Development of the brain

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Chapter 2

Development of the brain

Neural tube formation

The central nervous system is derived from the neural tube, which appears during the fourth week after fertilization. At this early stage the embryo takes the form of a trilaminar germ disc, lying in the floor of the amniotic sac (Fig. 2.1). The germ disc is composed of three layers of tissue from which all the structures of the body originate:

Fig. 2.1 The trilaminar germ disc in the floor of the amniotic sac, bisected in the coronal plane.
**(A)** The germ disc is composed of three primitive germ layers from which all body tissues are derived. A complex process of folding (not illustrated) transforms the germ disc so that the ectoderm comes to lie on the outside and the endoderm lines the gut lumen; **(B)** The body can be represented in cartoon form as a hollow cylinder with the mouth at one end and the anus at the other.

The ectoderm (Greek: ektos, outside) contributes mainly to the skin, but also gives rise to the central and peripheral nervous systems.

The mesoderm (Greek: misos, middle) is the origin of the cardiovascular, musculoskeletal, urinary and reproductive systems.

The endoderm (Greek: endon, within) contributes chiefly to the respiratory and gastrointestinal tracts, including the liver, gallbladder and pancreas.

The process by which the embryonic ectoderm gives rise to the neural tube is called primary neurulation (Fig. 2.2). It is initiated by the notochord, a rod-like mesodermal structure that helps to define the longitudinal axis of the embryo. The notochord releases soluble mediators including cell adhesion molecules and trophic factors, which influence the overlying ectoderm. This process is termed neural induction.

Fig. 2.2 The origin of the neural tube and neural crest.
**(A)** The mesodermal notochord releases soluble mediators that induce neural tube formation in the overlying ectoderm (neural induction); **(B)** The neural tube forms from the paired neural folds which flank the neural groove; **(C)** The neural crest cells detach from the dorsolateral margins of the neural tube and will give rise to much of the peripheral nervous system, including the spinal and autonomic ganglia.

Ultrasound studies show that in humans the neural tube begins to form at around 21-23 days after fertilization, when the embryo is just 2–3 mm in length. The first change (which occurs at about day 18) is the appearance of the neural plate, a broad area of thickening in the dorsal ectoderm. A shallow longitudinal depression termed the neural groove separates the neural plate into paired neural folds which gradually roll up to form a cylinder. The neural folds ultimately meet in the midline and unite to create the neural tube and neural canal. Fusion begins in the presumptive cervical region and proceeds both rostrally and caudally in a ‘zipper-like’ fashion. The open ends of the neural tube are called the cranial and caudal neuropores, which have normally closed by the beginning of week five. Disorders resulting from faulty neural tube closure are discussed in Clinical Box 2.1.

Clinical Box 2.1: Neural tube defects

Incomplete closure of the neural tube is responsible for a group of developmental disorders called neural tube defects. The incidence is approximately 1 in 500 live births. The most common form is spina bifida which results in malformation of the lower spinal cord due to abnormal caudal neuropore closure. The severity is variable, ranging from little or no neurological impairment to paralysis of the lower limbs with lack of bladder and bowel control. An asymptomatic partial form that only affects the vertebral arches (spina bifida occulta) is present in up to 10% of the population. Defective closure of the cranial neuropore can lead to anencephaly in which the forebrain fails to develop (Greek: a-, without; enkephalos, brain). Anencephalic fetuses are often stillborn, but may survive for a few hours after birth. It has been shown that folic acid supplements in women of child-bearing age reduce the incidence of neural tube defects by around 70%.

The sacral and coccygeal segments derive from the caudal eminence, a solid mass of cells that arises just below the developing neural tube and ultimately fuses with it. A central cavity forms within the caudal eminence and becomes continuous with the central canal of the spinal cord. This process is termed secondary neurulation.

Origin of neurons and glial cells

The wall of the neural tube can be divided into three concentric zones (Fig. 2.3). The ventricular zone is closest to the fluid-filled neural canal (which will become the cerebral ventricles) and is composed of proliferating neural progenitor cells. These include neuroblasts (neuronal precursors) and glioblasts (glial precursors) that give rise to most of the specialized cells of the central nervous system. Microglia are the resident phagocytes of the brain, but originate from the bone marrow and are of mesodermal rather than ectodermal lineage.

