Neuroblasts of the brainstem develop in a manner similar to those in the spinal cord. Alar and basal plates form sensory and motor columns of cells that supply cranial nerves, but the topographical layout of these nuclei differs in the brainstem, as compared with the cord. The mesencephalon remains undivided and consists of the basal midbrain and alar quadrigeminal plate. The pons consists of two parts, the basis pontis and the pontine tegmentum . The former is ventrally located and is phylogenetically newer. The latter is the older portion, is dorsal in position and is continuous with the medulla. The pontine tegmentum and the medulla together form the floor of the fourth ventricle. Here, the alar and basal plates are separated by a sulcus limitans , but unlike in the spinal cord, they are disposed laterally and medially, instead of dorsal and ventral. With continued development, alar and basal plates shift laterally but retain their respective functions, with the alar plates containing afferent nuclei and the basal plates forming efferent nuclei. Portions of the alar plate migrate ventrally and form the inferior olivary nucleus. Nuclei of the basis pontis migrate there from the alar plate. They receive synapses of cortically originating fibres. Medullary pyramids consist of fibres from the cerebral cortex and develop on the ventral surface near the midline

Caudal to the mesencephalon lies the metencephalon, which is the rostral portion of the hindbrain. It differentiates into two major structures, the cerebellum and the pons. At the rostral edge of the roof of the fourth ventricle lie the rhombic lips, which arise from the dorsolateral alar plates of the rhombencephalon. At about the fifth or sixth week, these lips start forming the cerebellar primordia . Their growth and infolding into each other causes them to fuse in the midline, creating the cerebellar plate, which covers the fourth ventricle caudal to the mesencephalon. Although the cerebellum accounts for approximately 10 % of the human brain’s volume, it contains over 50 % of the total number of neurons in the brain. The cerebellum, like the frontal lobe, is the last of the structures to develop. Chiari tonsillar descent, for example, has not been identified earlier than 10 weeks on antenatal ultrasound scans (Blaas et al. 2000). Another example of the effect of disordered development and growth on this late maturation is seen in severe prematurity,⁵ where cerebellar function and volume may be affected. Recent evidence shows that individuals born very preterm have significantly smaller cerebella than their term-born peers, and that this difference remains statistically significant after controlling for whole brain volume and other potentially confounding variables (Allin et al. 2001).

By the 5th week of gestation, all cranial nerves are recognisable except for the olfactory and optic nerves. The pure motor cranial nerves (III, IV, VI and XII) have no external ganglia and arise from the basal (motor) plate. Sensory nerves have conspicuous ganglia near the brain and most have motor components, except for the eighth. Apart from the third and fourth cranial nerves, which arise from the midbrain, the 5th to the 12th cranial nerves arise from the rhombencephalon (Table 4.2). Hox genes play an important role in temporospatial development of motor neurons of the trigeminal and facial nerves, as we will see later.

The cranial part of the neural canal (lumen of neural tube) forms the ventricular system of the brain. The shape of the ventricles is determined by the brain folding around the two primary flexures (cephalic and cervical), forming three primitive vesicles, during week 4 of gestation. These bends arise as a result of tremendous cell proliferation, occurring within the confined space of the cranial vault, causing the neural tube to buckle as the brain develops. Towards the end of week 4 and early into week 5, the primitive 3-vesicle brain divides further to become a 5-vesicle structure. Each vesicle contains its own ventricle (Table 4.3). The prosencephalon gives rise to paired lateral telencephalic vesicles , which become the cerebral hemispheres. It also forms the diencephalon, from which the optic vesicles also extend. During week 6, in the 5-vesicle stage, the pontine flexure develops. This divides the rhombencephalon into a rostral metencephalon, which will form the pons and cerebellum, and a caudal myelencephalon, which becomes the medulla. Later, the disproportionate expansion of the cerebral hemispheres alters the configuration of the lateral ventricles , which become ‘C’-shaped. These flexures also create specific narrowings within the ventricles. The foramina of Monro are located at the level of the telencephalon/diencephalon division. The cerebral aqueduct remains as a relatively simple tubular channel within the unflexed mesencephalon. During the fifth and sixth weeks, the roof of the fourth ventricle thins out in the midline to form the foramen of Magendie and, laterally, the foramen of Luschka (Melsen 1974; Koseki et al. 1993). By approximately the 7th week, a connection between the fourth ventricle and the subarachnoid space is established. The foramina of Luschka and Magendie lie at the division of the rostral metencephalon and caudal myelencephalon. More caudally, below the cervical flexure, the central canal lies within and along the spinal cord.

The development of the three primary vesicles (5th week) and subsequently, at 7 weeks, the five secondary vesicles (telencephalon, diencephalon, mesencephalon, metencephalon and myelencephalon) is accomplished by the development of flexures. These flexures may also help maintain the CSF between them in a state of tension, so as to expand the ventricular system in an asymmetric way. Our ventricular system was moulded by flexural kinks into different shapes and sizes, aided by the moulding weight of the developing brain around it (Fig. 4.5). The hydrostatic tension within the ventricles acts as a vital scaffold upon which the parenchyma develops and grows. Premature unfolding of a particular flexure will impact on the CSF tension within the corresponding vesicle and almost certainly cause a degree of collapse of the dorsal structures upon it. Hypothetically, if the distal pontine flexure – which develops around the seventh week, between the pons, cerebellum and medulla oblongata – and/or the cervical flexure were to ‘unkink’, then this could result in lesser tension in the metencephalic vesicle and a smaller posterior fossa, as seen in occipital somite (skull base) development anomalies. On the other hand, if there was a continuous caudal CSF leak, as we see with leaking myelomeningocoeles, then the normal tension within the ventricular system would be reduced. The effect would be a sequential collapse of dorsal structures upon the floppy metencephalic and myelencephalic vesicle centres, causing a small posterior fossa and its caudal dislocation. An inward suction/decompression effect on the most rostral part of the ventricle could also occur, leading to flattening of the forehead. This may hypothetically explain why foetuses develop the typical lemon appearance of the forehead and the banana sign ⁶ on ultrasounds of myelomeningocoele and Chiari II malformation. It may also help explain the tectal beaking and neuronal migration disorders seen in association with Chiari II malformations and myelomeningocoele.

