear that Otx2 gene, Puelles (2019) argued that the midbrain
the thalamic ‘columns’ are derived from transversely ori- belongs to the forebrain as it was already suggested by
ented zones, the prosomeres. The prosomeres p1–p3 form His (1893, 1895).
. Fig. 1.16 Median section of a CS 13 embryo. Rhombomeres 2, 4 and 6 can be recognized by ventral bulges. cb cerebellum, is isthmus, M1,
M2 mesomeres, Rp Rathke’s pouch, syn synencephalon, tel telencephalon, v4 fourth ventricle. (From O’Rahilly 1975, with permission)
a The subdivision of the mesencephalon into two,

b almost even large, mesomeres has also been questioned.
Fate mapping and gene expression data showed that
only a very small caudal mesomere 2 can be distin-
guished, the large remainder of the mesencephalon aris-
ing from the rostral mesomere 1 (Martínez et al. 2012;
. Fig. 1.19; 7 Chap. 7). With the site-specific recombi-
nase technique, by which transient developmental
expression can trigger persistent expression of a reporter
gene, the Fgf8–Cre lineage, it was possible to sharply
c define the presumptive isthmic territory (Watson et al.
2017). The isthmic region so defined contains the troch-
lear nucleus, the dorsal raphe nucleus, the dorsal nucleus
of the lateral lemniscus and the vermis of the cerebel-
lum. The cerebellar hemispheres arise from the first
rhombomere that lacks Fgf8 expression. Other charac-
teristics of the isthmus are: (1) it contains serotonergic
raphe neurons, whereas such neurons are not generated
in the midbrain (Alonso et al. 2013); the rostral part of
the dorsal raphe nucleus extends into the caudal mid-
brain as a result of migration from the isthmus; and (2)
it houses the hindbrain cholinergic neurons, the parabi-
geminal nucleus (Ch8), the laterodorsal nucleus (Ch6)
and the pedunculopontine or pedunculotegmental
nucleus (Ch5). It should also be emphasized that the
. Fig. 1.17 a, c Segmentation of the human brain; b shows the decussation of the superior cerebellar peduncles lies
classic O’Rahilly and Müller subdivision. ap alar plate, bp basal across the floor of the isthmus as already described by
plate, cb cerebellum, CI colliculus inferior, CS colliculus superior, di His (1895), not in the newly defined midbrain.
diencephalon, ev eye vesicle, hyp hypothalamus, mes mesencephalon
In colloquial neuroanatomy, the term pons is used
(in light red), met metencephalon, myel myelencephalon, nc noto-
chord (in medium red), p1–p3 prosomeres, r0–r11 rhombomeres, sp for the region that extends from the midbrain to the
secondary prosencephalon, tel telencephalon (see text for further myelencephalon. In a transverse section through the
explanation). (After Puelles et al. 2008) pons at the level of the abducens nucleus, the trape-
27 1
. Fig. 1.18 Prosomeric model of the mouse brain. The roof plate hypothalamic basal plate, in light red. Dg diagonal band, ep epiphy-
(rp) has been indicated in light grey, in between the two parts, the sis, ev eye vesicle, hy1, hy2 hypothalamic prosomeres, nh neurohy-
choroid plexus of the third ventricle is shown in black. The red line pophysis, Pal pallium, Pd pallidum, Poa preoptic area, p1–p3
separates the alar and basal parts. The floor plate (fp) is shown in diencephalic prosomeres, Str striatum, zli zona limitans intrathal-
red, the substantia nigra (SN) in medium red and the subthalamic amica. (After Puelles et al. 2012; see text for further explanation)
nucleus (Sth) and the mammillary body (M), both derivatives of the
a b
. Fig. 1.19 Diagrams showing a the traditional view of the mesen- peduncle, isth isthmocerebellar rhombomere (r0), LGB lateral genic-
cephalon and b the new, prosomeric view (modified after Puelles ulate nucleus, MB mammillary body, mcp middle cerebellar pedun-
2019 Front Neuroanat 13:20; with permission, courtesy Luis Puelles, cle, MGB medial geniculate nucleus, MO medulla oblongata, NH
Murcia; see text for explanation; from ten Donkelaar 2020). In the neurohypophysis, ot optic tract, m1, m2 mesomeres, pc posterior
prosomeric model, part of the caudal mesencephalon is included in commissure, ped cerebral peduncle, PG pineal gland, PHy peduncu-
the rostral hindbrain, whereas the pretectum and related tegmentum lar hypothalamus, PN pontine nuclei, Pre pretectum, Pth prethala-
are included in the diencephalon. The diencephalohypothalamic mus, pyr pyramid, p1–p3 diencephalic prosomeres, r1–r5
boundary (DHyB) marks the border between the hypothalamus and rhombomeres, SC superior colliculus, scp superior cerebellar pedun-
the diencephalon, the midbrain–diencephalic boundary (MDB) that cle, Th thalamus, Thy terminal hypothalamus, tpt transverse pedun-
between the diencephalon and the midbrain and the midbrain–hind- cular tract, nIII oculomotor nerve, nIV trochlear nerve, V trigeminal
brain boundary (MHB) that between the midbrain and the rostral nerve root, nVI abducens nerve, VII facial nerve, VIII vestibuloco-
hindbrain. Ha habenula, IC inferior colliculus, icp inferior cerebellar chlear nerve
zoid body separates the pontine tegmentum from the isthmus or r0 and rhomobomere 1. The large remainder
1 basilar part of the pons. The term pons, however, as of the hindbrain is marked by the expression of Hox
pons Varolii, means the large protrusion with the pon- genes and can be divided into ten segments (r2–r11).
tine nuclei and associated fibre pathways. In fact, the Rhombomeres r2–r6 can be recognized as overt bulges
pontine nuclei arise from the lower rhombic lip in r6 separated by constrictions in the embryonic hindbrain.
and r7, and migrate to the ventral margin of r3 and r4. The caudal hindbrain was first subdivided into two
Therefore, the term ‘pons’ as a regional descriptor of a rhombomeres, r7 and r8 (Lumsden and Krumlauf
zone ventral to the cerebellum reaching from the mid- 1996). Fate mapping and differential Hox gene expres-
brain to the medulla oblongata should be abandoned, sion in the avian medulla oblongata (Marín et al. 2008)
