Roof plate Fig. 17.20 A transverse section through the
developing hindbrain of a human embryo 10.5 mm
Special somatic afferent column
long, showing the relative positions of the columns
General somatic afferent column of grey matter from which the nuclei associated
Otocyst with the different varieties of nerve components are
Special visceral afferent column
derived. Postganglionic neurones are associated
General visceral afferent column with the general visceral efferent column, bipolar
neurones are associated with the otocyst, and
General visceral efferent column Skin unipolar afferent neurones are associated with the
Branchial efferent column other alar plate columns.
Somatic efferent column
Floor plate
Striated muscle in the
pharyngeal arches (branchial)
Taste bud
Somatic striated muscle
Smooth muscle Visceral epithelium


DEvEloPmENT of THE NERvous sysTEm
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NoITCEs
to elementary learning. The emergent neurobiological mechanisms are, intermediate layer. It is possible that the grey matter of the reticular
in fact, much more complex and less well understood.) Although they formation is derived from the basal plate and that of the nuclei pontis
tend to retain their primitive positions, some of these nuclei are later from the alar plate by the active migration of cells from the rhombic
displaced by differential growth patterns, by the appearance and growth lip. However, at about the fourth month, the pons is invaded by cortico-
of neighbouring fibre tracts, and possibly by active migration. pontine, corticonuclear and corticospinal fibres, becomes proportion-
It has been suggested that a neurone tends to remain as near as pos- ately thicker, and takes on its adult appearance; it is relatively smaller
sible to its predominant source of stimulation, and that, to achieve this in the full-term neonate.
aim, it will migrate around intervening structures, towards the greatest The region of the isthmus rhombencephali undergoes a series of
density of stimuli. The curious paths of the axons arising from the facial changes that are notoriously difficult to interpret, but which result in
nucleus and the nucleus ambiguus have been regarded as exemplars of the incorporation of the greater part of the region into the caudal end
this phenomenon of neurobiotaxis. In a 10 mm embryo, the facial of the midbrain. Only the roof plate, in which the superior medullary
nucleus lies in the floor of the fourth ventricle, occupying the position velum is formed, and the dorsal part of the alar plate, which becomes
of the special visceral efferent column, and it is placed at a higher level invaded by converging fibres of the superior cerebellar peduncles,
than the abducens nucleus. As growth proceeds, the facial nucleus remain as recognizable derivatives in the adult. Early in development,
migrates at first caudally and dorsally, relative to the abducens nucleus, the decussation of the trochlear nerves is caudal to the isthmus, but as
and then ventrally to reach its adult position. As it migrates, the axons growth changes occur, it is displaced rostrally until it reaches its adult


to which its somata give rise elongate and their subsequent course is position.
assumed to map out the pathway along which the facial nucleus has
travelled. Similarly, the nucleus ambiguus initially arises immediately fourth ventricle and choroid plexus
deep to the ventricular floor but, in the adult, it is more deeply placed Caudal to the developing cerebellum, the roof of the fourth ventricle
and its efferent fibres pass first dorsally and medially before curving remains epithelial, and covers an approximately triangular zone from
laterally to emerge at the surface of the medulla oblongata. the lateral angles of the rhomboid fossa to the median obex (see Figs
17.18, 17.21). Nervous tissue fails to develop over this region and vas-
Myelencephalon
cular pia mater is closely applied to the subjacent ependyma. At each
The caudal slope of the embryonic hindbrain constitutes the myelen- lateral angle and in the midline caudally, the membranes break through,
cephalon, which develops into the medulla oblongata (see Figs 17.3, forming the lateral (Luschka) and median (Magendie) apertures of the
17.18, 17.21). The nuclei of the ninth, tenth, eleventh and twelfth roof of the fourth ventricle. These become the principal routes by which
cranial nerves develop in the positions already indicated, and afferent cerebrospinal fluid, produced in the ventricles, escapes into the sub-
fibres from the ganglia of the ninth and tenth nerves form an oval arachnoid space. The vascular pia mater (tela choroidea), in an inverted
marginal bundle in the region overlying the alar (dorsolateral) lamina. V formation cranial to the apertures, invaginates the ependyma to form
Throughout the rhombencephalon, the dorsal edge of this lamina is vascular fringes, which become the vertical and horizontal parts of the
attached to the thin, expanded roof plate and is termed the rhombic choroid plexuses of the fourth ventricle.
lip. (The inferior rhombic lip is confined to the myelencephalon, the
superior rhombic lip to the metencephalon.) As the walls of the Cerebellum


rhombencephalon spread outwards, the rhombic lip protrudes as a The cerebellum develops from the rhombic lip (dorsal rhombomere 1
lateral edge that becomes folded over the adjoining area. The rhombic (r1)), the dorsal part of the alar plate of the metencephalon, which
lip may later become adherent to this area, and its cells migrate actively constitutes the rostral margin of the diamond-shaped fourth ventricle.
into the marginal zone of the basal plate. In this way, the oval bundle This region is specified as the isthmus organizer (Yu et al 2013). Two
that forms the tractus solitarius becomes buried. Alar plate cells that rounded swellings develop, which, at first, project partly into the ven-
migrate from the rhombic lip are believed to give rise to the olivary and tricle (Fig. 17.21), forming the rudimentary cerebellar hemispheres. The
arcuate nuclei and to the scattered grey matter of the nuclei pontis. most rostral part of the roof of the metencephalon originally separates
While this migration is in progress, the floor plate is invaded by fibres the two swellings, but it becomes invaded by cells derived from the alar
that cross the median plane (accompanied by neurones that cluster in plate, which form the rudiments of the vermis. At a later stage, extrover-
and near this plane), and it becomes thickened to form the median sion of the cerebellum occurs, its intraventricular projection is reduced
raphe. Some of the migrating cells from the rhombic lip in this region and the dorsal extraventricular prominence increases. The cerebellum
do not reach the basal plate and form an oblique ridge, the corpus now consists of a bilobar (dumbbell-shaped) swelling stretched across
pontobulbare (nucleus of the circumolivary bundle), across the dorso- the rostral part of the fourth ventricle (see Fig. 17.21). It is continuous
lateral aspect of the inferior cerebellar peduncle. rostrally with the superior medullary velum, formed from the isthmus


The lower part (caudal half) of the myelencephalon takes no part in rhombencephali, and caudally with the epithelial roof of the myelen-
the formation of the fourth ventricle and, in its development, it closely cephalon. With growth, a number of transverse grooves appear on the
resembles the spinal cord. The gracile and cuneate nuclei, and some dorsal aspects of the cerebellar rudiment: these are the precursors of the
reticular nuclei, are derived from the alar plate, and their efferent numerous fissures that characterize the surface of the mature cerebel-
arcuate fibres and interspersed neurones play a large part in the forma- lum (Fig. 17.22).
tion of the median raphe. The first fissure to appear on the cerebellar surface is the lateral part
At about the fourth month, the descending corticospinal fibres of the posterolateral fissure, which forms the border of a caudal region
invade the ventral part of the medulla oblongata to initiate formation corresponding to the flocculi of the adult. The right and left parts of
of the pyramids. Dorsally, the inferior cerebellar peduncle is formed, this fissure subsequently meet in the midline, where they form the
contemporaneously, by ascending fibres from the spinal cord, and by boundary between the most caudal vermian lobule, the nodule, and the
olivocerebellar and parolivocerebellar fibres, external arcuate fibres, and rest of the vermis. The flocculonodular lobe can now be recognized as
two-way reticulocerebellar and vestibulocerebellar interconnections. the most caudal cerebellar subdivision at this stage and it serves as the
(The reticular nuclei of the lower medulla probably have a dual origin attachment of the epithelial roof of the fourth ventricle. Because of the
from both basal and alar plates.) In the neonate, the brainstem is more expansion of the other divisions of the cerebellum, the flocculonodular
oblique and has a distinct bend as it passes through the foramen lobe comes to occupy an anteroinferior position in adults. At the end


magnum to become the spinal cord. of the third month, a transverse sulcus appears on the rostral slope of
the cerebellar rudiment and deepens to form the fissura prima. This
Metencephalon cuts into the vermis and both hemispheres, and forms the border
The rostral slope of the embryonic hindbrain is the metencephalon, between the anterior and posterior lobes. Contemporaneously, two
from which both the cerebellum and the pons develop. Before forma- short transverse grooves appear in the caudal vermis. The first is the
tion of the pontine flexure, the dorsolateral laminae of the meten- fissura secunda (postpyramidal fissure), which forms the rostral border
cephalon are parallel with one another. After its formation, the roof of the uvula; the second, the pre-pyramidal fissure, demarcates the
plate of the hindbrain becomes rhomboidal and the dorsal laminae of pyramid. The cerebellum now grows dorsally, rostrally, caudally and
the metencephalon lie obliquely. They are close at the cranial end of laterally, and the hemispheres expand much more than the inferior
the fourth ventricle, but widely separated at the level of its lateral angles vermis, which therefore becomes buried at the bottom of a deep hollow,
(see Figs 17.18, 17.21). Accentuation of the flexure approximates the the vallecula. Numerous other transverse grooves develop, the most
cranial angle of the ventricle to the caudal, and the alar plates of the extensive being the horizontal fissure.
metencephalon now lie almost horizontally.
The basal plate of the metencephalon becomes the pons. Ventricular, Cellular development of the cerebellum
intermediate and marginal zones are formed in the usual way, and the The cerebellum consists of a cortex, beneath which are buried a series
nuclei of the trigeminal, abducens and facial nerves develop in the of deep nuclei. The organization of the cerebellar cortex is similar to


