A Textbook of Neuroanatomy

PART 1

General Principles of the Nervous System

CHAPTER 1

Introduction to the Nervous System

CELLS OF THE NERVOUS SYSTEM

CENTRAL NERVOUS SYSTEM

PERIPHERAL NERVOUS SYSTEM

QUESTIONS TO PONDER

The human nervous system is an extremely efficient, compact, fast, and reliable computing system, yet it weighs substantially less than most computers and performs at an incredibly greater capacity. It has the capability of performing tasks that are far beyond the abilities of any computer yet devised. The present textbook deals mostly with the anatomy of the central nervous system, and in case the reader wonders why we study neuroanatomy, we should remember that it is our central nervous system more than anything else about us that makes us what we are, human beings.

The nervous system is subdivided, morphologically, into two compartments, the central nervous system (CNS), the brain and the spinal cord, and the peripheral nervous system (PNS), which emanates from and is a physical extension of the CNS. The PNS is composed of cranial and spinal nerve fibers and ganglia. Functionally, the nervous system is also subdivided into two components, the somatic nervous system, which is under the individual’s conscious control, and the autonomic nervous system, which controls the myriad of activities in conjunction with the voluntary nervous system. The autonomic nervous system is a tripartite organization, in that it has a sympathetic, a parasympathetic, and an entreric component. Simply stated, the first initiates the flight or fight response, the second is concerned with the body’s vegetative activities, whereas the enteric nervous system is involved in regulating the process of digestion. It must be understood, however, that the interplay of these three systems maintains homeostasis. The autonomic nervous system acts upon three cell types to perform its functions, these are cells of glands, smooth muscle, and cardiac muscle. Moreover, the nervous system has two other functional components, sensory and motor. The sensory component collects information and transmits it to the CNS (and is therefore called afferent), where the information is sorted, analyzed, and processed. Generally speaking, the motor component delivers the results of the analysis away from the CNS (and is therefore called efferent) to the effector organs, i.e., muscles and glands, resulting in a response to the stimulus.

Discussion of the topics of neuroanatomy requires that the student be familiar with some of the specialized terminology of the subject matter. One of the problems that students have in studying neuroanatomy is that there is a plethora of terms applied to the same or similar structures. It is important, therefore, to begin the discussion of this subject matter by listing and defining in Table 1.1 some of the terminology the student will encounter.

CELLS OF THE NERVOUS SYSTEM

Neurons

Neurons are the functional units of the central nervous system

The functional unit of the nervous system is the neuron. There are several types of neurons (detailed in Chapter 3) but they all have similar structures and functions. Neurons are capable of receiving, conducting, and transmitting impulses to each other as well as to muscle cells and cells of glands. Usually, neurons receive information at processes known as dendrites and transmit information along their single axon. Thus dendrites conduct information toward the cell body, whereas axons conduct information away from the cell body. Neurons usually communicate with each other as well as with other cells at synapses, where neurotransmitter substances are released from the axon terminal of the first neuron and bind to receptor molecules on the surface of the second neuron (or muscle/gland cell). Neurons may also communicate with each other via gap junctions, intercellular pores that permit the movement of small secondary messenger molecules from the cytoplasm of one cell into the cytoplasm of the neighboring cell, initiating a requisite response in the target cell.

Table 1.1 Common terms in neuroanatomy.

Neuroglia

Neuroglia constitute several categories of non-neuronal cells, namely microglia, macroglia, and ependymal cells.

Additional cells, known as neuroglia, constitute several categories of non-neuronal supporting cells. Those in the central nervous system are known as macroglia, ependymal cells, and microglia. The first two are derived from cells of the neural tube, whereas microglia are macrophages whose origins are monocyte precursors of the bone marrow.

Ependymal cells form a simple cuboidal epithelium that lines the central canal of the spinal cord and the ventricles of the brain. Additionally, these cells also participate in the formation of the choroid plexus, vascular tufts of tissue that manufacture cerebrospinal fluid. Macroglia is a collective term for the protoplasmic astrocytes, fibrous astrocytes, and oligodendroglia. Protoplasmic astrocytes support neurons in the gray matter, form a subpial barrier, and envelop capillaries of the CNS. Fibrous astrocytes are located in the white matter and appear to function in a similar fashion to protoplasmic astrocytes. Astrocytes also function in scavenging ions and neurotransmitter substances from the extracellular spaces. Oligodendroglia form myelin sheaths around axons and also surround dendrites and cell bodies of neurons in the CNS. Schwann cells are located in the PNS and they function in forming myelin around axons of the PNS. They also envelop unmyelinated axons.

CENTRAL NERVOUS SYSTEM

The central nervous system is composed of the large, anteriorly situated brain and smaller, cylindrically shaped spinal cord.

The central nervous system is a complex, hollow tube, whose rostral end, the brain, is enlarged and folded in an elaborate manner, whereas its caudal end, the spinal cord, is a long, tubular structure (Fig. 1.1). The brain is housed in the cranial cavity and at the foramen magnum is continuous with the spinal cord, housed in the vertebral canal. The dorsal surface of the spinal cord is closer to the spinous processes of the vertebrae, whereas its ventral surface is closer to the bodies of the vertebrae. Since the CNS, as well as most of the body, is bilaterally symmetric, the sagittal (midsagittal, according to some) plane bisects it into right and left halves. Positioning toward the sagittal plane is considered to be the medial direction and away from the sagittal plane is the lateral direction.

Brain

The brain is subdivided into five regions: the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon.

The brain is subdivided into five major regions, the largest being the telencephalon, which is composed of the cerebral hemispheres; the other regions are: the diencephalon, whose component parts are the epithalamus, thalamus, hypothalamus and subthalamus; the mesencephalon, consisting of the cerebral peduncles (tegmentum and crus cerebri) and the tectum (superior and inferior colliculi); the metencephalon, including the pons and cerebellum; and the myelencephalon (medulla oblongata). Frequently the medulla oblongata, mesencephalon, and the pons are collectively termed the brainstem. The lumen of the CNS is a narrow slit, the central canal, in the spinal cord, but is expanded into a system of ventricles in the brain and is filled with cerebrospinal fluid. Twelve pairs of cranial nerves emerge from the brain to supply motor, sensory, and parasympathetic innervation for the head and neck and much of the viscera of the body.

Spinal cord

The spinal cord is a cylindrical structure whose neurons are arranged in such a fashion that the motor functions are ventrally positioned and the sensory functions dorsally positioned.

