Nervous Development

The nervous system is the body’s communication network that controls the bodies functions by receiving and sending messages. It has two main components which are the central nervous system (CNS) and the peripheral nervous system (PNS). The central nervous system, which is the part that processes information, consists of the brain and the spinal cord. The peripheral nervous system is the part that carries message between the CNS and various parts of the body. The basic unit of the nervous system is the neuron (nerve cell), which is a specialized cell that transmits electrical and chemical signals. The nervous system controls all basic body functions and is involved in complex processes such as learning and thinking. The system does its functions by the CNS receiving sensory information via the PNS, then processing it and generating response impulses, which are carried by the PNS to various parts of the body where appropriate actions are taken.

Fig. 17.1.  The illustration on the left shows the main components of the nervous system, whereas the one on the right show the structure of the neuron, the basic unit of the nervous system.

Development of the Nervous System 

The nervous system is ectodermal in origin; its development begins with the formation of neural plate which is a mid-longitudinal thickening of the ectoderm of the dorsal body surface. In the 3^rd week of embryonic development, the notochord (the axial mesoderm) starts to induce the overlying ectoderm to proliferate and form a thickened narrow flat sheet called the neural plate. Cells of the neural plate elongate and differentiate into neuroepithelial cells foreshadowing the development of the nervous system. Thereafter the neural plate elongates craniocaudally and becomes narrower mediolaterally. Then the lateral edges of the neural plate elevate forming the neural folds and a groove in between the folds called the neural groove. The neural groove deepens and the two neural folds are brought together towards the midline. The folds ultimately fuse with each other and according the groove transforms into a tube called the neural tube. The fusion of neural folds takes place first in the middle region of the embryo and then proceeds cranially towards the head of the embryo and caudally towards the tail. The anterior and posterior ends of the tube remain open for a long time thereafter and are respectively known as the anterior neuropore and the posterior neuropore. The neural tube separates from the general ectoderm and sinks down. During closure of the neural groove, some of the cells at the peripheries of the two neural folds are left behind not incorporated into either the neural tube or the general ectoderm. These left behind cells aggregate into masses forming the neural crest.

Fig. 17.2. The process of development of the neural tube in dorsal view of the embryo (on the left) and in cross sections (on the right) from the neural plate (up) to the neural tube (down).

Development of the Brain

The brain comprises the cerebrum, the cerebellum and the brain stem. It develops from the cranial part of the neural tube which during early stages of embryonic development differentiates into compartments known as the primary three vesicles of the brain; they are outpulgings of the neural tube, and are called the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). The prosencephalon will develop into those parts of the brain responsible for higher-level brain functions including thinking, processing of sensory information, generation of voluntary actions, and emotion control. The mesencephalon forms the upper parts of the brainstem connecting the forebrain with the cerebellum and pons. The rhombencephalon is responsible for the control of vital body functions such as breathing, heart beats, motor coordination and balance. It gives rise to the pons, cerebellum and the medulla oblongata.  

Fig. 17.3.  The illustration shows the three primary brain vesicles; the prosencephalon, the mesencephalon, and the rhombencephalon.

The three primary brain vesicles develop and further subdivide giving rise to the five secondary brain vesicles. The prosencephalon divides into telencephalon and diencephalon, the mesencephalon remains undivided, and the rhombencephalon subdivides into metencephalon and myelencephalon. Thus, the brain at this stages has five compartments namely the telencephalon, diencephalon, mesencephalon, metencephalon and myelencephalon arranged in an anteroposterior order.  

The telencephalon is the most anterior part of the brain that gives rise to the cerebral hemispheres. It is the largest of the secondary brain vesicles, and is responsible for higher functions such consciousness, cognition, reasoning, language, and control of voluntary movements.

The diencephalon is the central region of the brain being located between the cerebrum and the brainstem. It comprises the thalamus, the epithalamus, and the hypothalamus. The thalamus which is the largest part of the diencephalon, plays crucial roles in the relay of sensory signals (touch, pain, temperature) to the sensory regions of the cerebral cortex excluding olfactory signals. The epithalamus regulates the circadian rhythms with the help of the pineal gland and melatonin, whereas the hypothalamus functions in the control of body temperature, thirst, hunger, the control of endocrine functions (via the pituitary), and regulation of autonomic functions.  