although this will take a long time, especially in clini- suggested a further subdivision into rhombomeres r7–
cal terms. From an ontological point of view, the terms r11. Rodent data also suggest such a subdivision (Watson
prepontine, pontine and retropontine (or pontomedul- 2012; Puelles et al. 2013; Tomás-Roca et al. 2016; Watson
lary) tegmentum are preferred (Puelles et al. 2013; et al. 2019).
Watson et al. 2019; . Fig. 1.20). The term pons can
be properly applied to the nuclei and crossing fibres of
the traditional basilar part of the pons. The substan- 1.7.3 The Ganglionic Eminences
tial prepontine tegmentum includes the isthmus (r0)
and rhombomere 1, and contains the trochlear nucleus, At first, each cerebral hemisphere consists of a thick
the parabigeminal nucleus, the pedunculopontine or basal part, the subpallium, giving rise to the basal gan-
pedunculotegmental nucleus, the locus coeruleus, the glia, and a thin part, the pallium, that becomes the future
interpeduncular nucleus and the parabrachial nuclei. cerebral cortex. The subpallium appears as medial and
The pontine tegmentum (r2–4) includes among others lateral elevations, known as the ganglionic (Ganglionhügel
the motor trigeminal nucleus. Other structures, such as of His 1889) or ventricular eminences (. Fig. 1.21). The
the trapezoid body, the superior olivary complex and caudal part of the ventricular eminences is also known
the abducens nucleus, are strictly retropontine (r5, r6) as the caudal ganglionic eminence, and gives rise to the
and associated with rhombomere 5. subpallial parts of the amygdala. The medial ganglionic
Currently, the hindbrain is subdivided into 12 rhom- eminence is involved in the formation of the globus pal-
bomeres (r0–r11), counting the isthmus as r0 (Martínez lidus, whereas the larger lateral ganglionic eminence
et al. 2012; Watson 2012; Watson et al. 2019; . Fig. 1.20). gives rise to the caudate nucleus, the putamen and olfac-
The rostral hindbrain corresponds to the part influenced tory bulb interneurons (7 Chap. 9). As the internal cap-
by the isthmic organizer and can be divided into the sule develops, its fibres separate the caudate nucleus
. Fig. 1.20 New view on the hindbrain organization (from Watson retropontine regions. The prepontine part arises from the isthmic
C, Bartholomaeus C, Puelles L 2019 Time for radical changes in brain rhombomere (isth) or r0 and the rhombomere r1, the pontine part
stem nomenclature – applying the lessons from developmental gene from the rhombomeres r2–r4 and the retropontine part from the
patterns. Front Neuroanat 13:10; with permission; courtesy Charles rhombomeres r5 and r6. The caudal hindbrain or medulla oblongata
Watson, Perth). The diagram shows the current subdivision of the arises from the rhombomeres 7–11
rostral hindbrain into prepontine or isthmocerebellar, pontine and
1.8 · Foetal Development of the Brain
29 1
from the putamen, and the thalamus and the subthala- tion nuclei such as the pulvinar through a transient foe-
mus from the globus pallidus. The three ventricular emi- tal structure, the gangliothalamic body (Rakić and
nences are also involved in the formation of the cerebral Sidman 1969; Letinić and Kostović 1997; Letinić and
cortex. The pyramidal cells of the cerebral cortex arise Rakic 2001).
from the ventricular zone of the pallium, but the cortical
GABAergic interneurons arise from the three ganglionic
eminences, the medial and caudal eminence in particular 1.8 Foetal Development of the Brain
(Parnavelas 2000; Anderson et al. 2001; Marín and
Rubenstein 2001; Clowry 2015; Alzu’bi et al. 2017a, b; The most obvious changes in the foetal period are (1)
Clowry et al. 2018; Alzu’bi and Clowry 2019; 7 Chap. the outgrowth of the cerebellar hemispheres and the for-
9). In the human forebrain, cortical interneurons were mation of its median part, the vermis; (2) the continu-
assumed to arise in the ventricular and subventricular ous expansion of the cerebral hemispheres, the formation
zones of the dorsal telencephalon as well (Letinić et al. of the temporal lobe and the formation of sulci and
2002; Rakic 2009). More recent studies (Hansen et al. gyri; and (3) the formation of commissural connections,
2013; Ma et al. 2013; Alzu’bi and Clowry 2019), how- the corpus callosum in particular. The foetal period has
ever, suggest that intracortical interneurogenesis arises been extensively illustrated in Bayer and Altman’s Atlas
from dorsal progenitors or from ventral progenitors that of Human Central Nervous System Development (Bayer
have migrated dorsally and continue dividing. The cau- and Altman 2003, 2005, 2006, 2007). More recently,
dal part of the ganglionic eminence also gives rise to a Ivica Kostović and co-workers focussed on the transient
contingent of GABAergic neurons for thalamic associa- zones, the subplate in particular, and their role in brain
a b
. Fig. 1.21 Transverse sections through the human forebrain, ventricle, mge medial ganglionic eminence, pal pallium, plch plexus
showing the developing ganglionic or ventricular eminences at stages choroideus, v3 third ventricle. (From O’Rahilly 1975, with permis-
17 a and 20 b, respectively. lge lateral ganglionic eminence, lv lateral sion)
Another random document with
no related content on Scribd:
The Project Gutenberg eBook of Six
months on the Italian front
This ebook is for the use of anyone anywhere in the United States
and most other parts of the world at no cost and with almost no
restrictions whatsoever. You may copy it, give it away or re-use it
under the terms of the Project Gutenberg License included with this
ebook or online at www.gutenberg.org. If you are not located in the
United States, you will have to check the laws of the country where
you are located before using this eBook.
Title: Six months on the Italian front
Author: Julius M. Price
Release date: October 11, 2023 [eBook #71851]
Language: English
Original publication: New York: E. P. Dutton & Co, 1917
Credits: Peter Becker, John Campbell and the Online Distributed