The spinal cord (Fig. 1.2) is a cylindrical aggregate of nervous tissue, where white matter surrounds a central cylinder of gray matter. The neurons of the spinal cord are arranged in such a fashion that those concerned with somatic motor function are located in the ventral horn and their axons leave via the ventral rootlets. These are accompanied by axons of the preganglionic sympathetic neurons, located in the lateral horn of the spinal cord in the thoracic and upper lumbar regions, and axons of preganglionic parasympathetic neurons located in the lateral horn of the sacral spinal cord. The dorsal horn of the spinal cord is the location where central processes of unipolar neurons of dorsal root ganglia enter the spinal cord via dorsal rootlets bringing sensory information to the CNS. Interneurons connect two neurons to each other (e.g., unipolar sensory neurons of the dorsal root ganglia to motor neurons of the ventral horn). Thus, interneurons have the capability of facilitating or inhibiting a motor response to a sensory stimulus. For example, if you prick your finger the reflex response is to pull the finger away from the offending stimulus; however, if a health professional sticks your finger for a blood test, the interneuron inhibits the withdrawal of the finger.

Figure 1.1 The brain, spinal cord, spinal nerves, and major somatic plexuses. Note that the back of the skull as well as the spinal processes of the vertebrae have been removed and that the dura mater and the arachnoid have been opened up so that the spinal cord may be viewed in its entire length.

Figure 1.2 The spinal cord, its meninges, spinal nerves, and sympathetic chain ganglia.

The white matter of the spinal cord is composed of ascending and descending tracts of nerve fibers that connect regions of the CNS to one another. Ventral and dorsal rootlets at each level of the spinal cord join each other to form the spinal nerves that leave the spinal cord at regular intervals, indicative of its segmentation. Attached to each dorsal root is a dorsal root ganglion, housing the soma of the unipolar (pseudounipolar) neurons.

Gray matter and white matter

Gray matter is composed of neuron cell bodies, clusters of which within the CNS are known as nuclei, whereas white matter is recognized by the presence of myelinated axons

The nerve cell bodies of the CNS are grouped into large aggregates, known as gray matter. Gray matter may be arranged in sheaths, as in the cerebral cortex, or as a smaller collection of nerve cell bodies, known as a nucleus (or occasionally, and technically incorrectly, a ganglion, e.g., basal ganglia). There are two major categories of neurons, those whose axons leave the CNS and interneurons, whose axons remain within the CNS. The first group, called principal cells by some neuroanatomists, are generally motoneurons (somatic or autonomic), whereas interneurons relay information from one (or one group) of neurons to a second (or second group) of neurons within the CNS (e.g., the interneuron of a reflex arc).

White matter is composed of processes of neurons, many of whose axons are wrapped in a myelin sheath, which in a living individual has a white color. These axons are collected into small bundles, known as fasciculi, or large bundles, called funiculi. Certain larger fiber bundles are named tracts or capsules, whereas axons that cross the midline to connect identical structures on opposing sides are known as commissures. Axons that travel up or down the CNS and cross the midline from one side to the other are said to decussate at the point of crossing over.

PERIPHERAL NERVOUS SYSTEM

The peripheral nervous system is a continuation of the CNS; it is composed of clusters of nerve cell bodies, known as ganglia, as well as of bundles of axons and central processes, known as nerves

The peripheral nervous system is composed of cranial nerves, spinal nerves, their associated ganglia, and nerve fibers of the autonomic nervous system. It must be understood that the PNS is in physical continuity with the CNS, in fact cell bodies of many of the nerve fibers (axons) of the PNS are located in the CNS.

Somatic nervous system

The somatic nervous system is composed of the 12 pairs of cranial nerves and their ganglia as well as of the 31 pairs of spinal nerves and their dorsal root ganglia

There are 12 pairs of cranial nerves, identified both by name as well as by Roman numerals I through XII. All cranial nerves, with the exception of the vagus (CN X), serve structures in the head and neck only. The vagus nerve has responsibilities in the head and neck, but also serves many of the thoracic and abdominal viscera, e.g., the heart and alimentary tract. Those cranial nerves that have sensory components possess sensory ganglia housing the cell bodies of unipolar neurons whose single process bifurcates into a central and a peripheral process. The central process of a unipolar neuron enters the brain, whereas its peripheral process goes to a sensory receptor. There are no synapses occurring in these sensory ganglia.

There are 31 pairs of spinal nerves (8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal), attesting to the segmentation of the spinal cord (see Fig. 1.1). The cell bodies of sensory neurons (unipolar neurons) are located in the dorsal root ganglia (sensory ganglia). Again, it must be remembered that there are no synapses occurring in the dorsal root ganglia. The single process of each neuron bifurcates and the short central process joins other central processes to form dorsal rootlets that enter the spinal cord. The peripheral process goes to a sensory receptor, which, when stimulated, causes depolarization of the peripheral process; the wave of depolarization spreads to the central process, which transmits the stimulus either to an interneuron (in a three neuron reflex arc) or to a motoneuron (in a two neuron reflex arc, e.g., the patellar reflex). Although the above description is true for reflex arcs, it must be realized that in most instances the incoming information is transmitted to higher levels in the brain and is processed either cognitively or subconsciously, or both, rather than just relying on simple reflex phenomena. These motoneurons are multipolar neurons whose cell bodies are located in the ventral horn of the spinal cord and serve skeletal muscle cells only. Their axons leave via the ventral rootlets that join the dorsal rootlets to form the spinal nerve.

Each spinal nerve bifurcates to form a smaller dorsal primary ramus and a larger ventral primary ramus. Dorsal primary rami supply sensory and motor innervation to the back, whereas ventral primary rami supply the lateral and anterior portion of the trunk. Ventral rami that supply the thorax and abdomen usually remain as separate nerves, whereas those of the cervical and lumbosacral regions join each other to form plexuses from which individual nerve bundles arise to serve the head, neck, and upper and lower extremities. Each spinal nerve receives sensory information from the skin of the segment, or dermatome, of the body that it serves. The entire body is mapped into a number of dermatomes; however, there are overlaps in the innervation, so that a single dermatome is supplied by more than one spinal nerve. Such overlaps prevent the total anesthesia of a particular dermatome if the dorsal rootlets of the spinal nerve supplying it are damaged.

