Development of the Central Nervous System
Embryological development is an intricate process, with the formation of the human nervous system being only one, albeit vital, component. The development of our bodies makes us what we are; but the development of our brains makes us who we are, giving us the ability to think, see, feel (both physically and emotionally), etc.
The nervous system has multiple elements, each of which, when fully formed and active, will have different responsibilities. The central nervous system (CNS) is composed of the brain and spinal cord. The brain interprets information received by the spinal cord and generates its own signals and instructions for the body to carry out. The spinal cord transmits information from the brain to the body, and vice versa.
The peripheral nervous system (PNS) consists of all neurons outside of the brain and spinal cord, including the cranial nerves and spinal nerves. These nerves are either afferent (i.e. sensory, receiving signals in the body to be transmitted for processing in the brain) or efferent (motor, delivering signals from the brain to the body).
Finally, the autonomic nervous system (ANS), which is made up in part by the CNS and in part by the PNS, contains neurons that supply cardiac muscle, smooth muscle, and glands. The PNS has two components: the sympathetic nervous system provides signals to the body to prepare for “fight or flight;” and the parasympathetic nervous system signals the body that it can “rest and digest.”
The following article will focus on the embryological development of the CNS.
In the early stages of development, three iconic layers of tissue develop within the embryo: the endoderm, mesoderm, and ectoderm.
The nervous system develops from a section of the ectoderm called the neural plate, which begins to differentiate under the influence of the nearby notochord and paraxial mesoderm around the third week. The edges of the neural plate then elevate to form the neural folds. In a process called neurulation, the neural folds curve upward and fuse to form the neural tube, which will eventually become the CNS. The neural plate also forms the neural crest, cells of which will later migrate to different parts of the body and become most of the cells in the PNS and ANS.
Neurulation begins in the fourth week of development (around the 22-23 day). The neural folds fuse first in the cervical region and continue to fuse in both cranial (head) and caudal (tail) directions until only the very ends of the tube remain open and connected with the amniotic cavity. These openings are called neuropores, with the opening at the cranial end of the embryo being the rostral neuropore, and the opening at the caudal end being the caudal neuropore. The rostral neuropore closes around day 25, and the caudal neuropore closes approximately two days after.
The neural tube becomes vascularized around the time that the neuropores close. Regions of the neural tube begin to thicken, forming the brain and spinal cord, and the opening within the tube begins to form the ventricles and central spinal canal.
During this time in development, certain genes become vital in ensuring accurate structural layout of the CNS: Sonic hedgehog (Shh), the Pax genes, bone morphogenic proteins, and a transforming growth factor (TGF-B) called dorsalin. These components are all influential in the appropriate dorsoventral patterning of the developing neural tube.
Spinal Cord Development
The caudal part of the neural tube (i.e. the neural tube after the fourth pair of somites) becomes the spinal cord. As the walls of the neural tube thicken, the neural canal becomes smaller and smaller, until only a very thin central canal remains. The neuroepithelium surrounding this canal transitions from pseudostratified columnar ependymal epithelium (the cell layer surrounding the ventricles, constituting the ventricular zone) to instead form neurons and macroglia (including astrocytes and oligodendrocytes) within the spinal cord.
The formation of neurons from neuroepithelial cells occurs when neuroepithelial cells in the ventricular zone differentiate into primordial neurons called neuroblasts. These neuroblasts form an intermediate zone called the mantle layer in between the ventricular and marginal zones. It is in this layer that neurons will eventually form the gray matter of the spinal cord.
The primordial supporting cells of the CNS are called glioblasts or spongioblasts. As previously noted, these cells also differentiate from neuroepithelial cells in the ventricular zone, but they do so after the neuroblasts have already formed. After their formation, glioblasts migrate into the intermediate and marginal zones, where they become astroblasts and oligodendroblasts. Eventually, astroblasts will form astrocytes and oligodendroblasts will form oligodendrocytes. When neuroblasts and glioblasts are no longer being produced, the remaining cells become ependymal cells. These cells will line the central canal of the spinal cord as the ependyma. The marginal zone becomes the white matter of the spinal cord as axons develop and project into it from neuronal cell bodies of the brain, ganglia, and spinal cord.
In the late fetal period, once the CNS becomes fully vascularized, small cells called microglia migrate into the CNS and can be found scattered throughout both the gray and white matter. These derivatives of mesenchymal cells are mononuclear phagocytes that develop in the bone marrow.