Fig. 17.4. The illustration shows components of the diencephalon and their location between the cerebrum (telencephalon) on one side and the midbrain, pons, medulla oblongata, and the cerebellum on the other side.

The mesencephalon, the third and middle one of the five secondary brain vesicles. The primary mesencephalon differentiate into the secondary mesencephalon without change or subdivisions. Its derivatives are located between the thalamus and hypothalamus on one side and the pons on the other side. These derivatives connect the diencephalon and the cerebrum on one side to the pons and cerebellum on the other. The mesencephalon participates in visual reflexes, eye movements, and auditory reflexes. Auditory and visual signals are processed in the mesencephalon (midbrain). The superior colliculi of the mesencephalon are involved in visual reflexes, whereas the inferior colliculi are involved in auditory reflexes. The midbrain (mesencephalon) also serves as a conduit for signals travelling between the cerebral cortex and the spinal cord.

The metencephalon is the fourth one of the five secondary brain vesicles; it develops from the anterior (rostral) part of the rhombencephalon and differentiate to form the pons and the cerebellum in the 5^th week of embryonic development. The complete separation of pons and the cerebellum takes place in 3^rd month of embryonic development. The pons occupies the ventral part of the brainstem and constitutes a bridge that connects the cerebrum and the cerebellum. It contains the neurons which give rise to several cranial nerves such as the trigeminal, abducens, and facial nerve. The cell bodies of these neurons are organized in groups within the pons forming the pontine nuclei. The cerebellum occupies a position on the dorsal aspect of the pons, and functions in the coordination of motor activities, maintenance of body balance, and the regulation of muscle tone.

The myelencephalon is the most caudal part of the developing brain. It develops from the caudal part of the rhombencephalon and differentiates into the medulla oblongata, which is a crucial component of the brainstem. Medulla oblongata is a site for regulation breathing, heart rate and blood pressure. It represents a bridge connecting the brain and the spinal cord. and participates significantly in the regulation of breathing, heart rate, and blood pressure.

Fig. 17. 5. The illustrations show main parts of the adult brain that develop from the metencephalon (the pons and the cerebellum) and those that develop from the myelencephalon (the medulla oblongata).

Development of the Spinal Cord

Caudal to the medulla oblongata, the neural tube does not bulging and vesical formation but retains its uniform cylindrical shape. The wall thickens and lumen narrows and the whole structure enlarge but retains the regular cylindrical shape. However, the component neuroepithelial cells of the neural tube in the region of the spinal cord and in the brain region undergo immense differentiation giving rise to various components of the CNS, particularly the gray matter, the white matter and nuclei.

Fig. 17. 6. The illustration shows the structure of the adult brain derived from each of the five secondary brain vesicles.    

Development of the Lumen of the Neural Tube

The lumen of the neural tube is a fluid-filled cavity present within the developing neural tube. As the neural tubes develops and enlarges the lumen also enlarges; in the brain region it develops into a complicated set of cavities known as the brain ventricles, while it maintains its narrow cylindrical shape in the region of the spinal cord forming the central canal of the spinal cord. The brain ventricles and the central canal are filled with the cerebrospinal fluids which plays important roles in protecting and nourishing the various parts of the CNS.

During development of the telencephalon, the lumen of the neural tube within the telencephalon bulge out to form lateral outpocketing that develops into the lateral ventricle of the brain. The walls of the neural tube surrounding the lateral ventricles enlarge and differentiate greatly to form the cerebral hemispheres. The central part of the lumen of the telencephalon remains unchanged and form the anterior part of the 3^rd ventricle of the brain, the lateral ventricles of the brain being designated as the 1^st and 2^nd ventricles of the brain. The communication between the 3^rd ventricle and the 1^st and 2^nd ventricles becomes narrower and form a connecting foramen on each side known as the foramen of Monro, or the interventricular foramen. The of the diencephalon (the second secondary brain vesicle) forms the caudal part of the 3^rd ventricle. The lumen of the rhombencephalon (metencephalon and myelencephalon) enlarges to form the 4^th ventricle of the brain, whereas the lumen of the mesencephalon remains narrow form the cerebral aqueduct of Sylvius which connects the 3^rd and 4^th ventricles. The lumen of spinal cord remains narrow and regularly cylindrical forming the central canal of the spinal cord.