Fig. 2.3 Transverse section through the neural tube, illustrating the ventricular, intermediate and marginal zones.
Cell division (mitosis) occurs in the ventricular zone, giving rise to neurons and glia.

Cells that have arisen in the ventricular zone migrate outwards through the wall of the neural tube. This is facilitated by radial glia which provide a ‘scaffold’ along which cells are able to crawl, guided by signalling molecules. Neurons and glial cells accumulate in the intermediate zone of the neural tube where they extend processes and begin to make connections with other cells. The outermost layer is the marginal zone. It is relatively cell-poor and is mainly composed of neuronal and glial processes.

Formation of the cerebral cortex

The three-layered arrangement of the neural tube is modified extensively to form the brain. In the developing cerebral hemispheres there is a second (superficial) neuronal layer called the cortical plate which is the precursor of the cerebral cortex. Beneath it is a transient structure called the subplate.

Cortical neurons arise in the ventricular zone (referred to as the germinal matrix in the brain) and migrate along radial glia to enter the cortical plate – or form transient connections within the subplate. Those neurons that will ultimately occupy the deepest of the six cortical laminae arrive first, with more superficial layers being added in sequential waves of neurogenesis and migration. This means that the cerebral cortex is constructed ‘inside-out’.

Proper neuronal migration depends on a layer of Cajal–Retzius cells (pronounced: ka-HARL) located in the most superficial part of the cerebral cortex. The outward migration of newly formed neurons is regulated by the protein reelin, a molecular ‘stop-signal’ that is secreted by Cajal–Retzius cells. This ensures that neurons reach the appropriate layer of the cerebral cortex.

In the cerebral hemispheres the majority of neurons ultimately vacate the intermediate zone or undergo programmed cell death (see Ch. 8) and this region eventually becomes the subcortical white matter. Up to 50% of neurons produced in the developing brain fail to (i) reach their intended targets or (ii) make appropriate functional connections and are consequently deleted by programmed cell death.

Sensory and motor areas

The neural tube has two functional divisions, separated by the sulcus limitans (Fig. 2.4A). The basal plate occupies the ventral portion of the neural tube (anterior to the sulcus limitans) and is predominantly a motor structure; the alar plate is located dorsally and is sensory. This dorsal–ventral division between sensory and motor areas is reflected in the adult spinal cord, with sensory fibres entering via the dorsal roots and motor fibres emerging in the ventral roots (Fig. 2.4B). It is echoed throughout the central nervous system so that motor structures (e.g. cortical areas, tracts, nuclei) tend to be anterior to sensory structures.

Fig. 2.4 Transverse sections through (A) the developing neural tube and (B) the adult spinal cord.
The basal (motor) plate is separated from the alar (sensory) plate by the sulcus limitans.

The neural crest

The peripheral nervous system is mainly derived from the neural crest. This is a population of cells that detaches from the lateral margins of the neural plate during neurulation (see Fig. 2.2). Neural crest cells that come to lie dorsolateral to the neural tube ultimately become the primary sensory neurons of the dorsal root ganglia. These neurons are initially bipolar but their central and peripheral processes fuse at a common T-shaped extension of the cell body to form a single continuous axon. For this reason they are described as pseudounipolar (Greek: pseudo-, false). The central processes of the dorsal root ganglion cells innervate the alar (sensory) plate of the neural tube, whereas the peripheral processes enter the spinal nerves at each segmental level (see Fig. 2.4B).

The ventral roots of the spinal nerves represent the axons of basal plate motor neurons. The primary sensory neurons of cranial nerve ganglia are also crest-derived, although not all cranial nerves carry sensory fibres. Other neural crest derivatives include the ganglia of the autonomic nervous system, peripheral Schwann cells and the inner two meningeal layers (pia and arachnoid). In contrast, the dura is a mesodermal derivative. The neural crest also gives rise to non-neural structures including skin melanocytes and components of the laryngeal cartilages and teeth.