As the neuroepithelial cells multiply and differentiate, they form thick walls, a thin roof, and floor plates within the spinal cord. This results in the formation of the sulcus limitans, a long, thin groove on each side of the spinal cord that separates the alar plates/lamina (the dorsal plates) from the basal plates/lamina (the ventral plates). These plates span the entire length of the spinal cord. The cell bodies in the alar plates develop into the dorsal gray columns (the dorsal gray horns on cross-section), which contain afferent nuclei that form the dorsal roots of the spinal nerves. As the alar plates continue to grow, the dorsal median septum is formed.
The ventral and lateral gray columns are formed from cell bodies in the basal plates (the ventral and lateral gray horns respectively on cross-section). The ventral roots of the spinal nerves form from the axons of cell bodies in the ventral horn as they project out of the spinal cord. Like the dorsal median septum, the ventral median septum forms with the enlargement of the basal plates, and eventually a deep longitudinal groove called the ventral median fissure will develop.
Spinal Ganglia and Meninges
Unlike the previously discussed neurons and macroglia of the spinal cord, the dorsal root ganglia (DRG) and unipolar neurons in the spinal ganglia originate from cells of the neural crest. Parts of these cells extend via the spinal nerves to somatic and visceral structures. Here, they provide various types of receptors for acquisition of sensory signals. The central processes of these cells, the dorsal roots of the spinal nerves, project into the spinal cord and assist in transmitting these signals to the brain for interpretation.
The primordial meninges form from the mesenchyme that surrounds the neural tube. The outer layer becoming the dura mater and the inner layer (originating from neural crest cells) becoming the leptomeninges, the arachnoid mater and pia mater. By the fifth week of development, cerebrospinal fluid (CSF) begins to form.
Spinal Nerves & Vertebral Levels
At week eight of gestation, the embryonic spinal cord spans the entire length of vertebral canal, and the spinal nerves pass through the intervertebral foramina at the exact level that they emerge from the cord. Due to different growth rates, however, this relationship does not last: the embryo grows faster than the cord, and with this continued growth the caudal end of the cord becomes shorter and shorter compared to the length of the embryo.
By 24 weeks, the spinal cord stops at the first sacral vertebra (S1); which causes the end of the cord to rest around the second or third lumbar vertebrae (L2, L3) in a newborn infant. By adulthood, the cord stops at the lower border of the first lumbar vertebra (L1). Because of this length disparity, the spinal nerve roots in the lumbar and sacral cord project obliquely from the spinal cord to their corresponding vertebral levels below. The nerve roots at the end of the spinal cord form the conus medullaris, with the nerves branching out inferiorly to form the cauda equina.
The latter is a bundle of nerve roots which resemble, and as such are often referred to as, the “horse’s tail.” In adults, the dura and arachnoid maters terminate at the second sacral vertebra (S2), and the pia mater forms a long thread-like structure called the filum terminale which starts at the conus medullaris and ends at the first coccygeal vertebra.
Myelination of the spinal cord begins in the late fetal period and continues during the first postnatal year. The motor roots become myelinated before the sensory roots. In the spinal cord, myelin sheaths are formed by oligodendrocytes. This is unlike the peripheral nerves, whose myelin sheaths are formed by the plasma membranes of neural crest-derived Schwann (a.k.a. neurolemma) cells. These cells wrap themselves around the axons of somatic motor neurons, presynaptic and postsynaptic autonomic motor neurons, and somatic and visceral sensory neurons.
Once myelination of the spinal cord takes place, the tissue looks white on gross inspection. Because of this, these regions of myelinated axons are referred to as the white matter of the spinal cord.
Development of the Brain
The brain develops from the section of the neural tube cranial to the fourth pair of somites. Before the neural folds fuse, three vesicles can be recognized at the rostral end of the neural tube: the prosencephalon, mesencephalon, and rhombencephalon. Each will form the forebrain, midbrain, and hindbrain respectively.
In the fourth week of gestation, the primitive brain bends ventrally along with the head fold, forming the midbrain and cervical flexures. Since parts of the brain grow at different rates, the pontine flexure forms in the opposite direction of the midbrain and cervical flexures. In the fifth gestational week, the prosencephalon divides into the telencephalon and diencephalon, and the rhombencephalon divides into the metencephalon and myelencephalon, forming five secondary brain vesicles. The sulcus limitans of the spinal cord extends cranially until the midbrain and forebrain meet, and the alar and basal plates are recognizable up through the midbrain only.