Proofreading Team at https://www.pgdp.net (This file was
produced from images generously made available by The
Internet Archive)
*** START OF THE PROJECT GUTENBERG EBOOK SIX MONTHS

ON THE ITALIAN FRONT ***
TRANSCRIBER’S NOTE
There is only one Footnote in this book, on page 166. This Footnote has been
moved and placed directly under the paragraph that has its anchor [A].
New original cover art included with this eBook is granted to the public domain.
Some minor changes to the text are noted at the end of the book.
SIX MONTHS
O N T H E I TA L I A N F R O N T
WORKS BY THE SAME
AUTHOR
FROM THE ARCTIC OCEAN TO THE
YELLOW SEA
THE LAND OF GOLD
FROM EUSTON TO KLONDIKE
DAME FASHION
MY BOHEMIAN DAYS IN PARIS
MY BOHEMIAN DAYS IN LONDON
The Author in San Martino del Carso.
From a snapshot by Robert Vaucher.
Correspondent of the Paris L’Illustration.
SIX MONTHS ON
THE ITALIAN FRONT
From the Stelvio to the Adriatic
1915-1916
By
Julius M. Price
War-Artist Correspondent of the
“Illustrated London News”
NEW YORK
E. P. DUTTON & COMPANY

681 FIFTH AVENUE
1917
PRINTED IN GREAT BRITAIN BY
THE WESTMINSTER PRESS
411A HARROW ROAD
LONDON W
To the Italian Military Authorities
in recognition of the courtesy and many kindnesses

extended to me during my six months’ work with the
glorious Army of Italy.
NOTE
I am indebted to the Directors of the Illustrated