Key Points

The brain and spinal cord develop from the neural tube, which is derived from the ectoderm. The neural folds rise up on either side of the neural groove and fuse to form a cylinder.

The wall of the neural tube is divided into three concentric zones spanned by radial glia. The ventricular zone contains proliferating progenitor cells that give rise to neurons and glia.

The neural tube is divided by the sulcus limitans into a basal (motor) plate anteriorly and an alar (sensory) plate posteriorly.

The neural crest arises from the dorsolateral margins of the neural tube and gives rise to most of the peripheral nervous system including neurons of the cranial, spinal and autonomic ganglia.

Folic acid supplementation in women of child-bearing age reduces the incidence of neural tube defects such as spina bifida and anencephaly by 70%.

Divisions of the brain

The three fundamental divisions of the brain can be identified in the neural plate as early as week three, before the neural tube has closed. They are illustrated schematically (at a later stage of development) in Fig. 2.5:

The prosencephalon (Greek: pro, before) is the precursor of the forebrain and will give rise to the cerebral hemispheres, basal ganglia and thalamic region (diencephalon).

The mesencephalon corresponds to the adult midbrain.

The rhombencephalon (Greek: rhomboeides, shaped like a rhombus) gives rise to the hindbrain, which includes the pons, medulla and cerebellum.

During weeks four and five the neural tube closes and the cranial portion undergoes an impressive transformation, differentiating into five regions that will become the major anatomical divisions of the adult brain (Fig. 2.6). Each of these components contains a fluid-filled cavity or channel that corresponds to the lumen of the neural tube (Fig. 2.7).

Fig. 2.6 The five major anatomical divisions of the brain can be identified by the end of the fifth week post-fertilization.
At this stage the embryo is around 10 mm in length.

Fig. 2.7 The brain and ventricular system.
Each part of the brain contains a fluid-filled cavity or channel corresponding to the lumen of the neural tube.

The forebrain (or cerebrum) gives rise to two large vesicles which are the forerunners of the cerebral hemispheres. These balloon out on either side of the forebrain in the most cranial part of the neural tube and collectively make up the telencephalon (Greek: telos, end). In humans, the telencephalon undergoes massive expansion and comes to dominate the entire brain. The remaining midline portion of the forebrain, situated between the cerebral hemispheres, is the diencephalon (Greek: dia, between). This part of the cerebrum will become the thalamus, hypothalamus and a number of related structures surrounding the cavity of the third ventricle (including the pineal gland).

The hindbrain also differentiates into two parts. The upper portion becomes the metencephalon, which is the precursor of the pons and cerebellum and makes up the bulk of the hindbrain (Greek: meta, behind). The lower part gives rise to the myelencephalon, which corresponds to the medulla.

In contrast, the mesencephalon

Key Points

The three fundamental divisions of the brain are the prosencephalon (forebrain), mesencephalon (midbrain) and rhombencephalon (hindbrain).

These give rise to five divisions that correspond to the principal anatomical components of the brain: telencephalon, diencephalon, mesencephalon, metencephalon, myelencephalon.

The forebrain (cerebrum) includes the telencephalon (cerebral hemispheres) and diencephalon (thalamic region). The hindbrain includes the metencephalon (pons, cerebellum) and myelencephalon (medulla). The mesencephalon (midbrain) is not further subdivided.

does not subdivide further. Instead, it retains a somewhat tubular structure as the adult midbrain, traversed by a narrow cerebral aqueduct.

Flexures and the neuraxis

The neural tube develops three flexures (bends). Two forward-flexures (cervical and mesencephalic; Figs 2.5 & 2.6) contribute to the change in the longitudinal axis of the nervous system (the neuraxis). This is vertical in the spinal cord but horizontal in the cerebral hemispheres. The 90-degree bend in the human neuraxis contrasts with that of other animals (partly because of our upright, bipedal stance) and alters the meaning of certain anatomical terms (Fig. 2.8).

Fig. 2.8 The human neuraxis is approximately vertical in the spinal cord and almost horizontal in the brain.
This is partly due to our upright, bipedal posture and alters the meaning of certain directional terms in the dorsoventral and rostrocaudal axes (i.e. in the spinal cord, dorsal = posterior and ventral = anterior; whereas in the brain, dorsal = superior and ventral = inferior).