Somites are masses of mesoderm, distributed along the two sides of the neural tube, that will eventually become dermis (dermatome ), skeletal muscle (myotome ) and vertebrae (sclerotome ). During the 4th week of gestation, 42 somites are formed.^. These are made up of 4 occipital somites, 8 cervical, 12 thoracic and 5 lumbar; the remainder are sacrococcygeal (Muller and O’Rahilly 1980; Gasser 1976; Arcy 1965) . Each somite then differentiates into an outer dermatome, an inner myotome and a medial sclerotome (Fig. 4.6). Because the sclerotome differentiates before the other two components, the term ‘dermomyotome ’ is sometimes used to describe the combined dermatome and myotome. Each sclerotome has three parts, a hypocentrum , a centrum and a neural arch . The first four sclerotomes go on to form the skull base and the foramen magnum. The hypocentrum forms different structures at each level (see Table 4.4). The sclerotomes are ventromedial to the neural tube and will surround the notochord and go on to form the vertebral bodies. This topography means that the skull base develops ventral to the rostral notochord (Melsen 1974).

The clivus and the occipital bone and, hence, the foramen magnum are derived from the four occipital somites. The first two occipital sclerotomes give rise to the basiocciput (Fig. 4.7). The tip of clivus, the anterior tubercle of the C1, the dens apex and the apical ligament are derived from the fourth occipital sclerotome, otherwise referred to as the proatlas (Menezes 1996; Gladstone and Wakeley 1925; Gasser 1976). The anterior margin of the foramen magnum, as well as the occipital condyles and the midline third occipital condyle (Fig. 4.8), arises from the ventral portion of the proatlas (Prescher et al. 1996). The cruciate ligament and the alar ligaments arise from the lateral part of proatlas. The C2 lateral mass and the superior portion of the posterior arch of the atlas develop from the caudal proatlas. The posterior rim of the foramen magnum and the occiput develop from the dorsal fusion of the first four (occipital) sclerotomes. The odontoid process and the atlas vertebra are formed from the first spinal sclerotome. The atlas shows several ossification centres in development (Keynes and Stern 1988). While the lateral masses of C2 are present at birth, complete ossification may not occur until about 3 years of age when a complete ring may then be seen. The dens is the central portion of the first sclerotome, which fuses with the axis body. The neural arch of this first spinal sclerotome proceeds to form the posterior and inferior portion of the C1 arch (Menezes 1995; Koseki et al. 1993). With further development, the hypocentrum of the second spinal sclerotome disappears, but the centrum goes on to form the body of the axis body. Division of the neural arch forms the facets and the posterior arch of the axis vertebra (Keynes and Stern 1988). In summary, most of the dens develops from the first spinal sclerotome, but the terminal portion of the odontoid process arises from the proatlas, and the most inferior portion of the axis body is formed by the second spinal sclerotome (Table 4.4).

The skull develops by two different processes. The calvarium and facial bones develop by membranous ossification (Kessel and Gruss 1991; Christ and Wilting 1992; Dietrich and Kessel 1997) as does the occipital skull above the nuchal line, although this component is thought to arise, originally, from neural crest cells, rather than from the paraxial mesoderm. The skull base and the remainder of the occipital bone develop from a cartilaginous framework, in which deposition of bone occurs. This process is driven mainly by distorting forces generated by the developing brain. Just as remodelling of the anterior cranial fossa occurs as the prosencephalon folds down, posterior fossa expansion occurs following the growth of its neural contents. In response to the pontine and medullary enlargement, the clivus elongates at the basiocciput and lowers the front margin of the foramen magnum. Downward cerebellar displacement pushes the opisthion downward and backward. These processes result from a combination of endochondral resorption and sutural growth.

Some parts of the skull base also continue to develop later in life, in response to the growth of surrounding structures. For example, growth of the sphenooccipital and sphenopetrosal synchondrosis , along with adjacent endochondral and intramembranous ossification, results in an elongation of the clivus and the posterior skull base (Menezes 1998). This process can continue until late adolescence and will ultimately model the final shape and size of the posterior fossa.

The process of segmentation at the craniocervical junction and along the spine is tightly regulated by control genes. Proteins promoted by these genes modulate the transcription of specific downstream genes, thereby controlling morphogenesis and providing specific identify for each vertebra (Lufkin et al. 1992). The main genetic groups involved in mesodermal and neuroectodermal development of the craniocervical junction are the SHH genes, for basal development, the Hox genes ⁷ for dorsal neural folding and tube closure and the PAX genes ⁸ for segmentation. Subsequent re-segmentation of the sclerotomes then occurs, to establish vertebral boundaries. This process seems to be independently controlled by two regulatory genes of the PAX family (Koseki et al. 1993).