Central nervous system
255
71
RETPAHC
A into the cerebellum. Thus, the cerebellum has an intraventricular
portion (cells proliferating from the ventricular zone) and an extraven-
Tectum of
tricular portion (cells proliferating from the external germinative layer)
mesencephalon
during development. The extraventricular portion becomes larger at
the expense of the intraventricular part, the so-called extroversion of the
Trochlear nerve cerebellum. Before the end of the third month, the main mass of the
cerebellum is extraventricular.
Cerebellum, The developed cerebellar cortex contains three layers: namely, the
early stage molecular layer, the Purkinje layer and the granular layer. The early
bilateral expansion of the ventricular surface reflects the production, by
the metencephalic alar plate ventricular epithelium, of neuroblasts that
Floor of
fourth ventricle will give rise to the radial glia, cerebellar nuclei and efferent neurones
of the cerebellar cortex (the Purkinje cells) (Fig. 17.23). The radial glia
play a role in guiding the Purkinje cells to the meningeal surface of the
Rhombic lip
cerebellar anlage. During this early stage of cerebellar development,
which is dominated by the production and migration of efferent cere-
Obex bellar neurones, the surface of the cerebellar anlage remains smooth.
The extroversion of the cerebellum begins later when cells of the exter-
nal germinative layer, also termed the superficial matrix, begin prolifera-
tion and migration. These cells produce the granule cells, which migrate
inwards along the radial glia, through the layers of Purkinje cells, set-
B Cerebellar hemisphere tling deep to them in the granular layer. This stage coincides with the
emergences of the transverse folial pattern. Proliferation and migration
Vermis of granule cells lead to a great rostrocaudal expansion of the meningeal
surface of the cerebellum, forming the transverse fissures and transform-
Posterolateral fissure
ing the multicellular layer of Purkinje cells into a monolayer. Purkinje


cells and nuclear cells are formed prior to the granule cells, and granule
Flocculus
cells serve as the recipient of the main afferent (mossy fibre) system of
Lateral recess of the cerebellum. Thus, the development of the efferent neurones of the
fourth ventricle cerebellar cortex and nuclei precedes the development of its afferent
organization.
Facial colliculus The early bilateral cerebellar anlage is changed into a unitary struc-
Ventricle ture by fusion of the bilateral intraventricular bulges and the disappear-
Gracile tubercle
ance of the ependyma at this site, the merging of the left and right
Mesencephalon
primitive cerebellar cortex over the midline, and the development of
Cuneate tubercle
Metencephalon the cerebellar commissure by ingrowth of afferent fibres and outgrowth
of efferent axons of the medial cerebellar nucleus.
Myelencephalon
When the external germinative layer is initially formed, the multicel-
Fig. 17.21 A, The developing brainstem of a human fetus at lular Purkinje cell layer beneath is not uniform, but subdivided into
approximately 3 months, left dorsolateral aspect. B, The developing clusters that form rostrocaudally extending columns (Fig. 17.24). The
cerebellum in the fifth month, dorsal aspect. medial Purkinje cell clusters develop into the future vermis. These
Purkinje cells will grow axons that connect to neurones in the vestibular
nuclei and the fastigial nucleus. The lateral clusters belong to the future
hemispheres and will grow axons terminating in the interposed and
A B Anterior lobe
dentate nuclei. The sharp border in the efferent projections from the
Primary fissure
vermis and hemispheres is thus established at an early age. These clus-
ters will give rise to Purkinje cell zones in the adult cerebellum, which
project to a single vestibular or cerebellar nucleus.
Posterolateral fissure
In the developing human brain, only the external germinative layer
Nodule
Isthmus can be seen at 17–18 weeks; the Purkinje cells become apparent between


rhombencephali 20 and 23 weeks. After 30 weeks, four layers can be recognized: the
external germinative layer (external granular layer), formed by 6–8 rows
of densely packed small round cells; the Purkinje cell layer, formed by
Anterior lobe 5–6 layers of larger, round, immature neurones external to the internal
C D granular layer; and the molecular layer, containing cells that resemble
external granular layer cells in migration (Lavezzi et al 2006). The exter-
Primary fissure
nal granular layer involutes between 5 and 7 months after birth; it is
Simple folium tuber only a discontinuous layer at 10 months, and is totally absent by
Pre-pyramidal fissure 12 months, after which time the cerebellar cortex shows a three-layered
Pyramid
Secondary fissure structure. From 5 to 7 months, the Purkinje cells are reduced in number
Nodule Uvula and more widely spaced, displaying mature polygonal somata with
Nodule evident axons and dendrites.
Relatively little is known about the molecular mechanisms involved
in cerebellar development in the human (but see Manto and Jissendi
Mesencephalon Metencephalon Myelencephalon Ventricle (2012), Yu et al (2013), Martinez et al (2013)). Very small preterm
infants are at particular risk of later cerebellar dysfunction with conse-
Fig. 17.22 Median sagittal sections through the developing cerebellum, at quences for cognition and behaviour. Cerebellar maturation occurs
four chronologically later stages. postnatally and so there is interest in therapeutic agents that may
improve long-term outcomes for such infants (Manto and Jissendi
2012).
that of the cerebral cortex, except that the latter has six layers while the
former has only three. However, whereas, in the cerebral cortex, neuro-
Mesencephalon
blasts originate from the ventricular zone and migrate ventriculofugally
towards the pial surface (in an ‘inside-out’ fashion), early in cerebellar
development a layer of cells derived exclusively from the metencephalic The mesencephalon or midbrain is subdivided early in development


rhombic lip initially migrates ventriculofugally to form a layer beneath into two neuromeres, mesencephalon 1 and mesencephalon 2. It per-
the glia limitans over the surface of the developing cerebellum. These sists for a time as a thin-walled tube enclosing a cavity of some size,
cells form the external germinative layer and, later in development, their separated from that of the prosencephalon by a slight constriction
progeny will migrate ventriculopetally (in an ‘outside-in’ manner), and from the rhombencephalon by the isthmus rhombencephali (see


DEvEloPmENT of THE NERvous sysTEm
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NoITCEs
A B Fig. 17.23 The histogenesis of the cerebellar
cortex and the cerebellar nuclei. A, Purkinje
cells and cells of the cerebellar nuclei are
produced by the ventricular zone and migrate
to their future positions. The cells of the
Purkinje cell layer
superficial matrix (the external granular layer)
Fourth ventricle
take their origin from the ventricular epithelium
at the caudal pole of the cerebellar anlage and
Cerebellar nuclei migrate rostrally over its surface. B, After
migration, the Purkinje cells constitute a
multicellular layer beneath the external
Ventricular matrix Ependyma: exhausted germinative layer. Cell production in the
ventricular matrix
Choroid plexus ventricular epithelium has stopped. The
remaining cells transform into ependymal cells.
C, Granule cells produced by the external
germinative layer migrate inwards through the
Purkinje cell layer to their position in the
Choroid plexus internal granular layer. Purkinje cells spread
into a monolayer. D, The adult position of
cortical and nuclear neurones.
C D Rostral
Purkinje cell layer
Internal granular layer Purkinje cell layer
Ependyma
Ependyma
Cerebellar nuclei
Cerebellar nucleus
Choroid plexus
Internal granular layer
Choroid plexus
Mesencephalon Myelencephalon Ventricular zone, germinative layer
Metencephalon Fourth ventricle Cerebellar external germinative layer
Caudal
that give rise to the trigeminal mesencephalic nucleus arise either side
EGL of the dorsal midline, from the isthmus rhombencephali rostrally across
the roof of the mesencephalon. The progenitors of these cells do not
m express neural crest cell markers.
The cells of the dorsal part of the alar (dorsolateral) plates proliferate
and invade the roof plate, which therefore thickens and is later divided
into corpora bigemina by a median groove. Caudally, this groove


becomes a median ridge, which persists in the adult as the frenulum
4
veli. The corpora bigemina are later subdivided into the superior and
D
inferior colliculi by a transverse furrow. The red nucleus, substantia
nigra and reticular nuclei of the midbrain tegmentum may first be
defined at the end of the third month. Their origins are probably mixed,
from neuroblasts of both basal and alar plates.
B The detailed histogenesis of the tectum and its main derivatives, the
colliculi, will not be followed here but, in general, the principles out-
lined for the cerebellar cortex, the palaeopallium and neopallium also
apply to this region. A high degree of geometric order exists in the
developing retinotectal projection (the equivalent of the retinogenicu-
late projection) and in the tectospinal projection. (For further reading,
Fig. 17.24 A coronal section through the cerebellum and the brainstem of see Cang and Feldheim (2013).)
65 mm human fetus. The Purkinje cells are located in five multicellular
clusters (stars) on both sides of the midline. The anlage of the dentate Prosencephalon
nucleus occupies the centre of the most lateral Purkinje cell cluster.
Abbreviations: B, brainstem; D, dentate nucleus; EGL, external granular
layer; m, midline; 4, fourth ventricle. (Courtesy of the Schenk Collection, At an early stage, a transverse section through the forebrain shows the
Dr Johan M Kros, Division of Neuropathology, Department of Pathology, same parts as are displayed in similar sections of the spinal cord and
Erasmus Medical Centre, Rotterdam, The Netherlands.) medulla oblongata, i.e. thick lateral walls connected by thin floor and
roof plates. Each lateral wall is divided into a dorsal area and a ventral
area separated internally by the hypothalamic sulcus (see Fig. 17.25).
Fig. 17.3; Fig. 17.25). Later, its cavity becomes relatively reduced in This sulcus ends rostrally at the medial end of the optic stalk. In the


diameter and, in the adult brain, it forms the cerebral aqueduct. The fully developed brain, it persists as a slight groove extending from the
basal (ventrolateral) plate of the midbrain increases in thickness to interventricular foramen to the cerebral aqueduct. It is analogous to, if
form the cerebral peduncles, which are at first of small size but enlarge not the homologue of, the sulcus limitans. The thin roof plate remains
rapidly after the fourth month, when their numerous fibre tracts begin epithelial but invaginated by vascular mesenchyme, the tela choroidea
to appear in the marginal zone. The neuroblasts of the basal plate of of the choroid plexuses of the third ventricle. Later, the lateral margins
mesencephalon 2 give rise to the nuclei of the oculomotor nerve and of the tela undergo a similar invagination into the medial walls of the
some grey masses of the tegmentum, while the nucleus of the trochlear cerebral hemispheres. The floor plate thickens as the nuclear masses of
nerve remains in the region of the isthmus rhombencephali. The cells the hypothalamus and subthalamus develop.