Autonomic nervous system

The autonomic nervous system regulates the activities of smooth muscle, cardiac muscle, and glands, and is divided into three systems: the sympathetic, parasympathetic, and enteric nervous systems

The autonomic nervous system is a motor system, but unlike somatic motoneurons, it does not serve skeletal muscle cells, instead it innervates cardiac muscle cells, smooth muscle cells, and secretory cells of glands. Additionally, whereas a somatic motoneuron directly innervates its muscle cell (Fig. 1.3), in the autonomic nervous system the neuron whose cell body is located in the CNS (preganglionic or presynaptic neuron) synapses with a second neuron (postganglionic or postsynaptic neuron) located in a ganglion in the PNS. It is the axon of the postganglionic neuron that synapses with the cardiac muscle cell, smooth muscle cell, or secretory cell of a gland. Thus the autonomic nervous system is said to be a two cell system, and synapses always occur within an autonomic ganglion (Fig. 1.3). The axon of the preganglionic neuron is myelinated and is known as the preganglionic fiber. The axon of the postganglionic neuron is not myelinated, and is known as the postganglionic fiber.

Figure 1.3 •Diagram demonstrating the difference between autonomic innervation (top) and somatic motor innervation (bottom). Observe that two neurons are present in the autonomic supply, whereas a single motoneuron is present in the somatic motor system.

The autonomic nervous system is responsible for the maintenance of homeostasis, and is composed of three functional components: sympathetic, parasympathetic, and enteric. The sympathetic component prepares the body for fight and flight, whereas the parasympathetic prepares the body for a vegetative state (e.g., digestion). The enteric nervous sytem is situated completely within the wall of the digestive tract and controls the entire process of digestion. Although the sympathetic and parasympathetic components of the autonomic nervous system modulate its activities, the enteric nervous system can function quite well on its own if the sympathetic and parasympathetic components are severed. Cell bodies of preganglionic sympathetic neurons are located in the lateral horn of the thoracic and upper lumbar spinal cord (T1 to L2,3), whereas those of the preganglionic parasympathetic neurons are located in the brain (and their axons travel with CN III, VII, IX, and X) and the lateral horn of the sacral spinal cord (S2–S4). Postganglionic cell bodies of sympathetic neurons are usually located near the spinal cord, within the sympathetic chain ganglia, or a little farther away, in collateral ganglia. The cell bodies of postganglionic parasympathetic neurons, however, are located in ganglia that are in the vicinity of the viscera being innervated.

The cell bodies of the sensory neurons that supply the viscera are located in the dorsal root ganglia of spinal nerves or in the sensory ganglia of cranial nerves, along with the somatic sensory neurons. However, their peripheral processes accompany the preganglionic autonomic fibers into their respective ganglia, but do not synapse in those ganglia. Moreover, these peripheral fibers continue to accompany the postganglionic autonomic fibers to the same destinations. In spite of their route, these sensory neurons are not considered to be a part of the autonomic nervous system. Sensory information relayed by these autonomic sensory nerves are not registered as part of the conscious experience, and even pain sensations are experienced as referred pain in somatic regions of the body (e.g., angina pectoris, where pain sensations arising in the heart muscle are experienced as pressure in the chest, back, and arm (regions served by the same segmental spinal nerve)).

QUESTIONS TO PONDER

1. What is the relationship between the central and peripheral nervous systems?

2. What is meant by the fight or flight response?

3. Why are there more oligodendroglia than neurons in the central nervous system?

4. What single characteristic is the major difference between microglia and the other neuroglia of the central nervous system?

5. What is the major difference between a two neuron reflex arc and a three neuron reflex arc, aside from the simplistic fact that one has an extra neuron associated with it?

CHAPTER 2

Development of the Nervous System

CLINICAL CASE

EARLY DEVELOPMENT

NEURULATION

EARLY DEVELOPMENT OF THE SPINAL CORD AND BRAI

DEVELOPMENT OF THE SPINAL CORD

DEVELOPMENT OF THE BRAIN

CLINICAL CONSIDERATIONS

SYNONYMS AND EPONYMS

FOLLOW-UP TO CLINICAL CASE

QUESTIONS TO PONDER

CLINICAL CASE

A 22-year-old woman presents to the emergency room. She is obviously pregnant and near term. There has been no prenatal care. A uterine ultrasound is performed that detects an abnormality. She is estimated to be 37 weeks pregnant. The obstetrician on call wishes to perform an emergency Caesarian section delivery because of the abnormality that was detected. This was performed without incident.

Examination of the newborn shows a fist-sized mass in the midline lumbosacral region. This protrudes above the skin surface and is dusky gray in appearance. The newborn has a normal cry and arms seem to move normally. Skin color is normal and temperature is normal. The legs do not move and are flaccid. There is deformity noted of the hips, ankles, and feet. Subsequent examination reveals a lack of cry or any physical response to sensory stimulation of the legs.

Embryogenesis, the development of the future individual, begins with the fusion of the male and female gametes, the spermatozoon and the oocyte, respectively. This occurs in the fallopian tube (oviduct). The process of fusion is known as fertilization, subsequent to which the fertilized ovum is referred to as a zygote, the very beginning of a new individual (Fig. 2.1). The mitotic activity of the zygote is responsible for the increase in the number of cells that will be required for the construction of the future individual as well as for the embryonic component of the supporting structures that will ensure the requisite nourishment for normal development and growth of the future embryo.

The normal development of the embryo is divided into a number of stages and the interested reader is referred to a textbook of human embryology. In the present textbook, human embryology is presented from the perspective of neuroanatomy and only those aspects of human development are presented that will assist the student in appreciating the complexity and beauty of how the nervous system progresses from an ill-defined cluster of cells to an amazingly intricate functional unit. In order for the reader to be able to grasp the manner in which this process occurs, it is advisable to show not only the development of the nervous system per se, but also that of the structures that envelop and surround the nervous system. Therefore, this chapter includes a description of early embryology, the development of the pharyngeal arches, formation of the face, and some of the molecular events that appear to govern this entire process.

Figure 2.1 The early development of a human embryo. Fertilization, the fusion of the haploid sperm nucleus with the ovum’s haploid nucleus, results in the formation of a diploid cell, known as a zygote. As the zygote undergoes mitosis, a solid cluster of cells is formed, the morula. Continued cell division and rearrangement of the newly formed cells results in the formation of a hollow sphere of cells, the blastocyst, whose cells form the bilaminar germ disc and later the trilaminar germ disc.