While the cervical flexure marks the transition from the hindbrain to the spinal cord, the pontine flexure separates the hindbrain into the rostral metencephalon, which becomes the pons and cerebellum. Inferiorly, the caudal myelencephalon becomes the medulla oblongata. The cavity in the hindbrain becomes the fourth ventricle, which is continuous with the central canal in the caudal medulla.
As the pontine flexure forms, the walls of the metencephalon shift laterally. The dorsal parts of the alar plates form the cerebellum. As the cerebellum grows, parts of it project into the fourth ventricle, eventually covering parts of the pons and medulla. Some neuroblasts from the alar plates become the cerebellar cortex, whereas others develop into the dentate, fastigial, globose, and emboliform cerebellar nuclei. Others develop into the pontine nuclei, cochlear and vestibular nuclei, and the sensory nuclei of the trigeminal nerve. Also passing through the pons are nerve fibers connecting the cerebrum, cerebellum, and spinal cord.
The medially situated gracile and laterally situated cuneate nuclei form when neuroblasts from the alar plate migrate into the the marginal zone of the myelencephalon. These nuclei receive the gracile and cuneate tracts, which extend from the dorsal spinal cord into the medulla. In the ventral medulla, bundles of fibers called pyramids contain the corticospinal tracts as they descend from the cerebral cortex into the spinal cord.
As the pontine flexure forms, the structure of the medulla changes: the alar plates move laterally towards the basal plates. This shift leads the sensory nuclei to develop laterally to the motor nuclei. Within the motor nuclei, neuroblasts organize into three columns. The general somatic efferents, which contain motor neurons of the hypoglossal nerve, lie medially. These are followed laterally by the special visceral efferents, which contain motor neurons supplying muscles derived from the pharyngeal arches. The general visceral efferents, which contain motor neurons of the vagus and glossopharyngeal nerves, are found at the most lateral edge of the nuclei.
With the exception of some neuroblasts that form the olivary nuclei more ventrally, neurons from the alar plates in the medulla arrange themselves in a similar manner. The general visceral afferents, receiving input from the viscera, lie medially; followed by the special visceral afferents, receiving taste fibers, and then the general somatic afferents, receiving sensory information from the surface of the face and head; and finally ending with the special somatic afferents, receiving auditory input, on the most lateral edge.
Choroid Plexus & Cerebrospinal Fluid
The pia mater covers the ependymal roof of the fourth ventricle, and with the ependymal cells forms the tela choroidea. As the pia mater proliferates, the tela choroidea extends into the fourth ventricle, forming the choroid plexus. Similar choroid plexuses are also found in the roof the third ventricle and the medial walls of the lateral ventricles. Ependymal cells in these plexuses are responsible for producing CSF. Three foramina, the two lateral foramina of Luschka and the medial foramen of Magendie, form in the fourth ventricle, allowing CSF to flow from the ventricles into the subarachnoid spaces.
In the mesencephalon, the primordial midbrain, the ventricular system narrows. This narrowing produces the cerebral aqueduct of Sylvius, a pathway which connects and allows CSF to flow between the third and fourth ventricles. Neuroblasts from the mesencephalon region of the alar plate migrate into the tectum (roof) where they form four structures: two superior colliculi, associated with visual reflexes; and two inferior colliculi, associated with auditory reflexes. Neuroblasts from the basal plates form the red nuclei, oculomotor nuclei, trochlear nuclei, and reticular nuclei of midbrain.
The midbrain also contains a region of gray matter called the substantia nigra, which is responsible for producing dopamine. Whether it originates from the basal plate or the alar plate is still debated. The cerebral peduncles, which lie directly adjacent to the substantia nigra, are comprised of corticopontine, corticobulbar, and corticospinal tract fibers descending from the cerebral cortex down to the brainstem and spinal cord.
As the rostral neuropore closes, the optic vesicles develop as two outgrowths on either side of the forebrain. These eventually become the retinas and optic nerves. More dorsally and rostrally, a second pair of diverticula called the telencephalic vesicles arise. These and the cavities within them become the cerebral hemispheres and lateral ventricles. The third ventricle forms from the cavities within the telencephalon and diencephalon, and is connected to each of the lateral ventricles via the ventricular foramina of Monro.
The pineal gland develops in the midline from the caudal part of the roof of the diencephalon. The pituitary gland, which is located more rostrally, develops from two different sources. The anterior part of the pituitary comes from an upgrowth of oral ectoderm called the hypophysial diverticulum, or Rathke’s pouch. Rathke’s pouch eventually forms the adenohypophysis, the glandular component of the pituitary. The posterior part comes from a downgrowth of neuroectoderm from the diencephalon. It forms the neurohypophysial diverticulum, which becomes the neurohypophysis, the nervous component of the pituitary.