London News for their kind permission to reproduce in
this book the sketches and drawings I made for them
whilst on the Italian Front, a great many of which have
already been published.
P R E FA C E
As the reader will discover for himself, I have no pretensions to pose

as a Military Expert. This book is the result of a few hasty
impressions gathered over a period which, with all its minor
inconveniences and little daily worries, I look back upon as among
the happiest and best filled of a somewhat varied career. I have not
yielded to the temptation to be interesting at the expense of veracity;
to that fact the indulgent reader will, I trust, attribute many of the dull
pages. If in the latter half of the book I have laid particular stress on
the operations leading up to and culminating in the capture of
Gorizia, I hope I may be forgiven, as I had the good luck to be the
only foreign correspondent on the spot at these scenes of History-
making. In my dedication I have paid a humble tribute to the many
kindnesses I received at the hands of the Military Authorities, from
His Excellency General Cadorna downwards. I can only repeat it
here.
Julius M. Price.
21, Golden Square,
London, W.
January, 1917.
CONTENTS
CHAPTER I: PAGE
Marching orders—I leave for Rome—Paris via Folkestone and
Boulogne in war time—My campaigning kit—The war-correspondent’s
list—Quaint item—Travelling “light”—A box of choice Havanas—
Boulogne to Paris; well-intentioned ladies and their “Woodbines”—The
one and only cigarette—Paris to Turin—Curious order on train—Method
and prescience—Few soldiers on route—Arrival in Rome—A cheap
room—No sign of excitement in streets—23rd May—Excitability of the
Italian no longer noticeable—Rome unruffled—The declaration of war—
On the Corso Umberto that evening—The Café Aragno—National
stoicism—The Day—Business as usual—The general mobilisation—A
triumph of organization—At the War Office 3
CHAPTER II:
My credentials—The War Zone—Italy’s preparedness—The Press
Censorship—General Elia’s advice—Disappointment—A pipe in the
Pincio—An inspiration—I leave for Venice—Venice in war time—The
lonely pigeons of the Place St. Marc—The Doge’s Palace—The bronze
horses—Interior of St. Marc, strange spectacle—First act of war
between Italy and Austria—Aeroplane bombs Venice—French Aviators
—Treasures of Venice—Everyday life in Venice during daytime—After
nightfall—On the qui vive—Extraordinary precautions—Dangers of the
streets—Spy fever—Permis de séjour—The angry crowd—Defences
against air attacks—Venice not a place forte—Nearest point of the
Front—The British Vice-Consul, Mr. Beak—A good Samaritan—The
letter of credentials—The Commandant of Venice—More advice—New
Rescript of the Generalissimo—Reference to Correspondents—Decide
attempt go to Udine—The language difficulty—The waiter at the Hotel
Danielli—His offer to accompany me—Make arrangements at once—
Introduced to Peppino Garibaldi—Amusing incident 15
CHAPTER III:
From Venice to Udine—Reservists rejoining—Interesting crowd— 25
Delays en route—Endless procession of military trains—Drawn blinds—
The Red Cross train—Arrived Udine—Scene on platform—In search of
an hotel—A little incident—The well-dressed civilian—The obliging
guide—My suspicions—Awkward questions—The best hotel in Udine—
A little “Trattoria” close by—A cheap room—First impressions of Udine
—At the Police Office—The permis de séjour—The Carabinieri and the
local police—The fascination of the big guns—The “Military
Commandant of Udine”—A difficult proposition—The luck of the
undelivered letter—My guide has to leave me—I change my quarters—
The Hotel “Tower of London”—Alone in Udine—An awkward
predicament—A friend in need—Still more luck—Dr. Berthod—I am
offered a studio—I accept—The delight of having this studio in Udine
CHAPTER IV:
The wonderful system on which everything was worked—Udine “the
Front”—The commencement of hostilities—The 24th May—The first
day of operations auspicious for Italy—Redemption of the province of
Friuli—New Italian Front—Cormons—The inhabitants of Italian origin—
A good practical joke—The moral of the troops—Unpretentious
attempts at wit—High spirits of the men—The road from Udine to
Cormons—Wonderful sight—Italian flags everywhere—A mystery
where they came from—Wild triumphant advance of the Italian troops—