EARLY DEVELOPMENT

During early development the zygote undergoes mitotic division to form a cluster of cells, known as the morula, whose cells rearrange themselves to form the hollow blastocyst

The zygote undergoes a series of mitotic divisions, known as cleavage, which will result in the formation of a solid cluster of cells, where each cell is smaller than the original zygote. This cluster of cells resembles a mulberry, and hence is known as the morula. The cells of the morula secrete a viscous fluid that creates a central cavity by pushing the cells to the periphery until a hollow ball of cells is formed, known as the blastocyst (Fig. 2.1).

Although most of the cells of the blastocyst are at the periphery, a few of the cells are trapped inside, adhering to one of the poles of this hollow ball of cells. These trapped cells are the embryoblasts (inner cell mass), whereas the peripherally positioned cells are the trophoblasts.

The embryoblasts will give rise to the embryo whereas the trophoblasts are responsible for the formation of the embryonic portion of the placenta.

Bilaminar germ disc

The bilaminar germ disc is composed of two cell layers: the epiblast and the hypoblast

The cells of embryoblasts rearrange themselves to form two layers, the epiblasts and the hypoblasts, and the embryo becomes known as the bilaminar germ disc. The epiblast is closer to the trophoblast cells than is the hypoblast, and the forming embryo is about 7–8 days old (Fig. 2.1). By this time it has reached the uterine cavity, where it burrows into the wall of the uterus. This process of implantation begins on the late sixth or early seventh day after fertilization and is completed on the eleventh day.

During the period of implantation some of the cells of the epiblast delaminate, forming a membrane over the remaining epiblast. This new layer of cells is composed of the amnioblasts, which will give rise to the amniotic sac, and the space between the amnioblasts and the epiblasts is known as the amniotic cavity.

Trilaminar germ disc

The trilaminar germ disc is responsible for the establishment of the three primary germ layers: the ectoderm, mesoderm, and endoderm

At about the fourteenth day post fertilization, at the anterior end of the bilaminar germ disc, a few cells of the epiblasts form desmosomal contacts with a few cells of the underlying hypoblast, thus forming the prochordal plate, which will be the future buccopharyngeal membrane. Approximately 1 day later a longitudinal furrow, the primitive groove, develops in the epiblast on the posterior aspect of the bilaminar germ disc, the anteriormost extent of which is deeper, and is referred to as the primitive pit. Bordering both sides of the primitive groove is an elevation of cells, the primitive streak, whereas the anterior border of the primitive pit is a small elevation of cells, the primitive node (Hensen’s node).

Formation of ectoderm, mesoderm, and endoderm

Cells of the epiblast undergo active mitosis along most of its surface and the newly formed cells migrate to the primitive streak. Here they enter the primitive groove and pass into the space between the epiblasts and the hypoblast, thus forming a new, intermediate layer of cells, the mesoderm. Some of these cells do not stop in the mesoderm space, but displace most of the original cells of the hypoblast, pushing the original cells of the hypoblast laterally. The cells of the hypoblast become incorporated into an extraembryonic region, known as the yolk sac. As this process is occurring, the epiblast is renamed the ectoderm and the new cell layer that replaces the hypoblasts is referred to as the endoderm. Thus, as a result of the conversion of the embryoblast of the blastocyst into the trilaminar germ disc, a process known as gastrulation, the embryo is composed of three layers (ectoderm, mesoderm, and endoderm), and is known as the trilaminar germ disc (Fig. 2.1). The entire embryo, at this time, is approximately 1 mm in length.

Cells of the mesoderm cannot penetrate the contact of the ectoderm and endoderm at the prochordal plate, but they can migrate around this region of adhesion, and some mesoderm cells will be located anterior to this structure. These cells are cardiogenic cells, and begin to form the future heart. An additional group of cells migrate from the primitive node into the primitive pit and proceed anteriorly, en masse, between the ectoderm and the endoderm until they reach the prochordal plate, where their progress is blocked. This pencil-shaped column of cells is known as the notochordal process, and it possesses special inductive capabilities. The notochord induces the cells of the ectoderm lying above it to proliferate and form the flat neural plate, the beginning of the primitive nervous system of the embryo.

NEURULATION

Neurulation is the process whereby the embryo internalizes its developing nervous system

Since, at this time the primitive nervous system is on the external aspect of the body, it has to be internalized. The process of internalization, known as neurulation, is accomplished by an alteration in cell shape and by increased mitotic activity, especially of the lateral edges of the neural plate. These activities begin to fold the neural plate into a longitudinal furrow, the neural groove, whose two walls are the neural folds. Further cell division and continued change in cell morphology cause the neural folds of the two sides to approximate and fuse with each other in the midline, forming the neural tube (Fig. 2.2). The process of fusion starts at the midcervical level and proceeds anteriorly (rostrally) and posteriorly (caudally) and is completed by the end of the fourth week of gestation. The final regions of the neural tube to be closed are the anterior and posterior neuropores. The cells of the neural tube just above the notochord differentiate to form the floor plate. These cells induce the differentiation of neuroblasts into motoneurons and establish the polarity of the neural tube.

Note that the clinical case at the beginning of the chapter refers to an embryonic abnormality detected during an ultrasound examination of the fetus.

1 Where is the lesion in relation to the innervation of the upper extremities?

2 Where is the lesion in relation to the motor innervation of the legs?

3 Where is the lesion in relation to the sensory innervation of the legs?

Figure 2.2 (A) The notochord is responsible for inducing the overlying ectodermal cells to form the neural plate. (B, C) As the embryo continues its development, it enters the stage of neurulation, the process whereby the forming nervous system is brought into the body by the formation of an intermediary neural groove, and finally a neural tube, the precursor of the brain and spinal cord. (D) Note that the neural crest, initially the lateral aspect of the neural plate, becomes separated as the neural tube is formed. Cells of the neural crest give rise to all of the ganglia of the peripheral nervous system as well as to numerous additional structures of the developing embryo.

Fusion of the lateral edges of the right and left sides of the central nervous system (CNS) is accompanied by fusion of the ectoderm, whose edges became approximated during neural tube formation. The simultaneous fusions permit a separation of the neural tube from the overlying ectoderm, and complete internalization of the nervous system. Incomplete fusion results in a relatively common developmental anomaly known as spina bifida. The nervous system, including the organs of special senses, originate from three sources: the neural tube (CNS, somatic motoneurons, and preganglionic autonomic neurons); the neural crest (see below); and the ectodermal placodes (lens of the eye, inner ear, pituitary gland, and contribution to the formation of somatic sensory ganglia of the cranial nerves).