Central nervous system
257
71
RETPAHC
A Thalamus B Rudiment of thalamus Isthmus
rhombencephali
Interventricular foramen
Cerebral
hemisphere Oculomotor Choroidal fissure
nerve
Rudiment
Trochlear nerve of corpus
Interventricular striatum
foramen Isthmus
Corpus striatum
Lamina terminalis Cerebellum
Hypothalamus
Motor root
Ganglia of facial and Sensory root Trigeminal nerve Lamina terminalis
vestibulocochlear nerves
Optic chiasma
Glossopharyngeal nerve
Hypophysis cerebri
Vagus nerve
Otocyst Pons Rudiment of
Medulla oblongata cerebellum
Hypoglossal nerve
Accessory nerve
Spinal cord
C Cerebral hemisphere, medial surface
Choroidal fissure
Roof of third ventricle
Corpus striatum
Interventricular foramen
Lamina terminalis
Thalamus
Pineal gland
Tectum of mesencephalon
Corpus mammillare
Frontal pole Telencephalon
Diencephalon
Olfactory bulb
Mesencephalon
Optic chiasma
Metencephalon
Hypothalamus Cerebellar rudiment Myelencephalon
Pontine flexure
Pons
Cervical flexure
Medulla oblongata
Spinal cord
Fig. 17.25 The shape of the developing ventricular system and the expansion of the medial portion of the telencephalon. The roof of the metencephalon
and myelencephalon has been removed in each case. A, A human embryo, approximately 10.2 mm long, left lateral surface of the diencephalon and
telencephalon removed. B, A human embryo 13.6 mm long, median section. C, A human fetus, approximately 3 months old, median section.
At a very early period, before the closure of the rostral neuropore, subsequently form the cerebral hemispheres. Their cavities are the rudi-
the subdivision of the prosencephalon into the most rostral telen- ments of the lateral ventricles and they communicate with the median


cephalon and two subdivisions of the diencephalon, D1 and D2, is part of the forebrain cavity by relatively wide openings, which ulti-
heralded (see Fig. 17.2). At this early time, two eye fields are separated mately become the interventricular foramina. The rostral limit of the
by the future neurohypophysis in the floor of the future D1. After head median part of the forebrain consists of a thin sheet, the lamina termi-
folding, the eye fields expand as two lateral optic evaginations, which nalis (see Fig. 17.25), which stretches from the interventricular foramina
become optic vesicles, one on each side of the early brain. For a time, to the recess at the base of the optic stalks. The rostral part of the fore-
they communicate with the cavity of the prosencephalon by relatively brain, including the rudiments of the cerebral hemispheres, consists of
wide openings. The distal parts of the optic vesicles expand, while the the telencephalon and the caudal part of the diencephalon; both con-
proximal parts become the tubular optic stalks. The optic vesicles tribute to the formation of the third ventricle, although the latter pre-
(which are described with the development of the eye in Ch. 40) are dominates. The fate of the lamina terminalis is described below.
thus derived from the lateral walls of the D1 subdivision of the pros-
Diencephalon
encephalon before the telencephalon can be clearly identified. The optic
chiasma is often regarded as the boundary between diencephalon and The diencephalon, D2, is broadly divided by the hypothalamic sulcus
telencephalon. into dorsal (pars dorsalis diencephali) and ventral (pars ventralis dien-
As the most rostral portion of the prosencephalon enlarges, it curves cephali) parts; each contributes to diverse neural structures. The dorsal
ventrally, and two further diverticula expand rapidly from it, one on part develops into the (dorsal) thalamus and metathalamus along
each side. These diverticula, which are rostrolateral to the optic stalks, the immediate suprasulcal area of its lateral wall, while the highest


DEvEloPmENT of THE NERvous sysTEm
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3
NoITCEs
Neopallial cortex
Lateral ventricle Hippocampal rudiment
(supracallosal)
Hippocampal cortex
Corpus callosum
Choroid plexus Cavum septi lucidi
Caudate nucleus
Fornix
Internal capsule
Corpus striatum lateral Claustrum
Corpus striatum medial Putamen Interventricular foramen
Piriform cortex Globus pallidus Thalamus
Tail of caudate nucleus
Hippocampus
Choroid plexus
Thalamus
Third ventricle Inferior horn of
lateral ventricle
Fig. 17.26 The development of the basal nuclei and internal capsule, coronal views. (Redrawn with permission from Hamilton WJ, Boyd JD, Mossman
HW 1972 Human Embryology: Prenatal Development of Form and Function. Baltimore: Williams and Wilkins.)
dorsocaudal lateral wall and roof form the epithalamus. The thalamus
Germinal matrix
(see Fig. 17.25) is first visible as a thickening that involves the rostral Superior
part of the dorsal area. Caudal to the thalamus, the lateral and medial sagittal sinus Mantle layer
geniculate bodies, or metathalamus, are recognizable at first as surface
Neopallial cortex
depressions on the internal aspect and as elevations on the external
aspect of the lateral wall. As the thalami enlarge as smooth ovoid
Marginal layer
masses, the wide interval between them gradually narrows into a verti-
cally compressed cavity that forms the greater part of the third ventricle.
After a time, these medial surfaces may come into contact and become Choroid
adherent over a variable area, the connection (single or multiple) con- Inferior plexus
sagittal sinus
stituting the interthalamic adhesion or massa intermedia. The caudal
Lateral
growth of the thalamus excludes the geniculate bodies from the lateral
Hippocampal ventricle
wall of the third ventricle.
cortex
At first, the lateral aspect of the developing thalamus is separated
from the medial aspect of the cerebral hemisphere by a cleft but, with Roof of third


growth, the cleft becomes obliterated (Fig. 17.26) as the thalamus fuses ventricle Caudate nucleus
with the part of the hemisphere in which the corpus striatum is devel-
oping. Later, with the development of the projection fibres (corticofugal Third
and corticopetal) of the neocortex, the thalamus becomes related to the ventricle
Lentiform nucleus
internal capsule, which intervenes between it and the lateral part of the
corpus striatum (lentiform nucleus). Ventral to the hypothalamic
sulcus, the lateral wall of the diencephalon, in addition to median
derivatives of its floor plate, forms a large part of the hypothalamus and
subthalamus.
Internal capsule
The epithalamus, which includes the pineal gland, the posterior and
habenular commissures and the trigonum habenulae, develops in asso- Anterior commissure
ciation with the caudal part of the roof plate and the adjoining regions Preoptic recess
of the lateral walls of the diencephalon. At an early period (12–20 mm Fig. 17.27 A coronal section of the left cerebral hemisphere in a 73 mm
crown–rump length), the epithalamus in the lateral wall projects into fetus. (Redrawn with permission from Hamilton WJ, Boyd JD, Mossman
the third ventricle as a smooth ellipsoid mass, larger than the adjacent HW 1972 Human Embryology: Prenatal Development of Form and
mass of the (dorsal) thalamus and separated from it by a well-defined Function. Baltimore: Williams and Wilkins.)
epithalamic sulcus. In subsequent months, growth of the thalamus
rapidly overtakes that of the epithalamus and the intervening sulcus is
obliterated. Thus, structures of epithalamic origin ultimately are rela- third month. The tuber cinereum develops rostral to the mammillary
tively diminutive topographically. bodies as a cellular proliferation that extends forwards as far as the
The pineal gland arises as a hollow outgrowth from the roof plate, infundibulum. In front of the tuber cinereum, a wide-mouthed diver-


immediately adjoining the mesencephalon. Its distal part becomes ticulum forms in the floor of the diencephalon, grows towards the
solid by cellular proliferation but its proximal stalk remains hollow, stomodeal roof, and comes into contact with the posterior aspect of a
containing the pineal recess of the third ventricle. In many reptiles, the dorsally directed ingrowth from the stomodeum (Rathke’s pouch).
pineal outgrowth consists of a rostral outgrowth (parapineal organ) that These two diverticula together form the hypophysis cerebri (see Fig.
develops into the pineal or parietal eye, and a glandular caudal out- 17.14). An extension of the third ventricle persists in the base of the
growth; the caudal outgrowth is homologous with the pineal gland in neural outgrowth as the infundibular recess. The remaining caudo-
humans. The rostral outgrowth also develops in the human embryo but lateral walls and floor of the ventral diencephalon are an extension of
soon disappears entirely. the midbrain tegmentum, the subthalamus. This forms the rostral limits
The nucleus habenulae, which is the most important constituent of of the red nucleus, substantia nigra, numerous reticular nuclei and a
the trigonum habenulae, develops in the lateral wall of the dien- wealth of interweaving, ascending, descending and oblique nerve fibre
cephalon and is, at first, in close relationship with the geniculate bodies, bundles, which have many origins and destinations.
from which it becomes separated by the dorsal growth of the thalamus.
The habenular commissure develops in the cranial wall of the pineal Third ventricle and choroid plexus
recess. The posterior commissure is formed by fibres that invade the The roof plate of the diencephalon rostral to the pineal gland, and
caudal wall of the pineal recess from both sides. continuing over the median telencephalon, remains thin and epithelial
The ventral part of the diencephalon forms the subsulcal lateral walls in character and is invaginated by the choroid plexuses of the third


of the third ventricle and takes part in the formation of the hypothala- ventricle (see Fig. 17.26; Fig. 17.27). Before the development of the
mus, including the mammillary bodies, the tuber cinereum and corpus callosum and the fornix, it lies at the bottom of the longitudinal
infundibulum of the hypophysis. The mammillary bodies arise as a fissure, between and reaching the two cerebral hemispheres. It extends
single thickening that becomes divided by a median furrow during the as far rostrally as the interventricular foramina and lamina terminalis.


Central nervous system
259
71
RETPAHC
Here, and elsewhere, choroid plexuses develop by the close apposition
of vascular pia mater and ependyma without intervening nervous tissue.
Corpus striatum
With development, the vascular layer is infolded into the ventricular
cavity and develops a series of small villous projections, each covered
Lateral ventricle
by a cuboidal epithelium derived from the ependyma. The cuboidal
cells display numerous microvilli on their ventricular surfaces and
complex folding of their basal plasma membranes. The early choroid
plexuses secrete a protein-rich cerebrospinal fluid into the ventricular
Lentiform nucleus
system, which may provide a nutritive medium for the developing
epithelial neural tissues. As the latter become increasingly vascularized,
the histochemical reactions of the cuboidal cells and the character of
Caudate nucleus
the fluid change to the adult type. Many regions of the lining of the
third ventricle become highly specialized, and develop concentrations
of tanycytes or other modified cells that are collectively termed the
circumventricular organs, e.g. the subfornical organ, the organum vas-
culosum (intercolumnar tubercle) of the lamina terminalis, the sub-
commissural organ, and the linings of the pineal, suprapineal and
infundibular recesses. Posterior horn
Inferior horn
Telencephalon
Central sulcus
The telencephalon consists of two lateral diverticula connected by a
median region, the telencephalon impar. The rostral part of the third
ventricle develops from the impar, and is closed below and in front by
the lamina terminalis. The lateral diverticula are outpouchings of the
lateral walls of the telencephalon, which may correspond to the alar
lamina, although this is uncertain. Their cavities are the future lateral
ventricles, and their walls are formed by the presumptive nervous tissue
Superior temporal sulcus Insula
of the cerebral hemispheres. The roof plate of the median part of the
telencephalon remains thin and is continuous behind with the roof Fig. 17.28 Lateral views of developing brains show the formation of the


plate of the diencephalon (see Figs 17.25–17.26). The rostral parts of basal nuclei and lateral ventricles as the telencephalon develops.
the hypothalamus, which include the optic chiasma, optic recess and (Redrawn with permission from Hamilton WJ, Boyd JD, Mossman HW
related nuclei, develop in the floor plate and lateral walls of the pros- 1972 Human Embryology: Prenatal Development of Form and Function.
encephalon, ventral to the primitive interventricular foramina. The Baltimore: Williams and Wilkins.)
chiasma is formed by the meeting, and partial decussation, of the optic
nerves in the ventral part of the lamina terminalis. The optic tracts
subsequently grow backwards from the chiasma to end in the dien- axons, the stems (or the whole) of efferent axons, and glial cells and
cephalon and midbrain. endothelial cells. Successive generations of neuroblasts migrate through
the layers of earlier generations to attain subpial positions (see below
Cerebral hemispheres and Fig. 17.32), which means that the surface of the cerebral hemi-
The cerebral hemispheres arise as diverticula of the lateral walls of the spheres expands at a rate greater than that of the hemispheres as a
telencephalon, with which they remain in continuity around the whole; the great expansion of the cerebral hemispheres is characteristic
margins of initially relatively large interventricular foramina, except of mammals and especially of humans. Neuroblast differentiation pro-
caudally, where they are continuous with the rostral part of the lateral duces a highly organized subpial surface coat of grey matter termed the
wall of the diencephalon (see Figs 17.3, 17.25). As growth proceeds, cortex or pallium. The growing hemispheres subsequently overlap, suc-
each hemisphere enlarges forwards, upwards and backwards and cessively, the diencephalon and the mesencephalon, and then meet the
acquires an oval outline, medial and superolateral walls, and a floor. As rostral surface of the cerebellum. The temporal lobes embrace the flanks
a result, the medial surfaces approach, but are separated by, a vascular- of the brainstem.