Fig. 17.7.  The illustrations show the development of the lumen of the five secondary brain vesicles into four interconnected brain ventricles, numbered from the 1^st (right lateral) to the last – the 4^th. The ventricle is interconnected connected by three passages, namely the two foramens of Monro and the cerebral aqueduct of Sylvius.

Differentiation of the Neural Tube Wall

The walls of the neural tube undergo robust cellular differentiation and profound anatomical changes, to give rise to the various parts of the CNS. The cellular differentiation of the tube wall yields three concentric layers within the wall. From inside outwards, these are ependymal layer, the mantle layer, and the marginal layer.

The ependymal layer resembles a simple epithelium that lines the lumen of the lube lumen, the future central canal of the spinal cord and the brain ventricles. The mantle layer or zone is the middle layer where the neuroepithelial cells differentiate into neurons and neuroglial cells, thus containing neuronal cell bodies. The marginal layer is the outermost layer and is devoid of nerve cell bodies; it contains axons originating from cell bodies in the mantle layer; later on, these axons form nerve fiber pathways.

Fig. 17.8.  The illustration on the left shows the wall of the newly formed neural tube is made of a neuroepithelium that looks like a high pseudostratified epithelium. This epithelium differentiates to from a three-layered wall consisting of the ependymal layer, the mantle layer and the marginal layer.

The Spinal Cord

The ependymal layer is the innermost layer of the neural tube that lines the lumen of the tube; this layer is also referred to as the ventricular zone. Its cells develop into ependymal cells and neuroblast. The ependymal cells form the lining of the lumen of the neural tube which transforms into the central canal of the spinal cord and the four ventricle of the brain. The neuroblasts differentiate into neurons and neuroglia that form the mantle layer and marginal layer which differentiate respectively into the gray and white matter of the spinal cord.

The mantle layer of the cylindrical neural tube, that extends caudal to the brain vesicles, differentiates into the gray matter of the spinal cord. During early stage of development of the spinal cord, neurons occupying the mantle layer migrate laterally and dorsally (posteriorly) or ventrally (anteriorly) and group in the posterolateral and anterolateral region of the developing spinal cord to form a posterior (dorsal) horn and an anterior (ventral) horn on each side of the developing spinal cord. The remainder of the cells of the mantle layer constitute the transverse commissure, which connects, thus showing the characteristic butterfly cross-sectional appearance of the gray matter of the spinal cord. Neurons migrating to the ventral (anterior) horns develop long axons that extend outside the developing spinal cord forming the ventral root of the spinal nerve. Their cell bodies enlarge greatly and along with their long axons are referred to as lower motor neurons. Neurons of the dorsal horn are smaller with their axons confined to the CNS; they receive axons of the sensory neurons developing in nearby neural crest. An intermediate lateral horn develops where there is a sympathetic outflow (thoracolumbar regions).

The marginal layer is the outermost layer of the developing spinal cord. To begin with, it is made of few widely separated cells. Axons of neurons developing in the mantle layer extend peripherally into the marginal layer. These axons are accompanied by neuroglial cells, especially oligodendrocytes, which start to lay myelin around the axons thus forming myelinated nerve fibers. These myelinated nerve fibers extend upwards and downwards along the peripheries of spinal cord in groups or fascicles. The gradual increase in the number and size of myelinated nerve fibers imparts a white colour on the marginal layer which according designated as the white matter of the spinal cord. The enlargement of the horns of the gray matter along the appearance of a dorsal septum and a ventral fissure divide the white matter on each side of the spinal cord into three white matter columns called the dorsal (posterior) column, the lateral column, and the ventral (anterior) column. The white matter contains the ascending and descending nerve fibers that connect the spinal cord to the brain and play a significant role in transmitting signals throughout the CNS.

Fig, 17.9. The illustration shows features of the gray matter (horns) and white matter (columns) of the fully developed spinal cord. The gray matter contains the cell bodies of neurons, the white matter is rich in myelinated fibers, whereas the central canal, the former lumen of the neural tube, is narrow and is lined by ependymal cells.  

The Brain

The wall of the neural tube in its cranial parts undergoes profound development changes and forms the three primary vesicle of the brain which transform into the five secondary brain vesicles: the telencephalon, the diencephalon, the mesencephalon, the metencephalon, and the myelencephalon which develop into the cerebrum, thalamus, pons, cerebellum, the medulla and other parts of the brain.