Neural crest

The neural crest is a narrow strip of cells at either edge of the developing neural plate

As the edges of the neural folds meet each other, some of their cells do not participate in the formation of the neural tube, instead they form a narrow strip of cells, the neural crest (Fig. 2.2). The cells of the neural crest will migrate throughout the body to form almost the entire peripheral nervous system, including the enteric nervous system, dorsal root ganglia, sensory ganglia of the cranial nerves, all postganglionic autonomic neurons, as well as melanocytes, parenchymal cells of the suprarenal medulla (chromaffin and ganglion cells), Schwann cells and satellite cells of the peripheral nervous system, and most of the mesenchymal cells of the head and anterior neck. Therefore, most of the mesenchymal cells of this region are not derived from mesoderm, instead they are neuroectodermal in origin and are referred to as ectomesenchyme. Derivatives of the neural crest, neural plate, and ectodermal placodes are summarized in Table 2.1. The cells of the neural crest follow four general pathways marked by signaling molecules manufactured and released by neighboring cells. Examples of these molecules are retinoic acid, transforming growth factor, and fibroblast growth factor. These signaling molecules contact cell surface receptors of target cells, activating intracellular molecular systems that cause specific responses within those cells. Some of these responses activate cytoplasmic enzyme systems, whereas other responses include the activation of transcription factors that regulate specific gene expressions, each resulting in the activation of specific inductive processes necessary for the formation of the nervous system.

Paraxial mesoderm

The paraxial mesoderm lies lateral to the developing neural tube and becomes segmented into clustered blocks of tissue known as somites

The mesoderm lying lateral to the neural tube and notochord in the region of the future trunk is known as the paraxial mesoderm, and it becomes segmented into paired blocks of tissue, known as somites (Fig. 2.3). Each somite is composed of three elements. These are the sclerotome, responsible for the formation of two succeeding vertebrae and their intervening intervertebral disc; myotome, responsible for the formation of the muscle masses associated with that segment of the trunk; and dermatome, responsible for the formation of the dermis of the skin in its particular area of the trunk.

The region of the paraxial mesoderm lateral to the somites is known as the intermediate mesoderm and it forms the urogenital system. The most lateral aspect of the paraxial mesoderm, known as the lateral plate mesoderm, splits into two sheaths and the intervening space between these two sheaths is known as the coelom, or body cavity (Fig. 2.3). The dorsal of the two sheaths of the lateral plate mesoderm becomes known as the somatic mesoderm, and together with its associated ectoderm this is referred to as the somatopleure. The ventral sheath is known as the splanchnic mesoderm and, together with its associated endoderm, is referred to as the splanchnopleure. The somatopleure gives rise to the body wall whereas the splanchnopleure forms the wall of the gut. The coelom becomes subdivided into the peritoneal, pleural, and pericardial cavities.

Table 2.1 Derivatives of the neural crest, neural plate, and ectodermal placodes.

Figure 2.3 Cross-section through a developing human embryo during the process of neurulation. Note the presence of somites, gut, and intraembryonic coelom (body cavity). It is interesting to realize that the precursors of many of the future organ systems, such as the digestive, respiratory, urogenital, musculoskeletal, and nervous systems are being established at this early stage of development.

Segmentation of the paraxial mesoderm of the head is incomplete and, instead of forming somites, it is said to form about 18–20 pairs of somitomeres, somite-like structures that are responsible for the formation of the muscles of the head. The anteriormost seven pairs of somitomeres remain as unsegmented structures, whereas the posterior somitomeres become transformed into somites.

Pharyngeal arches

Pharyngeal arches are pairs of ectodermally covered mesenchymal thickenings responsible for the formation of much of the head and neck

As the neural tube becomes internalized, its anterior region, the future brain—whose development is detailed below—is developing so rapidly that it grows above and anterior to the prochordal plate, it overlies the cardiogenic region, and approximates the amniotic sac. The anterior end of the embryo, possibly to provide more room for growth, begins to bend in an inferior direction (cephalic flexure). As that occurs, the future heart becomes neatly tucked beneath the embryo, and the prochordal plate, now referred to as the buccopharyngeal membrane, becomes positioned superiorly to the developing heart, separating the stomadeum, the primitive oral cavity, from the developing foregut (pharynx). Note that the stomadeum is in fact a space captured by the embryo from the amniotic cavity. The formation of the stomadeum is indicative of the initiation of the development of the face.

As the buccopharyngeal membrane degenerates during the fifth week of development and communication is established between the future oral cavity and the pharynx, the stomadeum deepens and begins to be surrounded by ectodermal-covered mesenchymal thickenings, the pharyngeal arches (previously named branchial arches). These bilaterally positioned arches develop in an anteroposterior direction. The first arch is the mandibular arch, the second is the hyoid arch, whereas successive arches are numbered 3, 4, and 6, with the notable absence of the fifth pharyngeal arch, which in humans is rudimentary. Between neighboring arches an external depression—the ectodermally lined pharyngeal groove—is encountered, with its anatomical counterpart on the inside, the pharyngeal pouch, an evagination of the endodermally lined pharynx.

Genetic influences of pharyngeal arch development

The connective tissue elements of the pharyngeal arches, especially those associated with the developing musculature, arise from somitomere mesoderm, whereas the majority of the mesenchyme, particularly in the anterior regions of the arches, arise from neural crest material. These neural crestderived cells arise from the midbrain and the rhombomeres and, during early pharyngeal arch formation, express homeobox gene products (Hoxb genes) that reflect their sites of neural origin.

Table 2.2 Pharyngeal arch derivatives and their innervation.

Pharyngeal arch derivatives (Table 2.2)

Each pharyngeal arch possesses its own vascular and neural supply as well as a supporting cartilaginous skeleton and associated skeletal muscles

Each pharyngeal arch possesses its own cartilage, nerve, vascular, and muscular components. The first two arches become developed to the greatest extent, whereas the last one is the most poorly developed. Only some of their derivatives will be discussed.

First pharyngeal arch (mandibular arch)

The first pharyngeal arch is responsible for the formation of the maxillary and mandibular arches and the muscles of mastication

The cartilage of the first (mandibular) arch is a horseshoe-shaped structure, known as Meckel’s cartilage. Most of this cartilage will disappear, except for its anteriormost extent which participates in the formation of the mental symphysis and its posteriormost extent which gives rise to the malleus and incus, two of the three ossicles of the ear. The perichondrium of Meckel’s cartilage becomes the sphenomandibular ligament and the anterior ligament of the malleus.