ized mesenchyme and pia mater, which fills the median longitudinal The terminology used to describe regions of the cortex is based on
fissure (see Fig. 17.27). At this stage, the floor of the fissure is the epi- evolutionary concepts. The oldest portions of cortex receive information
thelial roof plate of the telencephalon, which is directly continuous concerned with olfaction; they are termed the archicortex (archipal-
caudally with the epithelial roof plate of the diencephalon. lium) and palaeocortex (palaeopallium), and both are subdivisions of
At the early oval stage of hemispheric development, regions are an overall allocortex. The archicortex is the forerunner of the hippo-
named according to their future principal derivatives. The rostromedial campal lobe, and the palaeocortex gives rise to the piriform area. The
and ventral floor becomes linked with the forming olfactory apparatus remaining cortical surface expands greatly in mammals, forming the
and is termed the primitive olfactory lobe. The floor (ventral wall, or neocortex (young cortex), which displaces the earlier cortices so that
base) of the remainder of each hemisphere forms the anlage of the they come to lie partially internally in each hemisphere. The six-layered
primitive corpus striatum and amygdaloid complex, including its asso- mammalian neocortex is also described as isocortex.
ciated rim of lateral and medial walls (the striate part of the hemi-
sphere). The rest of the hemisphere, i.e. the medial, lateral, dorsal and Olfactory bulb
caudal regions, is the suprastriate part of the hemisphere. Although it A longitudinal groove appears in the anteromedial part of the floor of
is the largest in terms of surface area, initially it possesses comparatively each developing lateral ventricle at about the fifth week of embryonic
thin walls. The rostral end of each oval hemisphere becomes the defini- development. It deepens and forms a hollow diverticulum, which is
tive frontal pole. As the hemisphere expands, its original posterior pole continuous with the hemisphere by a short stalk. The diverticulum
moves relatively in a caudoventral and lateral direction, following a becomes connected on its ventral or inferior surface to the olfactory


curve like a ram’s horn; it curves towards the orbit in association with placode. Placodal cells give rise to afferent axons that terminate in the
the growth of the caudate nucleus and other structures to form the walls of the diverticulum. As the head increases in size, the diverticulum
definitive temporal pole. A new posterior part persists as the definitive grows forwards, loses its cavity and becomes converted into the solid
occipital pole of the mature brain (Figs 17.28–17.29). olfactory bulb. The forward growth of the bulb is accompanied by
The migration and differentiation of neural progenitors to form elongation of its stalk, which forms the olfactory tract. The part of the
nuclei is either minimal or limited throughout the brainstem and spinal floor of the hemisphere to which the tract is attached constitutes the
cord; the progeny of these progenitors remain immediately extra- piriform area.
ependymal or partially displaced towards the pial exterior, and are
arrested deeply embedded in the myelinated fibre ‘white matter’ of the Lateral ventricles and choroid plexus
region. In marked contrast, proliferation and migration of neuroblasts The early diverticulum or anlage of the cerebral hemisphere initially
in the cerebral hemispheres produce a superficial layer of grey matter contains a simple spheroidal lateral ventricle that is continuous with
in both the striate and the suprastriate regions, but not in the central the third ventricle via the interventricular foramen. The rim of the
areas of the original medial wall (where secondary fusion with the foramen is the site of the original evagination. The expanding ventricle
diencephalon occurs). The superficial layer of grey matter consists of develops the ram’s horn shape of the surrounding hemisphere, becom-
neuronal somata, dendrites, the terminations of incoming (afferent) ing first roughly ellipsoid and then a curved cylinder that is convex


DEvEloPmENT of THE NERvous sysTEm
260
3
NoITCEs
E Fig. 17.29 A–G, The superolateral surfaces of
A human fetal cerebral hemispheres at the ages
indicated, showing the changes in size, profile and
the emerging pattern of cerebral sulci with
increasing maturation. Note the changing
prominence and relative positions of the frontal,
occipital and, particularly, the temporal pole of the
hemisphere. At the earliest stage (A), the lateral
21 weeks cerebral fossa is already obvious; its floor covers
the developing corpus striatum in the depths of
B the hemisphere and progressively matures into the
30 weeks cortex of the insula. The fossa is bounded by
overgrowing cortical regions – the frontal, temporal
F and parietal opercula – which gradually converge
to bury the insula; their approximation forms the
lateral cerebral sulcus. By the sixth month, the
central, pre- and postcentral, superior temporal,
intraparietal and parieto-occipital sulci are all
24 weeks
clearly visible. In the subsequent stages shown, all
the remaining principal and subsidiary sulci rapidly
C appear, and by 40 weeks, all the features that
characterize the adult hemisphere in terms of
surface topography are present in miniature.
(Photographs provided by Dr Sabina Strick, The
Maudsley Hospital, London.)
34 weeks
G
26 weeks
D
28 weeks 40 weeks
dorsally (see Fig. 17.28). The ends of the cylinder expand towards, but develops between ependyma and pia mater, is termed the choroidal
do not reach, the frontal and (temporary) occipital poles; differentiat- fissure (see Figs 17.25C, 17.26). The subsequent assumption of the
ing and thickening neural tissues separate the ventricular cavities and definitive form of the choroidal fissure depends on related growth pat-
pial surfaces at all points, except along the line of the choroidal fissure. terns in neighbouring structures. Of particular importance are the rela-
Pronounced changes in ventricular form accompany the emergence of tively slow growth of the interventricular foramen, the secondary


a temporal pole. The original caudal end of the curved cylinder expands ‘fusion’ between the lateral diencephalon and medial hemisphere walls,
within its substance and the temporal extensions in each hemisphere the encompassing of the upper brainstem by the forward growth of the
pass ventrolaterally to encircle both sides of the upper brainstem (see temporal lobe and its pole towards the apex of the orbit, and the
Fig. 17.26). Another extension may develop from the root of the tem- massive expansion of two great cerebral commissures (the fornix and
poral extension in the substance of the definitive occipital pole and pass corpus callosum). The choroidal fissure is now clearly a caudal exten-
caudomedially; it is quite variable in size, often asymmetrical on the sion of the much-reduced interventricular foramen, which arches above
two sides, and one or both may be absent. Although the lateral ventricle the thalamus and is here only a few millimetres from the median plane.
is a continuous system of cavities, specific parts are now given regional Near the caudal end of the thalamus, it diverges ventrolaterally, its curve
names. The central part (body) extends from the interventricular reaching and continuing in the medial wall of the temporal lobe over
foramen to the level of the posterior edge (splenium) of the corpus much of its length (i.e. to the tip of the inferior horn of the lateral
callosum. Three cornua (horns) diverge from the body: anterior towards ventricle). The upper part of the arch will be overhung by the corpus
the frontal pole, posterior towards the occipital pole, and inferior callosum and, throughout its convexity, it is bordered by the fornix and
towards the temporal pole. its derivatives.
At these early stages of hemispheric development, the term pole is
preferred, in most instances, to lobe. Lobes are defined by specific Basal nuclei
surface topographical features that will appear over several months, and At first, growth proceeds more actively in the floor and the adjoining
differential growth patterns persist for a considerable period. part of the lateral wall of the developing hemisphere, and elevations


The pia mater, which covers the epithelial roof of the third ventricle formed by the rudimentary corpus striatum encroach on the cavity of
at this stage, is itself covered with loosely arranged mesenchyme and the lateral ventricle (see Figs 17.25–17.30). The head of the caudate
developing blood vessels. These vessels subsequently invaginate the nucleus appears as three successive parts – medial, lateral and interme-
roof of the third ventricle on each side of the median plane to form its diate – which produce elevations in the floor of the lateral ventricle.
choroid plexuses (see Fig. 17.26). The lower part of the medial wall of Caudally, these merge to form the tail of the caudate nucleus and the
the cerebral hemisphere, which immediately adjoins the epithelial roof amygdaloid complex, which both remain close to the temporal pole of
of the interventricular foramen and the rostral extremity of the dien- the hemisphere. When the occipital pole grows backwards, and the
cephalon, also remains epithelial. It consists of ependyma and pia general enlargement of the hemisphere carries the temporal pole
mater; elsewhere, the walls of the hemispheres are thickening to form downwards and forwards, the tail of the caudate is continued from the
the pallium. The thin part of the medial wall of the hemisphere is floor of the central part (body) of the ventricle into the roof of its tem-
invaginated by vascular tissue, which is continuous in front with the poral extension, the future inferior horn (see Fig. 17.28). The amy-
choroid plexus of the third ventricle and constitutes the choroid plexus gdaloid complex encapsulates its tip. Rostrally, the head of the caudate
of the lateral ventricle. This invagination occurs along a line that arches nucleus extends forwards to the floor of the interventricular foramen,
upwards and backwards, parallel with and initially limited to, the where it is separated from the developing rostral end of the thalamus
rostral and upper boundaries of the interventricular foramen. This by a groove; later, the head expands in the floor of the anterior horn of


curved indentation of the ventricular wall, where no nervous tissue the lateral ventricle. The lentiform nucleus develops from two laminae