Women kiss the ground—But a lever de rideau—Italians cross the
Isonzo—Austrians on Monte Nero—Monte Nero—The capture of Monte
Nero—Incredible daring of the Alpini—The story of the great
achievement—Number of prisoners taken—The prisoners brought to
Udine—Their temporary prison—The tropical heat—An ugly incident—
Austrian attempt to re-take Monte Nero—Success follows success—
Capture of Monfalcone and Gradisca; Sagrado and Monte Corrada—
Commencement of the attack on Gorizia—Subjects for my sketch book
—Touches of human nature—High Mass in the mountains—The tentes
d’abri—Cheerfulness of men in spite of all hardships 37
CHAPTER V:
Udine the Headquarters of the Army—The King—His indefatigability— 49
His undaunted courage—A telling incident—The King with the troops—
Love and sympathy between Victor Emanuele and the men—
Brotherhood of the whole Army—A pleasant incident—Men salute
officers at all times—Laxity shown in London—Cohesion between rank
and file—The Italians of to-day—The single idea of all—Udine crowded
with soldiers—The military missions of the allied nations—Big trade
being done—Orderly and sedate crowd—Restaurants—The food—The
market-place—The Cinemas—Proximity of the fighting—The Café
“Dorta”—Pretty and smartly-dressed women—An unexpected spectacle
—The Military Governor—The streets at night—Precautions against
“Taubes”—The signal gun—Curiosity of inhabitants—No excitement—
Udine a sort of haven—I remain there six weeks—A meeting with the
British Military Attaché, Colonel Lamb—My stay in Udine brought to an
abrupt ending—The police officer in mufti—Am arrested—Unpleasant
experience—An agent de la Sureté—At the police station—The
commissaire—Result of my examination—Novara—Magic effect of the
undelivered letter again—I write to General Cafarelli—My friends at the
“Agrario”—General Cafarelli—His decision—The third class police ticket
for the railway—Packed off to Florence—The end of the adventure
CHAPTER VI:
Florence in war time—War correspondents to visit the Front—I receive
a letter from Mr. Capel Cure of the Embassy—Return to Rome—Signor
Barzilai, Head of Foreign Press Bureau—I am officially “accepted”—
Correspondents to muster at Brescia—Rome to Brescia via Milan—The
gathering of the correspondents—Names of those present—Papers
represented—The correspondent’s armlet—Speech of welcome by
General Porro—Plan of journey announced—Introduced to officers of
Censorship—To leave war zone a conclusion of tour of Front
—“Shepherding” the correspondents—Censorships established at
various places—Correspondents’ motor cars—Clubbing together—Car-
parties—My companions—Imposing array of correspondents’ cars—
National flags—Cordiality amongst all correspondents and Censors—
Good-fellowship shown by Italians—Banquet to celebrate the occasion 63
CHAPTER VII:
Brescia—Rough sketch of arrangements—A printed itinerary of tour— 71
Military passes—Rendezvous on certain dates—The “off-days”—Much
latitude allowed—We make a start—Matutinal hour—First experience of
freedom of action—Like schoolboys let loose—In the valley of
Guidicaria—First impression of trenches on mountains—A gigantic
furrow—Encampments of thousands of soldiers—Like the great wall of
China—Preconceived notions of warfare upset—Trenches on summits
of mountains—A vast military colony—Pride of officers and men in their
work—Men on “special” work—“Grousing” unknown in Italian Army—
Territorials—Middle aged men—“Full of beans”—Territorials in first line
trenches—Modern warfare for three-year olds only—Hardy old
mountaineers—Heart strain—The road along Lake Garda—Military
preparations everywhere—War on the Lake—The flotilla of gun-boats—
The Perils of the Lake—A trip on the “Mincio” gun-boat—I make a
sketch of Riva—A miniature Gibraltar—Desenzano—Nocturnal activity
of mosquitoes—Return to Brescia—Something wrong with the car—
Jules Rateau of the Echo de Paris—Arrange excursion to Stelvio Pass
—A wonderful motor trip—The Valley of Valtellino—The corkscrew road
—Bormio—The Staff Colonel receives us—Permits our visiting
positions—Village not evacuated—Hotel open—Officers’ table d’hôte—
We create a mild surprise—Spend the night at hotel
CHAPTER VIII:
On the summit of the Forcola—We start off in “military” time—Our guide
—Hard climbing—Realize we are no longer youthful—Under fire—
Necessary precautions—Our goal in sight—An awful bit of track—