The cerebrum and the basal ganglia develop from the telencephalon, which is the first of the five secondary brain vesicles. It expands and forms the lateral telencephalic vesicles which develop into the cerebral hemispheres and the basal ganglia. It is the dorsal telencephalon develops into the right and left cerebral hemispheres, whereas the ventral diencephalon develops into the ganglia (basal nuclei). Nuclei are collection of nerve cell bodies within the white matter of the CNS. The cerebral hemispheres  grow enormously, covering adjacent regions of the developing brain, particularly the diencephalon. The increase growth of the hemispheres causes folding of its superficial parts, thus forming the characteristic cerebral gyri and sulci. Neurogenesis, neuronal migration and cellular organization of the outer parts of the hemispheres result in the formation of the cerebral cortex with the characteristic neuronal layering.

Fig. 17.10. The illustrations show the process of development of the cerebral hemispheres from about the 2^nd month of embryonic development (A), to the 4^th month (B) to end of gestation (C).

The thalamus, the hypothalamus and epithalamus, and the neurohypophysis develop from the diencephalon, which is the second of the five secondary brain vesicles. Development of the thalamus is orchestrated by signals from the mid-diencephalic organizer that resides between the thalamus and the prethalamic. Neurons differentiate within the wall of the diencephalon and then migrate and arrange themselves into groups that form specific thalamic nuclei. Likewise, the hypothalamus develops from the ventral wall of the diencephalon; the neurohypophysis (posterior pituitary develops as axonal extension of nerve cell bodies present in nuclei of the hypothalamus. This region contains the caudal part of the 3^rd ventricle of the brain.

The corpora quadrigemina, substantia nigra and the red nucleus develop from the mesencephalon, the 3^rd of the five secondary vesicles of the brain. The corpora quadrigemina which comprises a pair of superior colliculi and a pair of inferior colliculi develops from the alar plate of the mesencephalon. It is located on the dorsal surface of the midbrain. The superior colliculi participate in visual reflexes, whereas the inferior colliculi are involved in auditory reception. The substantia nigra also develops from the alar plate and contains dopaminergic neurons with axons extending to the basal ganglia. It is one of the midbrain nuclei. Similarly, the red nucleus is a midbrain nucleus. In this region, the lumen of the neural tube remains narrow and forms the aqueduct of Sylvius which connects the 3^rd ventricle with the 4^th ventricle.

The cerebellum and the pons develop from the metencephalon, which is the 4^th of the five secondary brain vesicles. The dorsal wall of the metencephalon, specifically its alar plate, develops into the cerebellum. The neuroepithelial cells migrate and differentiate into the cerebellar cortex and the cerebellar nuclei. Neurons of the cerebellar cortex are of different types and gradually arrange themselves into three distinct layers. The cerebellum enlarges and forms lobes and lobules separated by fissures. The pons develops from the ventral parts of the metencephalic wall. It contains nuclei made of neurons that have migrated from the alar plate of the metencephalon.

The medulla oblongata develops from the myelencephalon, which is the 5^th and last of the five secondary brain vesicles. The alar and basal plates of myelencephalon differentiate into sensory and motor neurons. Sensory nuclei that differentiate from the alar plate of the myelencephalon the cochlear nucleus, the vestibular nucleus, the spinal trigeminal nucleus and the solitary nucleus.

The lumen of the neural tube in the metencephalon and myelencephalon together form the 4^th ventricle of the brain.

Fig. 17. 11. The illustration shows the main parts of the brain and their embryological origins shown between brackets.

The Alar and Basal Plates

During early development of the neural tube, the alar plate and the basal plate develop as key structures that are separated by the sulcus limitans. The alar plate is situated dorsal and gives rise to sensory neurons and the basal plate is located ventrally and gives rise to motor neurons. Derivatives of the he alar plate include the dorsal or posterior horn of the spinal cord, the scending pathways of the spinal cord and the brain stem, sensory nuclei of the cranial nerves, the sensory relay center of the thalamus, and the cerebellum. The basal plate on the other hand forms the ventral or anterior horn of the spinal cord, motor nuclei of the cranial nerves, the hypothalamus, the midbrain and pons.