Central nervous system
261
71
RETPAHC
of cells, medial and lateral, which are continuous with both the medial Corpus callosum Choroidal fissure Dentate
and lateral parts of the caudate nucleus. The internal capsule appears Septum lucidum gyrus
first in the medial lamina and extends laterally through the outer Anterior Taenia
lamina to the cortex. It divides the laminae into two, the internal parts commissure thalami
join the caudate nucleus and the external parts form the lentiform
Lamina terminalis
nucleus (see Figs 17.26–17.27). In the latter, the remaining medial Thalamus
Olfactory bulb
lamina cells give rise mainly to the globus pallidus and the lateral
Posterior
lamina cells to the putamen. The putamen subsequently expands con-
commissure
currently with the intermediate part of the caudate nucleus.
Telencephalon Tectum
Fusion of diencephalic and telencephalic walls
As the hemisphere enlarges, the caudal part of its medial surface over- Diencephalon Aqueduct
laps and hides the lateral surface of the diencephalon (thalamic part), Mesencephalon Optic chiasma Cerebellum
from which it is separated by a narrow cleft occupied by vascular con-
Third ventricle
nective tissue. At this stage (about the end of the second month), a Metencephalon Cerebral
transverse section made caudal to the interventricular foramen would Myelencephalon Hypophysis peduncle
pass from the third ventricular cavity successively through the develop- ing thalamus, the narrow cleft just mentioned, the thin medial wall of Ventricle Pons Fourth
the hemisphere, and the cavity of the lateral ventricle, with the corpus Commissural fibres Medulla ventricle
oblongata
striatum in its floor and lateral wall (see Fig. 17.26).
As the thalamus increases in extent, it acquires a superior surface in Fig. 17.30 The anterior and posterior commissures in the brain of a
addition to medial and lateral surfaces. The lateral part of its superior 16-week human fetus; medial aspect of the left half of the brain.
surface fuses with the thin medial wall of the hemisphere so that this


part of the thalamus is finally covered with the ependyma of the lateral
ventricle immediately ventral to the choroidal fissure. As a result, the the area above and in front of the lamina terminalis (paraterminal
corpus striatum is approximated to the thalamus and is separated from area), and gradually extends backwards, curving into the region of the
it only by a deep groove, which becomes obliterated by increased temporal pole, where it adjoins the piriform area. The marginal zone
growth along the line of contact. The lateral aspect of the thalamus is in the neighbourhood of the hippocampus is invaded by neurones to
now in continuity with the medial aspect of the corpus striatum so that form the dentate gyrus. Both extend from the paraterminal area back-
a secondary union between the diencephalon and the telencephalon is wards above the choroidal fissure and follow its curve downwards and
affected over a wide area, providing a route for the subsequent passage forwards towards the temporal pole, where they continue into the piri-
of projection fibres to and from the cortex (see Fig. 17.26). form area. A shallow groove, the hippocampal sulcus, crosses the medial
surface of the hemisphere throughout the hippocampal formation. The
Formation of the insula efferent fibres from the cells of the hippocampus collect along its
At the end of the third month, while the corpus striatum is developing, medial edge and run forwards immediately above the choroidal fissure.
there is a relative restriction of growth between the frontal and temporal Rostrally, they turn ventrally and enter the lateral part of the lamina
lobes. The region lateral to the striatum becomes depressed to form a terminalis to gain the hypothalamus, where they end in and around the
lateral cerebral fossa with a portion of cortex, the insula, at its base (see mammillary body and neighbouring nuclei. These efferent hippocam-
Figs 17.28–17.29). As the temporal lobe continues to protrude towards pal fibres form the fimbria hippocampi and the fornix.
the orbit, and with more rapid growth of the temporal and frontal
cortices, the surface of the hemisphere expands at a rate greater than Projection fibres, internal capsule


the hemisphere as a whole, and the cortical areas become folded, The growth of the neocortex, and its enormous expansion during the
forming gyri and sulci. The insula is gradually overgrown by these latter part of the third month, are associated with the initial appearance
adjacent cortical regions and they overlap it, forming the opercula, the of corticofugal and corticopetal projection fibres and the internal
free margins of which form the anterior part of the lateral fissure. This capsule. The fibres follow the route provided by the apposition of the
process is not completed until after birth. The lentiform nucleus remains lateral aspect of the thalamus with the medial aspect of the corpus
deep to and coextensive with the insula. striatum. They divide the latter, almost completely, into a lateral part,
the lentiform nucleus, and a medial part, the caudate nucleus; these two
Olfactory nerve, limbic lobe and hippocampus nuclei remain confluent only in their anteroinferior regions (see Figs
The growth changes in the temporal lobe that help to submerge the 17.26–17.27). The corticospinal tracts begin to develop in the ninth
insula produce important changes in the olfactory and neighbouring week of fetal life, they reach the caudal medulla oblongata at 15 weeks,
limbic areas. As it approaches the hemispheric floor, the olfactory tract complete the pyramidal decussation by 17 weeks, extend to the cervical
diverges into lateral, medial and (variable) intermediate striae. The and thoracic segments of the spinal cord by 19 weeks, and reach their
medial stria is clothed with a thin archaeocortical medial olfactory caudal, lumbosacral, limits by 29 weeks. The fibres destined for the
gyrus. This curves up into further archaeocortical areas rostral to the cervical and upper thoracic regions, which innervate the upper limbs,
lamina terminalis (paraterminal gyrus, prehippocampal rudiment, are in advance of those that innervate the lower limbs, and these, in
parolfactory gyrus, septal nuclei) and these continue into the indusium turn, are in advance of fibres that innervate the face; the timing of the


griseum. The lateral stria, clothed by the lateral olfactory gyrus, and the appearance of reflexes associated with these three parts of the body is
intermediate stria (when present) terminate in the rostral parts of the similarly staggered. The proportions of crossed and uncrossed fibres in
piriform area, including the olfactory trigone and tubercle, anterior each corticospinal tract vary; a dominant uncrossed corticospinal tract
perforated substance, uncus and entorhinal area of the anterior part of and a complete absence of pyramidal decussation have been found in
the future parahippocampal gyrus. The lateral limit of the lateral stria posterior fossa malformations such as occipital encephalocele, Dandy–
is indicated by the rhinal sulcus. The forward growth of the temporal Walker malformation and Joubert’s syndrome. There is evidence of
pole and the general expansion of the neocortex cause the lateral olfac- substantial plastic reorganization of the motor cortex and corticospinal
tory gyrus to bend laterally, the summit of the convexity lying at the projections following pre- or perinatal lesions to the corticospinal
anteroinferior corner of the developing insula. During the fourth and system (Eyre 2007). For further reading about the development of the
fifth months, much of the piriform area becomes submerged by the human pyramidal tract, see ten Donkelaar et al (2004).
adjoining neocortex and, in the adult, only a part of it remains visible The majority of subcortical nuclear masses receive terminals from
on the inferior aspect of the cerebrum. descending fibres of cortical origin. These are joined by thalamocortical,
The limbic lobe is the first part of the cortex to differentiate and, at hypothalamocortical and other afferent ascending bundles. The internal
first, it forms a continuous, almost circular, strip on the medial and capsular fibres pass lateral to the head and body of the caudate nucleus,
inferior aspects of the hemisphere. Below and in front, where the stalk the anterior cornu and central part of the lateral ventricle, the rostro-
of the olfactory tract is attached, it constitutes a part of the piriform ventral extensions and body of the fornix, the dorsal thalamus and


area. The portion outside the curve of the choroidal fissure (see Fig. dorsal choroidal fissure, and medial to the lentiform nucleus (see Figs
17.26; Fig. 17.30) constitutes the hippocampal formation. In this 17.26–17.27).
region, the neural progenitors of the developing cortex proliferate and
migrate. The wall of the hemisphere thickens, producing an elevation Formation of gyri and sulci
that projects into the medial side of the ventricle. The elevation is the Apart from the shallow hippocampal sulcus and the lateral cerebral
hippocampus; it appears first on the medial wall of the hemisphere, in fossa, the surfaces of the hemisphere remain smooth and uninterrupted


DEvEloPmENT of THE NERvous sysTEm
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3
NoITCEs
until early in the fourth month (see Fig. 17.29). The parieto-occipital A 10 weeks
sulcus appears at about that time on the medial aspect of the hemi-
sphere. Its appearance seems associated with an increase in the number
Corpus
of splenial fibres in the corpus callosum. Over the same period, the callosum Habenular
posterior part of the calcarine sulcus appears as a shallow groove commissure
extending forwards from a region near the occipital pole. It is a true Hippocampal
infolding of the cortex in the long axis of the striate area and produces commissure
an elevation, the calcar avis, on the medial wall of the posterior horn
of the ventricle.
During the fifth month, the cingulate sulcus appears on the medial
Posterior
aspect of the hemisphere, and sulci appear on the inferior and supero- commissure
lateral aspects in the sixth month. The central, precentral and postcen-
tral sulci appear, each in two parts, upper and lower, which usually
coalesce shortly afterwards, although they may remain discontinuous. Anterior
The superior and inferior frontal, the intraparietal, occipital, superior commissure
and inferior temporal, occipitotemporal, collateral and rhinal sulci all
make their appearance during the same period. By the end of the eighth
month, all the important sulci can be recognized (see Fig. 17.29).
Optic chiasma
Development of commissures
The development of the commissures causes a very profound alteration
of the medial wall of the hemisphere. At the time of their appearance,
the two hemispheres are connected to each other by the median part
of the telencephalon. The roof plate of this area remains epithelial, B 16 weeks
while its floor becomes invaded by the decussating fibres of the optic
Corpus callosum Habenular commissure
nerves and developing hypothalamic nuclei. These two routes are thus
not available for the passage of commissural fibres passing from hemi- Genu of Posterior commissure
corpus callosum
sphere to hemisphere across the median plane, and these fibres there-


fore pass through the rostral wall of the interventricular foramen, i.e.
the lamina terminalis. The first commissures to develop are those asso-
ciated with the palaeocortex and archicortex. Fibres of the olfactory
tracts cross in the ventral or lower part of the lamina terminalis and,
together with fibres from the piriform and pre-piriform areas and the
amygdaloid bodies, form the rostral part of the anterior commissure
(see Fig. 17.30; Fig. 17.31). In addition, the two hippocampi become
interconnected by transverse fibres that cross from fornix to fornix in
the upper part of the lamina terminalis as the commissure of the fornix
(hippocampal commissure). Various other decussating fibre bundles
(known as the supraoptic commissures, although they are not true
commissures) develop in the lamina terminalis immediately dorsal to
the optic chiasma, between it and the anterior commissure.
The commissures of the neocortex develop later and follow the
pathways already established by the commissures of the limbic system.
Fibres from the tentorial surface of the hemisphere join the anterior Hippocampal Optic chiasma
commissure and constitute its larger posterior part. All the other com- commissure Anterior commissure
missural fibres of the neocortex associate themselves closely with the Fig. 17.31 Median sections showing the formation of the commissures.
commissure of the fornix and lie on its dorsal surface. These fibres The telencephalon gives rise to commissural tracts that integrate the
increase enormously in number and the bundle rapidly outgrows its activities of the left and right cerebral hemispheres. Tracts include
neighbours to form the corpus callosum (see Figs 17.30–17.31). the anterior and hippocampal commissures and the corpus callosum. The
The corpus callosum originates as a thick mass connecting the two small posterior and habenular commissures arise from the epithalamus.
cerebral hemispheres around and above the anterior commissure. (This
site has been called the precommissural area, but this use has been