Vertigo—A terrifying predicament—In the Forcola position—A gigantic
ant-heap—Unique position of the Forcola—A glorious panorama—The
Austrian Tyrol—The three frontiers—Shown round position—Self-
contained arsenal—Lunch in the mess-room—Interesting chat—The
“observation post”—The goniometre—Return to Bormio—Decide to
pass another night there—An invitation from the sergeants—Amusing
incident 85
CHAPTER IX:
From Brescia to Verona—Absence of military movement in rural 97
districts—Verona—No time for sightseeing—The axis of the Trentino—
Roveretto, the focus of operations—Fort Pozzachio—A “dummy
fortress”—Wasted labour—Interesting incident—Excursion to Ala—
Lunch to the correspondents—Ingenious ferry-boat on River Adige—
The Valley of the Adige—Wonderful panorama—“No sketching
allowed”—Curious finish of incident—Austrian positions—Desperate
fighting—From Verona to Vicenza—The positions of Fiera di Primiero—
Capture of Monte Marmolada—The Dolomites—Their weird fascination
—A striking incident—The attempted suicide—The Col di Lana—Up the
mountains on mules—Sturdy Alpini Method of getting guns and
supplies to these great heights—The observation post and telephone
cabin on summit—The Colonel of Artillery—What it would have cost to
capture the Col di Lana then—The Colonel has an idea—The idea put
into execution—The development of the idea—Effect on the Col di Lana
—An object lesson—The Colonel gets into hot water—The return down
the mountain—Caprili—Under fire—We make for shelter—The village
muck-heap—Unpleasant position—A fine example of coolness—The
wounded mule—An impromptu dressing
CHAPTER X:
Belluno—Venadoro in the heart of the Dolomites—A fine hotel—Tame
excursions—Visit to Cortina d’Ampezzo—Austrian attempts to
recapture it—305mm. guns on the Schluderbach—Long range
bombardment—Austrian women and children in the town—Italians
capture Monte Cristallo—Aeroplanes and observation balloons
impossible here—Tofana in hands of Italians—Serenity of garrison—
Cortina d’Ampezzo—General invites us to a déjeuner—Living at
Venadoro—Delightful camaraderie—Evenings in the big saloon—From
Belluno to Gemona—Description of Front in this Sector—Our excursion
to Pal Grande—The road—On mules up the mountain—A warning—
Rough track—Peasant women carrying barbed wire up to the trenches
—Pay of the women—Much competition for “vacancies”—The climb
from Pal Piccolo to Pal Grande—A wonderful old man—“Some” climb—
The entrenched position on Pal Grande—Spice of danger—Violent
artillery duel—The noise of the passing shells—Magnificent view—
Timau—The Freikoffel—Its capture by the Alpini—Wounded lowered by
ropes—Capture of Pal Grande—Presence of mind of a doctor—A
telling incident—Extraordinary enthusiasm of the troops—Food convoys
—The soldier’s menu—Daily rations—Rancio; the plat du jour—
Officers’ mess arrangements—An al fresco lunch on Pal Grande—The
“mess-room”—“Pot Luck”—A wonderful meal—A stroll round the
position—An improvised bowling alley—Use is second nature—In the
trenches—A veteran warrior—The pet of the position—Gemona—The
list of lodgings—My landlady—Good restaurants in Gemona—The
Alpini quartered there—The military tatoo in the evenings—Reception
by the Mayor—A delightful week 115
CHAPTER XI:
Gemona to Udine—Final stage of official journey—Regrets—Arrival at 131
Udine—List of recommended lodgings—My room—My landlady an
Austrian woman—I pay my respects to General Cafarelli—My friend Dr.
Berthod—My old studio at the Agrario—The Isonzo Front—Many
rumours—Off on our biggest trip; 245 kilometres in the car—Roads
excellent and well-looked after—A great change—Cormons quite an
Italian town—Same with other towns in conquered territory—
Observatory on Monte Quarin—A splendid bird’s-eye view—The plain
of Friuli—Podgora—The Carso—The hum of aeroplanes—The Isonzo
Sector—The immense difficulties—Received by the General—A
pleasant goûter—Lieutenant Nathan, Ex-Mayor of Rome—The Subida
lines of trenches—Explanation of Italian successes everywhere—
Caporetto via Tolmino—A desolate region—Road along the Isonzo—
The mighty limestone cliffs of Monte Nero—The great exploit of its
capture recalled—One mountain road very much like another—Nothing
to sketch—Perfect organization—The fog of dust—Caporetto—Not
allowed to motor beyond—Important strategic operations—Monte