Growth of the hypophysial diverticulum begins during the third week of gestation. By the fifth week, the elongated diverticulum is constricted at its attachment to the oral epithelium, and is in contact superiorly with the infundibulum. The infundibulum is a derivative, along with the median eminence and pars nervosa, of the neurohypophysial diverticulum. The stalk attaching the hypophysial diverticulum to the oral cavity soon disappears, and the components of the adenohypophysis are formed: the pars anterior, pars intermedia, and pars tuberalis..
In the sixth week of development, the corpus striatum begins to form in the floor of each cerebral hemisphere, which can be identified by the seventh week. As the hemispheres expand, they cover the diencephalon, midbrain, and hindbrain, and eventually meet in the midline and flatten along their medial surface. The cortical walls of each hemisphere grows much faster than their floors, and as a result the hemispheres and the lateral ventricles within them become C-shaped. As the hemispheres grow, the caudal ends containing parts of the lateral ventricles turn ventrally and then rostrally, forming the temporal lobes and temporal ventricular horns. The cortices also grow over the external surface of the corpus striatum, burying what becomes the insular lobe at the base of the lateral sulcus, the Sylvian fissure.
Nerve fibers traveling to and from the cerebral cortex pass through the internal capsule, a pathway that divides the corpus striatum into the caudate and lentiform nuclei. The internal capsule is one of the first structures of a pathway that connects the cerebral cortex to the spinal cord. It is not, however, the only axonal pathway in the brain: white matter pathways are also necessary to connect different areas of the cerebral cortex with one another. This is accomplished with groups of fibers called commissures, which allow different parts of the brain to “communicate.” One of these is the optic chiasm, which develops from the ventral part of the lamina terminalis and contains fibers from the medial retinas that cross over to join the optic tracts on the opposite sides from whence they originate.
Another is the anterior commissure, which connects the olfactory bulb to related cortical regions, and connects those brain regions to each other. As its name suggests, the hippocampal commissure connects the hippocampal formations. By birth, the largest cerebral commissure, the corpus callosum, covers the roof of the diencephalon and provides a bridge of communication between the left and right cortices.
As the cerebral hemispheres continue to grow, they invaginate and fold, forming grooves called sulci and convolutions called gyri. This allows the cortical surface area to increase without the need to further expand the skull.
Pharyngeal Hypophysis & Craniopharyngioma
A pharyngeal hypophysis occurs when a remnant of the stalk of the hypophysial diverticulum remains in the roof of the oral cavity. If remnants of the stalk persist in the pharynx, posterior sphenoid bone, or around the sella turcica, a craniopharyngioma can form. The most common location for a craniopharyngioma is in or above the sella turcica.
In approximately 1 in 2000 births, cranium bifidum (defective formation of the skull) results in congenital defects in the brain and/or meninges. These defects usually occur along the median plane and typically include part of the occipital bone. They may also include part of the foramen magnum. A small defect allowing herniation of the meninges alone is termed a cranial meningocele; whereas a large defect allowing herniation of the meninges and part of the brain is termed a meningoencephalocele. If the herniated region of the brain contains part of the ventricular system, it is termed a meningohydroencephalocele.
Holoprosencephaly results when the left and right cerebral hemispheres fail to separate during weeks five and six of development. This defect is believed to have a genetic influence, related to mutations in the sonic hedgehog (Shh) signaling pathway. The midline defects observed in cases of holoprosencephaly are also associated with trisomy 13 (Patau syndrome) and fetal alcohol syndrome (FAS). Moderate cases can present with cleft lip and/or palate, and severe cases can present with cycloplegia (a single eye in the midline of the face).
In infants with microcephaly, the calvaria (the bones making up the skullcap) are small, but the size of the face is normal. Because the cranium is underdeveloped, development of the brain is also affected, and infants typically present with severe mental disability. While some cases may be genetic, others are related to environmental disturbances: these could include exposure in utero to ionizing radiation, drugs, or infections such as cytomegalovirus (CMV) or Zika virus.
Hydrocephalus occurs due to an overabundance of CSF in the ventricular system, which leads to dilation of the ventricles and increased pressure on the brain matter. In infants (whose skull bones have yet to fuse) this results in expansion of the brain and unfused skull.