The pontine flexure bends in the opposite direction to the other two and marks the boundary between the pons and medulla. It also causes the neural tube to split along its relatively weak line of fusion and ‘gape open’ posteriorly (Fig. 2.9; see also Fig. 2.6). The pontine flexure thus contributes to the rhomboid shape of the fourth ventricle, which is the origin of the term rhombencephalon.

Fig. 2.9 How the pontine flexure causes the neural tube to ‘splay open’ posteriorly, creating the rhomboid fossa (the floor of the fourth ventricle).
The neural tube is seen from the posterior aspect. This view would normally be obscured by the cerebellum which covers the rhomboid fossa and contributes to the roof of the fourth ventricle. [This can be reproduced by bending a piece of rolled-up A4 paper.]

Expansion of the telencephalon

The cerebral hemispheres and lateral ventricles become C-shaped as a result of the non-uniform expansion of the telencephalon (Fig. 2.10). As the frontal, parietal, temporal and occipital lobes grow the telencephalon expands like an inflating balloon. A small island of tissue overlying the basal ganglia expands comparatively little and is progressively ‘swallowed up’ by the surrounding frontal, parietal and temporal lobes. This region corresponds to the insula, which is hidden within the depths of the lateral sulcus in the mature brain (Latin: insula, island).

As the telencephalon continues to expand it eventually envelops and fuses with the diencephalon. Once this has happened, axons can pass directly between the cerebral hemispheres and brain stem, traversing the basal ganglia and partially dividing them (see Ch. 3). Many internal hemispheric structures are distorted by the expansion of the cerebral hemispheres and take on the same C-shaped profile as the lateral ventricles. These include the hippocampus and its outflow pathway, the fornix (Fig. 2.11) which are involved in memory formation (see Ch. 3).

Fig. 2.11 The descent of the hippocampus during expansion of the telencephalon.
**(A)** The hippocampus originates as a dorsal midline structure, superior to the thalamus and in other species remains in this position; **(B)** As the human telencephalon expands, the hippocampus is carried downwards and forwards, coming to lie in the floor of the temporal lobe; **(C)** The hippocampus leaves behind an arching trail of white matter, the fornix, which echoes the C-shaped curvature of the cerebral hemisphere and lateral ventricle. Modified from Fitzgerald: Clinical Neuroanatomy and Neuroscience 5e (2006) with permission.

Formation of gyri and sulci

Gyral development is maximal in the third trimester. At 24 weeks after fertilization the surface of the fetal brain is almost smooth, apart from the lateral and central sulci. The normal arrangement of gyri and sulci gradually emerges over the following weeks and the pattern of surface convolutions in the term fetus is similar to that of the adult. However, neural development at birth is far from complete and the mass of the brain is only around 350 g (in comparison to the adult mass of 1350 g). In particular, the cerebral hemispheres are poorly myelinated in the neonate.

Development of the cerebellum

The cerebellum originates from a dorsal outgrowth of the metencephalon (in the hindbrain). It thus overlies the pons and fourth ventricle (Fig. 2.12). The alar (sensory) plates of the metencephalon (including the rhombic lips, which overhang the upper part of the fourth ventricle) fuse to form the cerebellar plate. Expansion of the cerebellar plate gives rise to the cerebellar hemispheres and vermis which eventually cover the rhomboid fossa, forming the roof of the fourth ventricle. In keeping with its origin as an alar (sensory) plate derivative, the cerebellum has many more afferent than efferent connections and has no direct role in movement initiation.

The cerebellum is initially divided into the corpus cerebelli and the flocculonodular lobe by the posterolateral fissure. The main body of the cerebellum (Latin: corpus, body) is then subdivided into a small anterior lobe and much larger posterior lobe by the primary fissure. The narrow midline portion of the adult cerebellum is called the vermis which is said to resemble a segmented worm (Latin: vermis, worm). This is flanked on either side by the cerebellar hemispheres.

Key Points

The cervical and mesencephalic flexures contribute to the shift in the axis of the nervous system from vertical (in the spinal cord) to horizontal (in the brain).