Rombon—Difficulty to locate Austrian guns—A glimpse of Plezzo—The
situation here—Excursion to Gradisca via Palmanova, a semi-French
town—Romans—Curious rearrangement of cars—Only two allowed
proceed to Gradisca under fire—The Italian batteries at work—The
deserted streets—The “observatory” room—The iron screens—View of
Monte San Michele being bombarded—Stroll through the town—A big
shell—Excursion to Cervignano, Aquileia and Grado—Peaceful
country-side—Grado the Austrian Ostend—Fish-lunch at a café—The
town continually bombarded by aircraft—Arrival of Beaumont, the
French airman—Conclusion of official tour of Front—No permission
given for correspondents to remain—Success of tour—Comments on
organization, etc.
CHAPTER XII:
Conclusion of Correspondents’ tour of Front—I return to London— 149
Awaiting events—Brief official communiqués—Half Austrian Army held
up on Italian Front—Harrying tactics—Trench warfare during the winter
—Recuperative powers of the Austrians—Gorizia a veritable Verdun—
Italian occupation of Austrian territory—Many thousand square miles
conquered—A bolt from the blue—Serious development—Awakening
Austrian activity—400,000 troops in the Trentino—Front from Lake
Garda to Val Sugana ablaze—Totally unforseen onslaught—Towns and
villages captured—Genius of Cadorna—Menace of invasion ended—I
go and see Charles Ingram with reference going back to Italy—His
journalistic acumen—My marching orders—Telegram from Rome—My
journey back to Italy—Confidence everywhere—Milan in darkness—
Improvement on the railway to Udine—Udine much changed—Stolid
business air—Changes at the Censorship—Press Bureau and club for
correspondents—The Censorship staff—Few accredited
correspondents—Remarkable absence of Entente correspondents—
Badges and passes—Complete freedom of action given me—I start for
Vicenza en route for Arsiero—Scenes on road—From daylight into
darkness—Hun methods of frightfulness—Arsiero—Its unfavourable
position—Extent of the Austrian advance—Rush of the Italians—
Austrians not yet beaten—Town damaged by the fire and bombardment
—Villa of a great writer—Rossi’s paper-mills—The town itself—The
battlefield—Débris of war—A dangerous souvenir for my studio
CHAPTER XIII:
The fighting on the Asiago plateau—Brilliant counter-offensive of
General Cadorna—I go to Asiago—Wonderful organization of Italian
Army—Making new roads—Thousands of labourers—The military
causeway—Supply columns in full operation—Wonderful scenes—
Approaching the scene of action—The forest of Gallio—The big
bivouac—Whole brigades lying hidden—The forest screen—
Picturesque encampments—The “bell” tent as compared with the tente
d’abri—Our car stopped by the Carabinieri—“Nostri Canoni”—We leave
the car—The plain of Asiago—The little town of Asiago in distance—
The Austrian and Italian batteries and Italian trenches—Hurrying across
—The daily toll of the guns—Asiago in ruins—Street fighting—
Importance attaching to this point—An ominous lull—Regiment waiting
to proceed trenches—Sad spectacle—The quarters of the divisional
commandant—His “office”—Staff clerks at work—Telephone bells
ringing—The commandant’s regret at our coming—Big artillery attack to
commence—A quarter of an hour to spare—A peep at the Austrian
trenches—A little, ruined home—All movements of troops to trenches
by night—Artillery action about to commence—Not allowed go trenches
—Adventure on way back—Attempt cross no man’s land at the double
—My little “souvenir” of Asiago—Bursting shells—Ordered to take cover
—The wounded soldiers and the kitten—Anything but a pleasant spot—
The two Carabinieri—Cool courage—In the “funk-hole”—An inferno—
My own impressions—Effect on soldiers and our chauffeur—The
wounded sergeant—We prepare to make a start back—Irritating delay
—A shrapnel—My companion is wounded—Transformation along road
—Curious incident 163
CHAPTER XIV:
Slow but certain progress on the Trentino front—An open secret—The 183
mining of the Castalleto summit—Carried out by Alpini—Recapture of
Monte Cimone: also by Alpini—Heroic exploits—Udine one’s pied à
terre—An ideal “News centre”—The Isonzo Front—The old days of the
war correspondent as compared with the present conditions—Well to
be prepared—Returning to Udine for lunch—Attracting attention—
Unjustifiable—Things quiet at the Front—Unusual heat of the summer