The ectomesenchyme of the first pharyngeal arch forms the muscles of mastication (temporalis, masseter, and lateral and medial pterygoid muscles), as well as the following muscles: the tensor veli palatini, tensor tympani, anterior belly of the digastric, and mylohyoid. Since these muscles are derived from the mandibular arch, they are innervated by the nerve of this arch, the trigeminal nerve (CN V). The mandibular arch, as will be evident later in this chapter, is responsible for the formation of much of the face.

The development of the mandibular arch is dependent on the presence of the epidermally derived signaling molecule, endothelin-1 (ET-1). This molecule probably functions in the facilitation of the interaction between the ectomesenchymal cells and the epithelial components of the arch, a process necessary for the development of structures that originate in the mandibular arch.

Second pharyngeal arch (hyoid arch)

The second pharyngeal arch overgrows the remaining arches and is responsible for the formation of the muscles of facial expression and part of the hyoid bone

The cartilage of the second or hyoid arch is known as Reichert’s cartilage. Most of this cartilage will also disappear, but parts of it will be responsible for the formation of the stapes, the third ossicle of the ear, as well as the styloid process, and the lesser cornu and superior aspect of the body of the hyoid bone. Additionally, the stylohyoid ligament is derived from the perichondrium of Reichert’s cartilage.

The muscles of facial expression take their origin in the hyoid arch mesoderm, along with the stapedius, stylohyoid, and the posterior belly of the digastric muscles. All of the above muscles are, therefore, innervated by the nerve of the second arch, the facial nerve (CN VII).

The homeobox gene Hoxa-2 is responsible for the normal development of the hyoid arch and its derivatives. In the absence of Hoxa-2 the formation of second arch derivatives does not occur, instead first arch derivatives develop in the hyoid arch. The implication of this switch is that mandibular arch substances form by default and Hoxa-2 gene products prevent the default condition from taking place.

Third pharyngeal arch

The third pharyngeal arch is responsible for the formation of the stylopharyngeus muscle and part of the hyoid bone

The cartilage of the third arch is unnamed, but it is responsible for the formation of the greater horn and the inferior half of the body of the hyoid bone. The only muscle to be derived from the mesoderm of the third arch is the stylopharyngeus muscle, innervated by the glossopharyngeal nerve (CN IX), the nerve of the third arch.

Fourth and sixth pharyngeal arches

The fourth and sixth pharyngeal arches participate in the formation of the larynx and its muscular apparatus

The cartilages of the fourth and sixth pharyngeal arches are also unnamed. They participate in the formation of the skeleton of the larynx. It is believed that the muscles associated with the larynx and pharynx are derived from the mesenchyme of these arches. The innervation of these muscles is somewhat confusing, for they receive their nerve supply from the pharyngeal plexus (composed of fibers from CN IX, X, and XI). The nerves of the fourth and sixth arches, however, are the superior laryngeal and recurrent laryngeal branches of the vagus nerve (CN X), respectively.

Pharyngeal groove derivatives

Pharyngeal grooves are external depressions located between succeeding pharyngeal arches; the first pharyngeal groove forms the external ear canal, while the others disappear during development

Only the first pharyngeal groove, that between the mandibular and hyoid arches, gives rise to a definitive structure. This groove becomes deeper and approximates the first pharyngeal pouch, so much so, that only a thin membrane, the pharyngeal membrane (closing plate), separates the groove from the pouch. This closing plate becomes the tympanic membrane whose external surface is covered by the ectodermal derivative of the first pharyngeal groove. The remainder of the first pharyngeal groove becomes the external auditory canal.

The subsequent pharyngeal grooves are submerged by the sudden spurt of growth experienced by the second pharyngeal arch, which grows in an inferior direction, to form the future neck. Occasionally, the submerged pharyngeal grooves do not become obliterated, and thus remain as cervical sinuses, which may result in the formation of cervical cysts.

The message for this sudden growth spurt arises from the epithelium covering the tip of the second arch. These ectodermal cells express BMP-7, sonic hedgehog, and fibroblast growth factor 8, which are responsible for the proliferation of the mesenchymal cells of the hyoid arch.

Pharyngeal pouch derivatives (Table 2.3)

Pharyngeal pouches are internal depressions located between succeeding pharyngeal arches

The first pharyngeal pouch, lying between the mandibular and hyoid arches, forms the Eustachian tube, the tympanic cavity, and the endodermal lining of the eardrum. The second pharyngeal pouch forms the palatine tonsils. The third pharyngeal pouch gives rise to the thymus and the inferior parathyroid glands. The fourth pharyngeal pouch forms the superior parathyroid gland, and perhaps part of the thymus, and the fifth pharyngeal pouch gives rise to the parafollicular cells of the thyroid gland.

Genetic and molecular aspects of development

Development of an embryo is controlled by a sequence of genetically controlled temporospatial phenomena

Development of the embryo requires a blueprint of spatial phenomena that occur at specific, predetermined periods of time, a process referred to as patterning. This blueprint is located in the nucleus of each cell, present in the chromosomes as a group of related genes. Various intra- and extracellular parameters cause the activation or suppression of these genes and in this fashion facilitate the normal sequence of growth and development.

Table 2.3 Derivatives of the pharynx and pharyngeal pouches.

Homeobox genes and growth factors

Homeobox genes control the temporal sequence of transcription factor synthesis

Genes code for the synthesis of specific proteins, many of which are enzymes that are responsible for the occurrence of specific events. Certain genes have been conserved through evolution and their study in lower organisms, such as the fruitfly, has provided information that is directly applicable to the developmental processes of higher organisms, including humans. A family of genes, known as the homeobox genes, code for the synthesis of transcription factors, proteins that bind to and regulate the expression of other genes.

The time sequence of the events controlled by products of these homeobox genes and by growth factors are essential for normal development because certain genes can be switched on only if some other genes have already been activated and if still other genes have not as yet been switched on. In other words, there are windows of opportunity for the occurrence of certain events and if that timeframe is missed then development will not proceed normally. Therefore, these homeobox genes become activated in a specific order, and their sequential expression establishes a pattern of developmental events. In order for development to progress in a normal manner, cells must interact with each other. These interactions may involve the physical contact of two cells or the release of a particular substance by one cell, referred to as the signaling cell, to act as a message for the other cell, known as the target cell.