Fig. 17. 12. The illustration shows differentiation of the mantle layer of the neural tube wall into a dorsal sensory alar plate and ventral basal motor plate.

Development of the Meninges

The meninges are preceptive connective tissue coverings that surround the brain and the spinal cord. There are three meninges: the dura mater the toughest and the outermost. The arachnoid, the middle one with CSF-filled spaces, and pia mater which is a thin layer that directly covers the nervous tissue of the CNS. The meninges are of mesodermal and neural crest origin. The dura mater is primarily derived from the paraxial mesoderm, whereas the arachnoid and pia mater -which are together known as the leptomeninges- are derived from neural crest cells.

Congenital Anomalies of the Nervous system

The central nervous system is affected by a wide array of abnormalities that occur at different stages of differentiation of the neural plate, neural groove, neural tube, or the brain vesicles. They range from minor abnormalities with minor effects to severe life-threatening anomalies that affect the brain or the spinal cord or both of them. They include anencephaly, encephalocele, microcephaly, spina bifida, Chiari malformation, Dandy-Walker malformation, and hydrocephalus.

Anencephaly is quite a serious anomaly where the newborn lacks parts of the brain, particularly the cerebral hemispheres. It is a fatal condition where newborns die shortly after birth. The remaining parts of the brain often lack a skull-bone covering. The anomaly results from incomplete closure of the cranial parts of the neural tube during early embryonic development. Possible factors eliciting the anomaly include folate deficiency, toxins and epilepsy medications.

Fig. 17. 13. The illustration on the left shows a normal brain with normal cerebral hemispheres, whereas the one in the middle shows anencephaly characterized by underdeveloped cerebral hemisphere. The picture on the right is a child with anencephaly with a small forehead.   

Encephalocele is also a serious condition that affects the brain, and results from incomplete closure of the neural tube leading to formation of sac-like evaginations made of nervous tissue protruding out of the skull. It is related to folic acid deficiency, exposure to toxins such as trypan blue and toxoplasma infections.

Fig. 17.14.  The illustration on the left shows encephalocele as sac protruding out of the back of the head, whereas the illustration on the right shows it as herniation of the nervous tissue of the brain outside the skull.

Microcephaly is a birth defect where the head of the newborn is markedly smaller than normal due to improper prenatal growth of the brain vesicles, the telencephalon in particular. Non-congenital microcephaly occurs postnatally due to postnatal growth failure.

Chiari malformation is an anomaly where the cerebellum or another part of the brain bulges out of the cranium into the spinal canal causing blockage of the flow of the cerebrospinal fluid. It often results from the posterior fossa of the skull being too small to accommodate the developing cerebellum, pushing it down the foramen magnum from the cranium into the spinal canal.

 Fig. 17.15.  The illustration on the right is of normal brain with a normal cerebellum whereas the one on the right shows the cerebellum protruding into the spinal canal (Chiari malformation).

Hydrocephalus is a condition where there is excessive cerebrospinal fluid (CSF) in the brain causing pressure on the brain; it could be congenital or acquired. Hydrocephalus results from an imbalance between CSF production and elimination. Congenital hydrocephalus results neural tube developmental anomalies that restrict CSF flow including Chiari malformation and spina bifida.

Spina bifida is a congenital defect of the spine and the spinal cord, where part of the spinal cord and its meninges are exposed through a gap in the vertebral column, that could be serious and cause paralysis of the lower limbs. It is primarily a neural tube defect caused by failure of closure of the neural tube all the way its length causing spinal failure of normal development of the spinal cord and the surrounding vertebral column. There are three types of spinae bifida, namely the spina bifida occulta, meningocele and myelomeningocele. Spina bifida occulta is the mildest form, is characterized by a gap in the vertebral column without protrusions and is often asymptomatic. Meningocele is a fluid-filled sac that protrudes through a spinal cord defect, but the spinal cord does not protrude. Spina bifida Aperta is the severest condition where the spinal cord and the meninges protrude via a defect in the vertebral column (myelomeningocele).

Fig. 17.16.  The illustration on the right is a longitudinal section of the normal spine, the one on the middle shows spina bifida occulta (closed spina bifida), whereas the one on the right shows spina bifida Aperta (open spina bifida). The picture on the right is of a child with spina bifida Aperta.

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