Clinical Neuroembryology: Development and Developmental Disorders of The Human Central Nervous System Hans J. Ten Donkelaar

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Clinical Neuroembryology: Development and Developmental Disorders of The Human Central Nervous System Hans J. Ten Donkelaar

Uploaded by

Copyright:

Available Formats

Clinical Neuroembryology:

Development and Developmental

The Human Brain during the First Trimester 40- to 42-mm

WHO Classification of Tumours Central Nervous System

Therapeutic Development in the Absence of Predictive

Financial Incentives to Encourage Development of

Harnessing Mobile Devices for Nervous System Disorders:

Diseases of the Nervous System, 2nd Edition Harald

Glycobiology of the Nervous System 2nd Edition Cara-

Primer on the Autonomic Nervous System Italo Biaggioni

Eleonora Aronica Willy O. Renier

ISBN 978-3-031-26097-1 ISBN 978-3-031-26098-8 (eBook)

Apart from a general updating of the extensive literature on developmental neurobiol-

Hans J. ten Donkelaar

Apart from a general updating of the extensive literature on developmental neurobiol-

Hans J. ten Donkelaar

Preface to the First Edition

The spectacular progress in developmental neurobiology, the tremendous advances in

Hans J. ten Donkelaar

1 Overview of the Development of the Human Brain and Spinal Cord...............1

2.5.6 Specification of Cell Fate in the Telencephalon......................................................................................112

3 Causes of Congenital Malformations.....................................................................................171

4 Neurulation and Neural Tube Defects...................................................................................249

4.4.8 Foetal Sex and Neural Tube Defects...........................................................................................................269

5 The Neural Crest and Craniofacial Malformations........................................................313

6 Development and Developmental Disorders of the Spinal Cord........................379

6.7.4 Development of the Human Pyramidal Tract.........................................................................................408

7 Development and Developmental Disorders of the Brain Stem.........................445

8 Development and Developmental Disorders of the Human Cerebellum......523

8.7.2 Cerebellar Hypoplasia.....................................................................................................................................572

9 Development and Developmental Disorders of the Forebrain............................595

10 Development and Developmental Disorders of the Cerebral Cortex..............725

10.3 Overview of Main Cortical Connections............................................................................................ 733

Eleonora Aronica, M.D., Ph.D. Department of Pathology, Amsterdam UMC, Amsterdam,

Marianna Bugiani, M.D., Ph.D. Department of Pathology, Amsterdam UMC, Amsterdam,

Johannes R. M. Cruysberg, M.D., Ph.D. Department of Ophthalmology, Radboud University

Akira Hori, M.D., Ph.D. Department of Neuropathology, Medizinische Hochschule Hannover,

Ronald J. E. Pennings, M.D., Ph.D. Department of Otorhinolaryngology, Radboud University

Willy O. Renier, M.D., Ph.D. Kortrijk, Belgium

Pieter Wesseling, M.D., Ph.D. Department of Pathology, VU Medical Centre, Amsterdam,

Overview of the Development

Corner’s ten-somite embryo

1.2  ajor Stages in the Development of the Human

1.3 The First Three Weeks of Development – 12

1.5 Development of the Spinal Cord – 19

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023

1.7 Early Development of the Brain – 21

1.8 Foetal Development of the Brain – 29

1.9 Development of the Meninges and Choroid Plexuses – 45

1.10 Development of the Blood Supply of the Brain – 48

1.11 Development of Fibre Tracts and Their Myelination – 55

1.12 The Foetal Connectome – 63

. Fig. 1.2 (continued)

1 . Table 1.1 Developmental stages and features of human embryos

2 2–3 From 2 to about 16 cells

.. Table 1.1 (continued)

After O’Rahilly and Müller (1987, 2001)

Age (postcon- Average Average foot Average Main external characteristics

After Moore et al. (2000)

1 . Table 1.3 Major stages of human CNS development

Based on Aicardi (1992)

the prechordal plate. Caudally, the epiblast is closely

a The subdivision of the mesencephalon into two,

1 Overview of the Development of the Human Brain and Spinal Cord...............1

2.5.6 Specification of Cell Fate in the Telencephalon......................................................................................112

3 Causes of Congenital Malformations.....................................................................................171

4 Neurulation and Neural Tube Defects...................................................................................249

4.4.8 Foetal Sex and Neural Tube Defects...........................................................................................................269

5 The Neural Crest and Craniofacial Malformations........................................................313

6 Development and Developmental Disorders of the Spinal Cord........................379

6.7.4 Development of the Human Pyramidal Tract.........................................................................................408

7 Development and Developmental Disorders of the Brain Stem.........................445

8 Development and Developmental Disorders of the Human Cerebellum......523

8.7.2 Cerebellar Hypoplasia.....................................................................................................................................572

9 Development and Developmental Disorders of the Forebrain............................595

10 Development and Developmental Disorders of the Cerebral Cortex..............725

10.3 Overview of Main Cortical Connections............................................................................................ 733

1.2 ajor Stages in the Development of the Human

1.3 The First Three Weeks of Development – 12

1.5 Development of the Spinal Cord – 19

1.7 Early Development of the Brain – 21

1.8 Foetal Development of the Brain – 29

1.9 Development of the Meninges and Choroid Plexuses – 45

1.10 Development of the Blood Supply of the Brain – 48

1.11 Development of Fibre Tracts and Their Myelination – 55

1.12 The Foetal Connectome – 63