Signaling molecules

Signaling molecules are released by signaling cells to convey a message to particular target cells that possess receptor molecules specific for the released signal

The substance that is released is known by various names, such as signaling molecule, growth factor, or ligand, and it reaches its target cell by traveling in the body fluids. Since the signaling molecule may meet a number of other cells, it is important that only the target cells become influenced by that particular molecule and this process is ensured by the presence of receptor molecules on the surfaces of cells. Usually, a specific receptor molecule recognizes only a particular signaling molecule. This is similar to a lock and key concept, where a specific lock can be opened only by a particular key.

If physical contact between cells is required, it is important that the two cells recognize each other. Cell recognition is also a function of a series of cell surface receptor molecules, some of which act as the keys and the others as locks. Usually several molecules are involved on each cell so as to ensure that only the intended target cell is influenced by the signaling cell.

Once the cell surface receptors come into contact with and bind the signaling molecule, or come into contact with the molecules on the signaling cell’s surface, a sequence of intracellular events is initiated resulting in the regulation of a single gene or a series of genes of the target cell. The expression of these genes may cause the release of further signaling molecules, may alter the activities of the target cell, may prompt the target cell to differentiate into another cell type, may compel the cell to proliferate, or may direct the cell to undergo apoptosis and die. Each of these events is necessary for normal development to occur. The process whereby one cell causes its target cell to differentiate, that is become transformed into a different cell type, is known as induction.

It is interesting to note that the number of growth factors that regulate development are relatively small. The reason for the paucity of their number is that they act in combination with each other, and by simple permutations and combinations of just a few of these factors a tremendous number of signals may be generated.

EARLY DEVELOPMENT OF THE SPINAL CORD AND BRAIN

During its early development the neural tube is subdivided into three regions: the prosencephalon, mesencephalon, and rhombencephalon

Initially, the neural tube is composed of a single layer of columnar cells, known as neuroepithelial cells. Proliferation of these cells results in a thickened tubular structure whose cephalic region begins to form three enlargements: the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). The caudal extent of the neural tube forms the spinal cord. As the three vesicles are developing, the cephalic flexure in the region of the mesencephalon and the cervical flexure, between the rhombencephalon and the future spinal cord, are also forming.

By the fifth week of gestation the prosencephalon is divided into two regions: the telencephalon with its two lateral swellings, the future cerebral hemispheres, and the diencephalon, whose optic vesicles are in the process of development. The rhombencephalon is also subdivided, by the pontine flexure, into two regions: the metencephalon, which will form the pons and the cerebellum, and the myelencephalon, which will develop into the medulla oblongata. These flexures provide increased space for the folding and three-dimensional organization of the brain.

The lumen of the developing CNS is subdivided into the ventricles of the brain and the central canal of the spinal cord. The lateral ventricles of the cerebral hemispheres communicate with the third ventricle of the diencephalon via the interventricular foramina (of Monro). The fourth ventricle, located in the rhombencephalon, communicates with the third ventricle via the cerebral aqueduct (of Sylvius) located in the mesencephalon.

Neuroepithelial cells

The neuroepithelial cells form a three-layered neural tube, composed of ventricular, intermediate, and marginal zones

As the neuroepithelial cells continue to proliferate, they establish a thicker wall composed of a pseudostratified epithelium, each of whose cells initially extends the entire thickness of the developing neural tube. As development progresses, some of these neuroepithelial cells remain adjacent to the lumen, whereas most cells migrate away from it, resulting in a three-layered neural tube. The layer adjacent to the lumen is known as the ventricular zone (ependymal layer), some of whose cells develop into ependymal cells that line the ventricles of the brain and the central canal of the spinal cord. The middle region of the developing neural tube is the mantle layer (intermediate zone). The third layer of the developing neural tube, located the farthest from the lumen is the marginal layer (marginal zone).

Since these neuroepithelial cells are quite long, initially they extend from the lumen of the neural tube to its periphery, spanning all three layers. Hence one may name regions of these cells according to the zone in which they are located. When a neuroepithelial cell is ready to undergo mitosis its nucleus migrates from the ventricular zone to the region of the cell occupying the marginal layer and the cell enters the S phase (DNA synthesis) of the cell cycle. Upon completion of the S phase, the nucleus returns to the ventricular zone, and the cell shortens and becomes round so that the cell is located completely in the ventricular zone. It is here that the cell divides to give rise to two daughter cells, which may remain in the ventricular zone or migrate to the mantle layer or into the marginal layer (Fig. 2.4).

There appear to be at least two types of neuroepithelial cells: those that can be stained for glial fibrillary acidic (GFA) proteins (GFA positive) and those that lack GFA proteins (GFA negative). GFA-negative cells give rise to an enormous number of daughter cells that eventually differentiate into migratory neuroblasts that are no longer able to divide. GFA-positive cells also give rise to an immense number of daughter cells that will differentiate into glioblasts and ependymal cells. Neuroblasts arise first and glioblasts and ependymal cells originate later. Neuroblasts migrate from the ventricular zone into the mantle layer where they differentiate into neurons. Glioblasts give rise to all macroglia (astrocytes and oligodendroglia), and ependymal cells line the ventricles of the brain and the central canal of the spinal cord.

As the neuroblasts are differentiating into neurons within the mantle layer they develop axons that grow into the marginal layer. Concomitantly, many glioblasts will migrate into the marginal layer, and those that become oligodendroglia form a protective cellular sheath around the developing axons, dendrites, and cell bodies within the mantle layer. Many of the axons will become myelinated by the oligodendroglia. Thus, in the spinal cord, the mantle layer is the future gray matter, whereas the marginal layer, composed of numerous myelinated axons and attendant neuroglia, becomes the white matter.

Myelination in the CNS begins around the sixteenth week of gestation and continues until the individual is about 3 years old, although recently it has been shown that in the frontal lobes of the brain this process may continue into the early twenties. It is interesting to note that there is a phylogenetic component to the sequence of myelination, in that the older pathways are myelinated before newer pathways; also motor roots of spinal nerves are myelinated before sensory roots.

Figure 2.4 Neuroepithelial cells are long cells that initially extend from the pial (marginal) to ependymal surface of the neural tube. As they enter the cell cycle to form new cells, their nuclei migrate along the length of the cell. G1 phase: the nucleus is in the vicinity of the ventricular surface and begins to migrate to the pial surface. S phase: the nucleus is in the pial surface and at the end of the S phase the nucleus begins its return to the ventricular surface. G2 phase: the nucleus reaches the ventricular surface and the cell begins to shorten. Mitosis (M phase): the cell divides to give rise to two daughter cells in the ventricular zone.