rejected here because of the increasing use of the adjective precommis- of a transient population of radial glial cells transform the neuroepi-
sural to denote the position of parts of the limbic lobe, i.e. prehippo- thelium of the embryonic forebrain into the adult cerebral cortex
campal rudiment, septal areas and nuclei and strands of the fornix, in (Noctor et al 2004). Neurones are derived from a lineage of radial glia
relation to the anterior commissure of the mature brain.) The upper stem cells and transit amplifying intermediate progenitor cells; expan-
end of this neocortical commissural area extends backwards to form the sion in one or both cell populations has been proposed as a potential
trunk of the corpus callosum. The rostrum of the corpus callosum mechanism for neocortical expansion (Kriegstein and Gotz 2003, Lui
develops later and separates some of the rostral end of the limbic area et al 2011). The earliest-generated cortical neurones accumulate in an
from the remainder of the cerebral hemisphere. Further backward outside-in sequence to form the preplate. Subsequent generations of
growth of the trunk of the corpus callosum then results in the entrapped neurones migrate into the preplate, forming a series of layers called the
part of the limbic area becoming stretched out to form the bilateral cortical plate, which splits the preplate into a superficial layer at the pial
septum pellucidum. As the corpus callosum grows backwards, it extends surface, the marginal zone, and a deeper layer, the subplate. Subplate
above the choroidal fissure, carrying the commissure of the fornix on neurones integrate into the intra- and extracortical circuitry; they extend
its undersurface. In this way, a new floor is formed for the longitudinal axons via the internal capsule towards the thalamus and superior col-
fissure, and additional structures come to lie above the epithelial roof liculus at times before other cortical neurones have been born (Kanold
of the third ventricle. In its backward growth, the corpus callosum and Luhmann 2010). In humans, the subplate is maximal at approxi-


invades the area hitherto occupied by the upper part of the archaeocorti- mately 25 weeks’ gestation and recedes by 6 months postnatally (Kos-
cal hippocampal formation, and the corresponding parts of the dentate tovic et al 2012). For a review of subplate development, modulation
gyrus and hippocampus are reduced to vestiges, the indusium griseum and demise, see Hoerder-Suabedissen and Molnar (2015). Subplate
and the longitudinal striae. However, the posteroinferior (temporal) neurones are vulnerable to injury during prenatal stages; their prema-
archaeocortical regions of both dentate gyrus and hippocampus persist ture loss has been implicated in the pathogenesis of chronic deficits
and enlarge. such as cognitive delay, behavioural problems and epilepsy associated
with preterm birth (Jantzie et al 2014).
Cellular development of the cerebral cortex Neurones migrate along radial glial processes (see Fig. 17.5). The
Cortical neurones are not generated within the cortex itself but in pro- migration of neuronal precursors from the ventricular and intermediate
liferative transient embryonic zones such as the ventricular (VZ) and zones occurs radially towards the pial surface (Kriegstein and Noctor
subventricular (SVZ) zones. Precise patterns of cell division and the 2004). From the pial surface inwards, the following zones may be
subsequent migration of the progeny of these divisions along the shafts defined: marginal, cortical plate, subplate, intermediate, subventricular


Central nervous system
263
71
RETPAHC
A Marginal zone
Subpial layer
Cortical plate
Marginal zone
Subpial layer Subplate zone
Cortical plate
Subplate/
Intermediate zone Intermediate zone
Preplate
Subventricular zone
Subventricular zone
Preplate
Ventricular zone
Ventricular
zone
B 1
2
Pial surface 3
Marginal zone 4
5
Cortical plate 6
Subplate zone
Subplate/intermediate zone
Intermediate zone
Subventricular zone
Preplate
Ventricular zone
Mitotic cells Pial surface
Radial glial cells
Ventricular
zone
Ependyma
Ventricle
30 40 50
Days
Proliferation Proliferation and migration: peaking between 3 and 5 months
Fig. 17.32 A, The layers of the developing telencephalon. The early pseudostratified arrangement of the neural tube is defined by radial glia extending
from the ventricular surface to the pial surface. Neuroblasts and glioblasts divide in the ventricular and subventricular zones and migrate radially along
the radial glia to form a cortical plate and then a subplate. The preplate, subplate, subventricular and ultimately the ventricular zones recede during
development and early postnatal life. B, Successive migration of neuroblasts from the ventricular and subventricular zones to the cortex. The first cells to
migrate to the cortical plate and subplate zone form the deep cortical laminae. Later cells migrate radially between these cells to the outer part of the
developing cortex. Note the extensive early proliferation of the subventricular zone and its later diminution as the cells it contains migrate radially to the
cortex. The effect of this radial cell migration towards the developing cortical surface is expansion of the cortical area rather than an increase in cortical
thickness. Axons from cells in the cortex extend through the intermediate zone which becomes cerebral white matter. Once the earliest cortical layers
have formed, cells originating from the ganglionic eminences migrate tangentially into the cortical layers and form interneurones.
and ventricular (Fig. 17.32). (For a review of the nomenclature of the The time of the proliferation of different cortical neurones varies


developing zones, see Bystron et al (2008).) The marginal zone, the according to their laminar destination and cell type. The first groups of
outermost layer of the developing cerebral cortex, will form layer 1, and cells to migrate are destined for the deep cortical laminae and later
the neurones of the cortical plate and subplate form the neurones of groups pass through them to more superficial regions. The subplate
the remaining (2–6) cortical laminae, the complexity varying in differ- zone is most prominent during mid-gestation; it contains neurones
ent locations and with further additions of neurones from the deeper surrounded by a dense neuropil and is the site of the most intense
zones. The intermediate zone gradually transforms into the white synaptogenesis in the embryonic cortex. The cumulative effect of this
matter of the hemisphere. Meanwhile, other deep progenitor cells radial and tangential growth is evident in a marked expansion of the
produce generations of glioblasts, which also migrate into the more surface area of the cortex without a comparable increase in its thickness
superficial layers. As proliferation wanes and finally ceases in the ven- (Rakic 1988, Rakic 2009).
tricular and subventricular zones, their remaining cells differentiate In the pallial walls of the mammalian cerebral hemisphere, the
into general or specialized ependymal cells, tanycytes or subependymal phylogenetically oldest regions, which are the first to differentiate
glial cells. during ontogeny, are those that border the interventricular foramen and
xetroc
fo sreyaL
Later tangential migration of
interneurons from developing ganglionic eminences
White matter


DEvEloPmENT of THE NERvous sysTEm
264
3
NoITCEs
A Neonatal brain and reflexes
Medial ganglionic eminence
The brain of the full-term neonate ranges from 300 to 400 g in weight,
Hippocampus
with an average of 350 g; the brains of neonatal males are slightly
Cerebral Dlx2, Mash1 heavier than those of females. Because the head is large at birth, measur-
cortex ing one-quarter of the total body length, the brain is also proportionally
CRBP1
larger and constitutes 10% of the body weight, compared with 2% in
Lateral Nksx2.1, Lhx6 the adult. At birth, the volume of the brain is 25% of its volume in
ganglionic adult life. The greater part of the increase occurs during the first year, at
eminence Lhx6, CRBP1
the end of which the volume of the brain has increased to 75% of its
adult volume. The growth can be accounted for partly by increase in
the size of nerve cell somata, the profusion and dimensions of their
Olfactory bulb Caudal ganglionic eminence dendritic trees, axons and collaterals, and by the growth of the neuro-
glial cells and cerebral blood vessels, but mostly it reflects the myelina-
tion of many of the axons: the sensory pathways – visual, auditory and
B somatic – myelinate first, and the motor fibres later. During the second
and subsequent years, growth proceeds much more slowly. The brain
PV PV Parvalbumin reaches 90% of its adult size by the fifth year and 95% by 10 years,
Medial SS attaining adult size by the seventeenth or eighteenth year, largely as a
SS Somatostatin
ganglionic result of the continuing myelination of various groups of nerve fibres.
eminence CR CR Calretinin The sulci of the cerebral hemispheres appear from the fourth month
of gestation (see Fig. 17.29). At full term, the general arrangement of
sulci and gyri is present, but the insula is not completely covered, the
central sulcus is situated further rostrally, and the lateral sulcus is more


oblique than in the adult. Most of the developmental stages of sulci
and gyri have been identified in the brains of premature infants. Of the
Caudal
Lateral ganglionic eminence ganglionic eminence cranial nerves, the olfactory nerve and the optic nerve at the chiasma
are much larger than in the adult, whereas the roots of the other nerves
Fig. 17.33 A, The ganglionic eminence of the subpallium is subdivided
are relatively smaller.
into three regions: lateral (LGE), medial (MGE) and caudal (CGE),
The brain occupies 97.5% of the cranial cavity from birth to 6 years
according to the expression patterns of various transcription factors (Dlx2,
of age, after which the space between the brain and skull increases in
Mash1, Nksx2.1 and Lhx6) and of the cellular retinol-binding protein 1
(CRBP1). B, The main migratory paths of interneurones derived from the volume until the adult brain occupies only 92.5% of the cranial cavity.
three subdivisions of the ganglionic eminence. MGE cells tend to migrate The cerebral ventricles are larger in the neonatal brain than they are in
laterally and spread throughout the cortex, and CGE cells migrate the adult. The newborn has a total of 10–15 ml of cerebrospinal fluid
predominantly towards the caudal telencephalon, whereas LGE cells when delivered vaginally and 30 ml when delivered by caesarean
migrate rostrally and contribute to interneurones in the olfactory bulb. It section. As the head moves down the birth canal and is compressed,
has been suggested that most MGE cells differentiate into parvalbumin the cerebrospinal fluid is pushed out into the venous sinuses; this does
(PV)- and somatostatin (SS)-immunoreactive interneurones, whereas most not happen in a caesarean delivery.
CGE cells differentiate into calretinin (CR)-immunoreactive interneurones.
Figure based on Métin et al 2006.
Myelination
Axons from cortical neurones elongate during prenatal and postnatal
life forming white matter tracts and fasciculi (Fig. 17.34). Oligodendro-