The pontine flexure causes the neural tube to ‘gape open’ along its weak line of fusion, contributing to the shape of the rhomboid fossa (floor of the fourth ventricle).

The cerebellum arises from the alar (sensory) plate of the metencephalon. It is divided into anterior, posterior and flocculonodular lobes by the primary and posterolateral fissures.

Ventricular system

The fluid-filled cavity of the neural tube is represented in the adult brain by the ventricular system. This consists of four interconnected cavities or ventricles which contain around 30 mL of colourless cerebrospinal fluid (CSF) (Fig. 2.13).

The lateral ventricles are C-shaped cavities within the cerebral hemispheres. Each lateral ventricle has a central body and three horns (frontal, occipital and temporal). The point at which the body joins with both the occipital and temporal horns is called the trigone (or atrium).

The slot-like third ventricle occupies the diencephalon (thalamic region). The two thalami form the upper part of the lateral wall, whereas the hypothalamus forms the floor and lower part of the lateral wall. The third ventricle is so narrow that in 80% of people the two thalami ‘kiss’ across the water, forming the thalamic interconnexus, but no axons are exchanged. This gives the third ventricle its distinctive shape which resembles a distorted ring-doughnut (the central ‘hole’ is where the two thalami touch). The lateral ventricles communicate with the third ventricle via the paired interventricular foramina (singular: foramen) which creates a Y-shaped profile on coronal views.

The fourth ventricle is situated between the brain stem and cerebellum. Its diamond-shaped floor corresponds to the posterior surfaces of the pons and medulla. The third and fourth ventricles communicate via the cerebral aqueduct, a narrow channel that passes through the midbrain.

Circulation of CSF

The choroid plexuses are highly vascular structures that project into each of the ventricles and continuously produce cerebrospinal fluid by active secretion from the blood.

CSF escapes from the fourth ventricle (to the subarachnoid space) via three openings: the single median aperture and the two lateral apertures. It is ultimately reabsorbed into the venous system via the arachnoid granulations which run along the superior aspect of the cerebral hemispheres (Fig. 2.14). These correspond to the arachnoid villi, finger-like projections into a large venous channel called the superior sagittal sinus. These structures allow the reabsorption of CSF into the venous circulation.

Fig. 2.14 The dorsal surface of the cerebral hemispheres.
The tough, leathery dura is not seen in this image (it is tightly adherent to the periosteum and is usually left inside the skull when the brain is removed) but the pia and arachnoid membranes are present on the right-hand side, including the arachnoid granulations. On the left side, the membranes have been stripped to reveal the underlying gyri and sulci. From Crossman: Neuroanatomy ICT 4e (Churchill Livingstone 2010) with permission.

The total volume of intracranial CSF is around 140 mL, most of which is in the subarachnoid space; the spinal CSF volume is more variable and difficult to estimate. Due to a constant cycle of production and reabsorption, the CSF is replaced up to four times each day. Interference with CSF production or drainage can lead to ventricular dilation and raised intracranial pressure (Clinical Box 2.2).

Clinical Box 2.2: Hydrocephalus

Enlargement of the ventricles due to accumulation of CSF is termed hydrocephalus (Greek: hydro, water; kephalē, head) (Fig. 2.15). This is usually associated with raised intracranial pressure which can lead to progressive brain damage. In infants with congenital hydrocephalus the cranium may become grossly enlarged since fusion of the skull bones is not complete until 18 months of age. Obstructive hydrocephalus is caused by occlusion of one of the CSF drainage channels and leads to dilation of that portion of the ventricular system above the level of the blockage. Communicating hydrocephalus results in dilation of the entire ventricular system; it is due either to inadequate reabsorption of CSF or (very rarely) excessive production by a choroid plexus tumour. Hydrocephalus can be treated surgically by the insertion of a shunt which diverts excess CSF, usually to the abdominal peritoneum (Fig. 2.16). A pressure-operated valve and sometimes also an anti-siphon device are incorporated into the system to ensure appropriate one-way flow. Unfortunately shunts are prone to infection, blockage, disconnection and valve malfunction and frequently need to be replaced (the failure rate is around 80% at 12 years).