DEVELOPMENT OF THE SPINAL CORD

Basal plates, alar plates, and dorsal root ganglia

The basal plates and alar plates of the mantle layer are separated from each other by the sulcus limitans, a longitudinal furrow extending the entire length of the future spinal cord

The mantle layer increases in thickness in a disproportionate fashion, causing a ventral and dorsal thickening (basal plate and alar plate, respectively) of the entire length of the wall of the future spinal cord. These two thickenings are separated from each other by a longitudinal furrow, known as the sulcus limitans. The neuroblasts of the basal plate differentiate into motoneurons, responsible for the motor function of the spinal cord (ventral gray column), whereas neuroblasts of the alar plate differentiate into interneurons. Some of these interneurons will receive sensory information from primary sensory neurons (including those of the dorsal root ganglia). In the thoracic and upper lumbar regions (T1 through L2–L3) of the future spinal cord an intermediate thickening is discerned. Neuroblasts of this region will give rise to preganglionic sympathetic neurons (forming the lateral gray column) of the autonomic nervous system. It should be noted that various synonyms are in common use among neuroanatomists and some of these are given at the end of the chapter.

The central midline of the floor (floor plate) and roof (roof plate) of the neural tube has few, if any, neuroblasts, and is devoid of nerve cell bodies. However, neuronal processes will be present in these regions, conveying information between the two halves of the spinal cord.

Neurons of the dorsal root ganglia arise from cells of the neural crest. These neurons are responsible for delivering information from the sensory receptor organs to the spinal cord for processing.

Histodifferentiation of neuroblasts

Neuroblasts are more or less spherical cells that differentiate to form the various classes of neurons: unipolar (pseudounipolar), bipolar, and multipolar

Neuroblasts, which begin their differentiation as relatively spherical cells, form two processes at opposite poles. Usually, one of the processes, the dendrite, begins to arborize, whereas the other process, the axon, remains unbranched. The manner in which the axon and dendrite are established and modified, permits neurons to be classified as unipolar (pseudounipolar), bipolar, and multipolar (Fig. 2.5).

Unipolar (pseudounipolar) neurons are located in sensory ganglia. The two processes of each of these cells begin to grow toward and fuse with one another, forming a single process. This unified process then divides into two processes that grow in opposing directions. One of the processes, the central process, enters the dorsal horn of the spinal cord where it may terminate or ascend to higher levels. Collections of central processes form the dorsal roots of the spinal nerve. Collections of peripheral processes join the ventral root fibers to form the spinal nerve.

Bipolar neurons retain their two processes at opposing poles of the cell body. Dendrites of these cells collect information from the periphery of the body, whereas their axons deliver information to the CNS for processing. Bipolar neurons are associated only with the olfactory epithelium, cerebral cortex, retina, cochlear nucleus, and the vestibular nucleus.

Multipolar neurons instead of having only two processes, develop several. One of these is the axon, whereas the remainder are dendrites. Collections of axons of multipolar neurons of the basal plate grow through the marginal zone to form the ventral root of the spinal cord. As mentioned above, they join with collections of peripheral processes of unipolar neurons of the dorsal root ganglia to form the spinal nerve.

Figure 2.5 The origin of the developing cells of the CNS. Note that all of the cells are derived from the original neural tube, with the notable exception of the microglial cells, which are phagocytes of the CNS and originate from mesenchymal cells. Ependymal cells will line the ventricles of the brain as well as the central canal of the spinal cord; they also participate in the formation of the choroid plexus. Glioblasts will give rise to macroglia, namely the protoplasmic and fibrous astrocytes, as well as to oligodendrocytes; these cells are supporting cells of the CNS and, in the case of oligodendroglia, form myelin sheaths of CNS neurons. Neuroblasts are responsible for the formation of the neurons of the CNS.

Further differentiation of the basal and alar plates

Neuroblasts of the basal plate differentiate into multipolar neurons, whereas those of the neural crestderived dorsal root ganglia differentiate into unipolar (pseudounipolar) neurons

As neuroblasts of the basal plate differentiate they become multipolar neurons whose axons grow not only into but through the marginal layer and pierce the external boundary of the neural tube. Collections of these axons travel together forming the ventral rootlets of the spinal cord. These ventral rootlets join others in their vicinity to form the ventral root of a spinal nerve.

At the same time, central processes of the unipolar neurons of the dorsal root ganglia pierce the external aspect of the neural tube at the dorsolateral sulcus, and enter the marginal zone or the alar plate. Central processes that enter the alar plate form synapses with the interneurons whose axons form synaptic contacts with motoneurons of the basal plate, and in this fashion form simple reflex arcs. Those that enter only the marginal layer travel to higher levels in the CNS. Many of these central processes travel en masse to reach their specific destinations. Collections of fibers going to the same destination are named accordingly.

As described above, collections of the peripheral processes of unipolar neurons join the ventral roots to form the mixed (motor and sensory) spinal nerves. Motor nerves effect muscle contraction or glandular secretion, whereas sensory nerves transmit information from outside or inside the body. Motor nerves propagate information that goes away from the CNS to a muscle (or gland) and are called efferent nerve fibers. Sensory nerves propagate information toward the CNS and are called afferent nerve fibers.

Development of modalities

A typical spinal nerve possesses all four functional components, known as modalities

Motor fibers of spinal nerves that innervate skeletal muscle are said to be general somatic efferent (GSE) fibers, whereas motor fibers that innervate smooth muscle, cardiac muscle, or glands are said to be general visceral efferent (GVE) fibers. Sensory fibers that bring information from the skin, skeletal muscle, tendons, and joints are called general somatic afferent (GSA) fibers, whereas those that bring information from the viscera (membranes, glands, and organs) are named general visceral afferent (GVA) fibers. The visceral components (GVE) belong to the autonomic nervous system (sympathetic and parasympathetic); however, GVA fibers are not autonomic fibers. A typical spinal nerve has all of these four functional components (also known as modalities). These modalities develop in specific regions along the alar and basal plates of the spinal cord, forming columns of recognizable gray matter along the length of the spinal cord, known as the GSA, GVA, GVE, and GSE columns.

It should be noted that GVE columns are present only in the thoracic, upper lumbar (L1–L3), and sacral levels (S2–S4). The regions of the GSE column responsible for motor innervation of the upper and lower extremities are quite extensive and are, therefore, divided into larger medial and smaller lateral motor columns. The medial motor columns are responsible for supplying the axial muscles, whereas the lateral columns serve the extremities. Similarly, in the alar