its extension, the choroidal fissure, the lamina terminalis and the piri- cyte progenitor cells are prevalent initially in the subventricular zone
form lobe. The pallidum also contributes interneurones to the forma- and later (19–22 weeks’ gestation) in the subplate zone (Jakovcevski
tion of the cerebral cortex. A large portion of GABAergic inhibitory et al 2009). Studies suggest three successive stages of the human oligo-
(non-pyramidal) cells are not generated in the cortical ventricular zone, dendrocyte lineage (pre-oligodendrocyte, immature oligodendrocyte,
but migrate tangentially through the striatocortical junction to reach and mature oligodendrocyte) in human cerebral white matter between
the cortex (Wonders and Anderson 2006, Métin et al 2006, Molnar and midgestation and term birth (Back et al 2001). Ventrodorsal gradients
Butt 2013, Hansen et al 2013; Fig. 17.33). of oligodendrocyte precursor cell density and of myelination are
The vast species differences between invertebrate, murine, non- described in the telencephalon.
human primate and primate nervous systems have long posed particu- Myelination occurs over a protracted period that starts during the
lar, sometimes intractable, problems for neuroscientists exploring the second trimester in the PNS. Motor roots start to myelinate before
evolution of the human cerebral cortex. Current understanding of the sensory roots in the PNS, whereas sensory nerves start to myelinate
pre- and postnatal events that regulate the numbers of neurones and before motor nerves. The cranial nerves of the midbrain, pons and
their associated glia; the dynamics of neuronal migration to proper medulla oblongata begin to myelinate at about 6 months’ gestation. For
layers, columns and regions; the enormous expansion of the cortical reviews of the molecular mechanisms currently known to regulate many
surface; and the development of connectivity, particularly networks of the stages involved in myelination in the CNS and PNS (including
mediating higher cognitive functions and language, remains in its precursor specification, proliferation, migration, differentiation and


infancy for the human cortex. (For further reading on the evolution of myelination of appropriate axons), see Mitew et al (2013) and Pereira
the neocortex, see Rakic (2009), Lui et al (2011), Geschwind and Rakic et al (2012), respectively.
(2013), Lister et al (2013).) The sequence of myelination of the motor pathways may explain, at
The Allen Human Brain Atlas (http://human.brain-map.org/) uses least partially, the order of development of muscle tone and posture in
DNA microarrays for transcriptional profiling of several hundred loca- the premature infant and neonate. Myelination of the corticospinal
tions spanning the adult human neocortex (Hawrylycz et al 2012), tracts starts some 10–14 days after birth in the internal capsule and
while the NIH Blueprint Non-Human Primate Atlas profiles individual cerebral peduncles, and then proceeds simultaneously in both tracts.
cortical layers in the rhesus monkey (http://www.blueprintnhpatlas.org/). Myelination of the various subcorticospinal pathways (vestibulospinal,
Similarly, the BrainSpan Atlas of the Developing Human Brain (http:// reticulospinal, olivospinal and tectospinal) starts at 24–30 weeks’ gesta-
www.brainspan.org/) is a resource for studying the transcriptome across tion for the medial tracts, and at 28–34 weeks’ gestation for the lateral
human brain development, using RNA sequencing on discrete cortical tracts. Evidence from diffusion tensor imaging (DTI) suggests that mye-
regions across the entire lifespan, as well as with microarrays at higher lination is the dominant process during the first year of life, starting
resolution in the mid-gestational cortex on laser-microdissected indi- centrally and spreading peripherally, and spreading forwards from the
vidual layers of different regions of the developing neocortex. occipital to the frontal lobe (Gao et al 2009). Myelin appears to start
Although the biological significance of the inside-out gradient of first around longer axons; thus, in the preterm infant, axial extension


neurogenesis is yet to be established, it is known that, if that gradient precedes flexion, whereas finger flexion precedes extension. By term, the
is disturbed, by either genetic or epigenetic factors, neurones display neonate at rest has a strong flexor tone accompanied by adduction of
abnormal cortical function. The consequences of failure or delay in all limbs. Neonates also display a distinct preference for a head position
neuronal migration cause a wide range of disorders, such as lissen- facing to the right, which appears to be independent of handling prac-
cephaly, schizophrenia, autism and mental retardation (Wu et al 2014). tices and may reflect the normal asymmetry of cerebral function at this


Central nervous system
265
71
RETPAHC
Preterm period (w) Post-term period (w) [1 year] [2 years]
10 20 30 40 10 20 30 40 50 60 70 80 90 100
Fibre growth
…? Fibre pruning …?
Fibre myelination …?
Bulb, pons
Midbrain, cerebellum
Cerebellar peduncles
Corpus callosum, body
Commissural fibres
~12w: corpus callosum Corpus callosum, splenium
Corpus callosum, genu
Projection fibres Thalamocortical fibres
~12w: thalamocortical fibres Corticospinal tract
~18w: corticospinal tract
Optic radiations
~18w: optic radiations
~24–32w: corona radiata Corona radiata
Auditory radiations
Internal capsule Posterior limb of internal capsule
~18w: posterior limb of internal capsule Anterior limb of internal capsule
~17–24w: anterior limb of internal capsule
Limbic fibres Fornix …?
~12w: fornix Cingulum
~19w: cingulum
Association fibres Association fibres in occipital, frontal, temporal and parietal lobes …?
~13–22w: uncinate fasciculus, External capsule
fronto-occipital fasciculus,
Extreme capsule …?
inferior longitudinal fasciculus
~17–24w: external capsule
>40w: arcuate fasciculus,
superior longitudinal fasciculus
Fig. 17.34 A general timeline of white matter development. (Based on Dubois et al 2014.)
age. Comparison of postnatal rates of myelination in human and prone position). Examination of the motor system and evaluation of
primate brains shows that humans achieve approximately 60% of adult these reflexes allow assessment of the nervous system in relation to
myelination during adolescence (compared to 96% in chimpanzees). gestational age. The neonate also exhibits complex reflexes, such as
Myelin growth continues in humans to the end of the third decade. nasal reflexes and sucking and swallowing. Infants with a corrected


Miller et al (2012) suggest this schedule of neural connectivity in gestational age of 32 weeks or more have a better-developed sucking
humans might contribute to the development of functional circuitry reflex and are quicker in achieving oral feeding (Neiva et al 2014).
with greater plasticity and capacity to be shaped by postnatal environ- An auditory reflex present at term is the production of otoacoustic
mental and social interactions. The greatest delay in myelination is seen emissions from sensory cell activity in the inner ear in response to
in the prefrontal cortex, an area where many neural circuits concerned sound and is now routinely tested in neonates as an assessment of
with learning and memory develop only after sexual maturity has been normal hearing.
attained. Nasal reflexes produce apnoea via the diving reflex, sneezing, sniff-
ing, and both somatic and autonomic reflexes. Stimulation of the face
Reflexes present at birth
or nasal cavity with water or local irritants produces apnoea in neonates.
A number of reflexes are present at birth and their demonstration is Breathing stops in expiration, with laryngeal closure, and infants
used to indicate normal development of the nervous system and exhibit bradycardia and a lowering of cardiac output. Blood flow to the
responding muscles. Five tests of neurological development are most skin, splanchnic areas, muscles and kidneys decreases, whereas flow to
useful in determining gestational age. The pupillary reflex is consist- the heart and brain is protected. Different fluids produce different
ently absent before 29 weeks’ gestation and present after 31 weeks; the effects when introduced into the pharynx of preterm infants. A com-
glabellar tap, a blink in response to a tap on the glabella, is absent parison of the effects of water and saline in the pharynx showed that
before 32 weeks and present after 34 weeks; the neck-righting reflex apnoea, airway obstruction and swallowing occur far more frequently
appears between 34 and 37 weeks; the traction response, where flexion with water than with saline, suggesting the presence of an upper airway
of the neck or arms occurs when the baby is pulled up by the wrists chemoreflex. Reflux of gastric content into the oesophagus is a well-


from the supine position, appears after 33 weeks; and head-turning in recognized cause of apnoea and constitutes an acute life-threatening
response to light appears between 32 and 36 weeks. The spinal reflex event in infants. Reflex responses to the temperature of the face and
arc is fully developed by the eighth week of gestation and lower limb nasopharynx are necessary to start pulmonary ventilation. Midwives
flexor tone is detectable from about 29 weeks. The Babinski response, have, for many years, blown on the faces of neonates to induce the first
which involves extension of the great toe with spreading of the remain- breath.
ing toes in response to stimulation of the lateral aspect of the sole of Sucking and swallowing are a particularly complex set of reflexes,
the foot, is elicited frequently in neonates; it reflects poor cortical partly conscious and partly unconscious. As a combined reflex, sucking
control of motor function by the immature brain. Generally, reflexes and swallowing require the coordination of several of the 12 cranial
develop as muscles gain tone. They appear in a sequential manner nerves. The neonate can, within the first couple of feeds, suck at the rate
from caudal to cephalic, i.e. in the lower limb before the upper, and of once per second, swallow after five or six sucks, and breathe during
centripetally, i.e. distal reflexes appear before proximal ones (Allen and every second or third suck. Air moves in and out of the lungs via the
Capute 1990). nasopharynx, and milk crosses the pharynx en route to the oesophagus
The usual reflexes that can be elicited in the neonate include Moro, without apparent interruption of breathing and swallowing, or signifi-
asymmetric tonic neck response, rooting–sucking, grasp, placing (con- cant misdirection of air into the stomach or fluids in the trachea.
tacting the dorsum of the foot with the edge of a table produces a Swallowing movements are first noted at about 11 weeks’ gestation;
‘stepping over the edge’ response), stepping, and trunk incurvation in utero fetuses swallow 450 ml of amniotic fluid per day. Sucking and
(elicited by stroking down the paravertebral area with the infant in the swallowing in premature infants (1700 g) is not associated with primary


DEvEloPmENT of THE NERvous sysTEm
266
3
NoITCEs
peristaltic waves in the intestine; however, in older babies and full-term marginal zone (Siegenthaler and Pleasure 2011). Should the meningeal
neonates, at least 90% of swallows will initiate primary peristaltic layer be incomplete, neural tissue may herniate in a cobblestone
waves. manner, as is seen in type II lissencephaly (Sun and Hevner 2014).
Sucking develops, generally, slightly later than swallowing, although Mesenchymal cells projecting from the rostral end of the notochord,
mouthing movements have been detected in premature babies as early and those in the region of the prechordal plate, extend rostrally into
as 18–24 weeks’ gestation, and infants delivered at 29–30 weeks’ gesta- the mesencephalic flexure and form the earliest cells of the tentorium
tion make sucking movements a few days after birth. Coordinated cerebelli; at the beginning of its development, the medial part of the
activities are not noted before 33–34 weeks. The concept of non- tentorium is predominantly leptomeningeal. By stage 17 (41 days), dura
nutritive and nutritive sucking has been introduced to account for the mater can be seen in the basal areas where the future chondrocranium
different rates of sucking seen in the neonate. Non-nutritive sucking, is also developing. The precursors of the venous sinuses lie within the
when rhythmic negative intraoral pressures are initiated that do not pachymeninx at stage 19 (48 days), and by stage 20, cell populations in
result in the delivery of milk, can be spontaneous or stimulated by an the region of the future falx cerebri are proliferating, although the dorsal
object in the mouth. This type of sucking tends to be twice as fast as regions of the brain are not yet covered with putative meninges.
nutritive sucking; the sucking frequency for non-nutritive sucking is By stage 23 (57 days), the dura is almost complete over the rhomben-