Hydrocephalus can result from either impaired circulation or absorption of CSF, or from increased CSF production. Impaired circulation of CSF is often due to obstruction, particularly congenital stenosis (narrowing) of the cerebral aqueduct connecting the third and fourth ventricles. In these cases, the ventricles proximal to the obstruction become dilated.
The most common congenital defect of the cerebellum is the Arnold-Chiari malformation. In these patients, the cerebellum is displaced downward such that part of it herniates through the foramen magnum, the hole in the skull through which the brainstem travels to meet the spinal cord.
In a Chiari type I malformation, only the cerebellar tonsils herniate through the foramen magnum. Affected individuals are typically asymptomatic as children, but can present in adulthood with headaches and symptoms of cerebellar dysfunction (i.e. movement disorders, ataxia). Blockage of the foramen magnum and subsequent inhibition of CSF flow in these patients is also associated with spinal cavitations (i.e. syringomyelia).
A Chiari type II malformation has a more serious prognosis. In these patients, the cerebellar tonsils and vermis herniate through foramen magnum. Patients experience stenosis of the cerebral aqueduct, which can lead to hydrocephalus. Chiari type II malformations are also associated with lumbosacral meningomyelocele.
Dandy Walker Malformation
Dandy Walker malformation occurs due to agenesis (failure of development) of the cerebellar vermis, the long central section of the cerebellum between the two lobes. This leads to expansion of the fourth ventricle, so that it fills the posterior fossa. The size of the lobes may be reduced as well. These abnormalities result in problems with movement and coordination, as well as other neurological functions. Dandy Walker malformation is also associated with hydrocephalus (and subsequently macrocephaly, increase in the size of the head), spastic paraplegia (muscle stiffness and partial paralysis of the lower extremities), agenesis of the corpus callosum, and spina bifida. While 10 to 20 percent of patients with this condition do not present with symptoms until childhood or even adulthood, most patients present with signs and symptoms at birth or during infancy.
In a lumbar puncture, otherwise known as a spinal tap, a needle is inserted into the lower back in order to withdraw CSF from the spinal cord for analysis. To avoid damaging the lower end of the spinal cord, the needle is inserted several segments below the level at which the cord terminates, but above the level of termination of the dural sac and subarachnoid space containing the desired CSF. In adults, the spinal cord terminates at L2-L3 and the dural sac and subarachnoid space terminate at S2. Consequently, a lumbar puncture is administered at the L4-L5 level.
A young woman recently gave birth to an apparently healthy baby girl with a five-minute APGAR score of 9. Upon examining the child, however, the physician notices a small tuft of hair on the baby’s lower back.
Failure of either the rostral or caudal neuropore during the fourth week of gestation results in a neural tube defect (NTD). Continued exposure to the contents of the amniotic cavity affects not only the spinal cord, but also the surrounding tissues, including the meninges, neural arches, muscles, and skin.
Although NTDs are associated with a variety of different factors, folic acid supplementation (400µg/day starting one month prior to conception and continued throughout the first trimester) has been shown to significantly reduce their incidence. As such, it should not be surprising that drugs which sequester folate—such as valproic acid and anticonvulsants like carbamazepine—can also induce NTDs if given during the fourth week of fetal development.
Failure of the neural arches to fuse and close the caudal neuropore results in spina bifida. In approximately 10% of otherwise normal infants, abnormal growth and failure of fusion of the neural arches result in spina bifida occulta. This typically occurs at L5 or S1, and with the exception a small tuft of hair at the location of the defect, it is usually asymptomatic (as in the infant described in the clinical vignette).
A more severe form of spina bifida, spina bifida cystica, occurs in 1 of 1000 births and involves protrusion of the spinal cord, meninges, or both in a cyst-like sac through the defect in the vertebral arches. When the sac contains meninges and CSF, the defect is referred to as spina bifida with meningocele. In these patients, the spinal cord and roots are normally positioned, but there may be abnormalities in the cord itself due to the defect. When the sac contains part of the spinal cord, nerve roots, or both, the defect is referred to as spina bifida with meningomyelocele. When the defect involves several vertebrae, merocephaly/anencephaly (partial or total absence of the brain) is also more likely to be observed. Merocephaly/anencephaly is also associated with failure of the rostral neuropore to close during the fourth week: when this occurs, the infant’s brain continues to be exposed to amniotic fluid, preventing its complete development. Infants that survive through birth have some observed brainstem activity, but limited functional neural tissue. For affected fetuses, amniocentesis revealing high alpha-fetoprotein (AFP) levels can indicate the diagnosis.