1.7 sucks/second in 37–38-week premature babies, 2 sucks/second in cephalon and mesencephalon but is only present laterally around the
term neonates, and 2.7 sucks/second at 7–9 months postnatally. Cor- prosencephalon. Subarachnoid spaces and most of the cisternae are
responding times for nutritive sucking are about 1 suck/second in term present from this time, after the arachnoid mater becomes separated
neonates, increasing to 1.5 sucks/second by 7 months postnatally. from the primitive dura mater by the accumulation of cerebrospinal
The taste of the fluid, as well as nutrient content, affects the efficiency fluid (which now has a net movement out of the ventricular system).
of nutritive sucking in the early neonatal period. There is more sucking The medial part of the tentorium is becoming thinner. A dural compo-
with milk than with 5% dextrose; however, sucking activities increase nent of the tentorium is seen from stage 19. The earlier medial portion
with solutions that are determined to be sweet by adult appraisal. disappears, leaving an incomplete partition that separates a subarach-
In full-term neonates, the placing of a spoon or food on to the noid area containing the telencephalon and diencephalon from one
anterior part of the tongue elicits an extrusion reflex: the lips are pursed containing the cerebellum and rhombencephalon.
and the tongue pushes vigorously against the object. By 4–6 months, There is a very close relationship, during development, between the
the reflex changes and food deposited on the anterior part of the tongue mesenchyme from which the cranial dura mater is formed and that
is moved to the back of the tongue, into the pharynx, and swallowed which is either chondrified and ossified, or ossified directly, to form the
(see Ch. 34 for a description of swallowing in the adult). Rhythmic skull. These layers are only clearly differentiated as the venous sinuses
biting movements occur by 7–9 months postnatally, even in the absence develop. The relationship between the developing skull and the under-
of teeth. lying dura mater continues during postnatal life while the bones of the


Difficulties in sucking and swallowing in infancy may be an early calvaria are still growing.
indication of disturbed nervous system function. There is an interesting The growth of the cranial vault is initiated from ossification centres
correlation between feeding styles of neonates and later eating habits. within the desmocranial mesenchyme. A wave of osteodifferentiation
Children who were obese at 1 and 2 years of age, as measured by triceps moves radially outwards from these centres, stopping when adjacent
skin-fold thickness, had a feeding pattern in the first month of life that bones meet at regions where sutures are induced to form. Once sutures
was characterized by sucking more rapidly, producing higher pressures are formed, a second phase of development occurs, in which growth of
during prolonged bursts of sucking, and having shorter periods between the cranial bones takes place at the sutural margins. This growth forms
bursts of sucking. Fewer feeds and higher sucking pressure seem to be most of the skull (Ch. 36). A number of hypotheses have been gener-
associated with greater adiposity. Infants who are unable to feed orally ated to explain the process of sutural morphogenesis. It has been sug-
in the first few weeks of life as a result of a congenital anomaly such as gested that the dura mater contains fibre tracts that extend from fixed
oesophageal atresia may develop food aversion. positions in the cranial base to sites of dural reflection underlying each
of the cranial sutures, and that the tensional forces so generated dictate
Postnatal brain maturation
the position of the sutures and locally inhibit precocious ossification.
Anatomical studies of neonatal and postnatal brains to evaluate matur- Other hypotheses support the concept of local factors in the calvaria
ational progression are now possible using diffusion tensor magnetic that regulate suture morphogenesis. Following removal of the entire
resonance imaging (DTMRI). A number of studies have assessed the calvaria, the skull regenerates and sutures and bones develop in ana-
growth status of white matter tracts from gestational ages to early child- tomically correct positions, suggesting that the dura can dictate suture
hood (Huang et al 2006, Huang et al 2009, Lodygensky et al 2010, position, at least in regeneration of the neonatal calvaria. In transplants


Huang and Vasung 2014) (see Fig. 17.34). Those babies born premature of sutures in which the fetal dura mater was left intact, a continuous
and with very low birth weight have been shown to have changed corti- fibrous suture remained between developing vault bones, whereas bony
cal thickness, which is still present in late teenage years (Bjuland et al fusion occurred in transplants in which the fetal dura mater was
2013), and white matter injury, including periventricular leukomalacia removed (Opperman et al 1993).
(Ment and Sould 2012, Molnar and Rutherford 2013). It is not clear The presence of fetal dura is not required for initial suture mor-
whether such changes are a consequence of preterm delivery, of perina- phogenesis, which appears to be controlled by mesenchymal cell pro-
tal brain injury or of fetal inflammatory response syndrome. liferation and fibrous extracellular matrix synthesis induced by the
overlapping of the advancing osteo-inductive fronts of the calvarial
bones. It is thought that, following overlap of the bone fronts, a signal
MENINGES
is transferred to the underlying dura, which induces changes in local-
ized regions beneath the sutures. Once a suture has formed, it serves
The meningeal layers originate from paraxial mesenchyme in the trunk as a primary site for cranial bone growth; constant interaction with
and caudal regions of the head and from neural crest in regions rostral the dura is required to avoid ossiferous obliteration.
to the mesencephalon (the prechordal plate has also been suggested as
making a contribution). Those skull bones that are formed from neural
crest, i.e. the base of the skull rostral to the sella turcica, and the frontal, VASCULAR SUPPLY
parietal and squamous temporal bones, overlie meninges that are also
formed from crest cells.
ARTERIES
The meninges may be divided in development into the pachymeninx
(dura mater) and leptomeninges (arachnoid mater, subarachnoid space
Cranial arteries
with arachnoid cells and fibres, and pia mater). All meningeal layers
are derived from loose mesenchyme that surrounds the developing


neural tube, termed meninx primitiva, or primary meninx. (For a The cranial extensions of the dorsal aortae that supply the head receive
detailed account of the development of the meninges in the human, blood entirely through the third aortic arches. The internal carotid
consult O’Rahilly and Müller (1986).) artery is formed progressively from the third arch artery (which contrib-
The first indication of pia mater, containing a plexus of blood vessels utes its proximal part) (see Fig 36.9) and a further forward continuation
that forms on the neural surface, is seen at stage 11 (24 days), around that differentiates, at the time of regression of the first and second aortic
the caudalmost part of the medulla; this extends to the mesencephalic arches, from the capillary plexus extending to the walls of the forebrain
level by stage 12. The pial basement membrane is formed from interac- and midbrain. At its anterior extremity, this primitive internal carotid
tion between the neural crest and the end feet of the radial glial cells. artery divides into cranial and caudal divisions. The former terminates
Removal of the meninges halts tangential migration of cells within the as the primitive olfactory artery and supplies the developing regions


vascular supply
267
71
RETPAHC
Vascularization of the brain
implied (see Fig. 36.8). The latter sweeps caudally to reach the ventral
aspect of the midbrain; its terminal branches are the primitive mesen- The brain becomes vascularized by angiogenesis (angiotrophic vascu-
cephalic arteries. Simultaneously, bilateral longitudinal channels dif- logenesis) rather than by direct invasion by angioblasts. Blood vessels
ferentiate along the ventral surface of the hindbrain from a plexus fed form by sprouting from vessels in the pial plexus that surrounds the
by intersegmental and transitory presegmental branches of the dorsal neural tube from an early stage. These sprouts form branches that elon-
aorta and its forward continuation. The most important of the preseg- gate at the junction between the ventricular and marginal zones; the
mental branches is closely related to the fifth nerve, the primitive branches project laterally within the inter-rhombomeric boundaries
trigeminal artery. Otic and hypoglossal presegmental arteries occur and and longitudinally adjacent to the median floorplate. Subsequently,
may persist. The longitudinal channels later connect cranially with the additional sprouts penetrate the inter-rhombomeric regions on the
caudal divisions of the internal carotid arteries (each of which gives rise walls and floor of the hindbrain. Branches from the latter elongate
to an anterior choroidal artery supplying branches to the diencephalon, towards and join the branches in the inter-rhombomeric junctions,
including the telae choroideae and midbrain), and caudally with the forming primary vascular channels between rhombomeres and longi-
vertebral arteries through the first cervical intersegmental arteries. tudinally on each side of the median floorplate. Later additional sprouts
Fusion of the longitudinal channels results in the formation of the invade the hindbrain within the rhombomeres, anastomosing in all
basilar artery, while the caudal division of the internal carotid artery directions.
becomes the posterior communicating artery and the stem of the pos- The leptomeningeal perforating branches pass into the brain paren-
terior cerebral artery. The remainder of the posterior cerebral artery chyma as cortical, medullary and striate branches (Fig. 17.35). The


develops comparatively late, probably from the stem of the posterior cortical vessels supply the cortex via short branches, which may form
choroidal artery, which is annexed by the caudally expanding cerebral precapillary anastomoses, whereas the medullary branches supply the
hemisphere, its distal portion becoming a choroidal branch of the white matter. The latter converge towards the ventricle but rarely reach
posterior cerebral artery. The posterior choroidal artery supplies the tela it; they often follow a tortuous course as they pass around bundles of
choroidea at the future temporal end of the choroidal fissure; its rami nerves. The striate branches, which penetrate into the brain through the
advance through the tela to become confluent with branches of the anterior perforated substance, supply the basal nuclei and internal
anterior choroidal artery. The cranial division of the internal carotid capsule via a sinuous course; they are larger than the medullary branches
artery gives rise to anterior choroidal, middle cerebral and anterior and the longest of them reach close to the ventricle. The periventricular
cerebral arteries. The stem of the primitive olfactory artery remains as region and basal nuclei are also supplied by branches from the tela
a small medial striate branch of the anterior cerebral artery. The cerebel- choroidea, which develops from the early pial plexus but becomes
lar arteries, of which the superior is the first to differentiate, emerge medially and deeply placed as the telencephalon enlarges.
from the capillary plexus on the wall of the rhombencephalon. The cortical and medullary branches irrigate a series of corticosub-
The source of the blood supply to the territory of the trigeminal cortical cone-shaped areas, each centred around a sulcus containing an
nerve varies at different stages in development. When the first and artery. They supply a peripheral portion of the cerebrum and are
second aortic arch arteries begin to regress, the supply to the corre- grouped as ventriculopetal arteries. In contrast, striate branches arborize
sponding arches is derived from a transient ventral pharyngeal artery, close to the ventricle and supply a more central portion of the cerebrum;