All living organisms respond to chemical and physical stimuli. The response may be a movement, or it may be the expulsion of biosynthetic products from cells. These receptive, motor, and secretory functions are combined in a single cell in both unicellular organisms and the simplest multicellular animals, the sponges. In all other groups of animals, cells are able to communicate, so that the reception of a stimulus by one cell may result in motile or secretory activity of other cells. Specialized cells known as neurons or nerve cells exist to transfer information rapidly from one part of an animal's body to another. All the neurons of an organism, together with their supporting cells, constitute a nervous system.
To carry out its communicative function, a neuron exhibits two different but coupled activities. They are conduction of a signal from one part of the cell to another and synaptic transmission, which is communication between adjacent cells. An impulse, also called an action potential, is a wave of electrical depolarization that is propagated within the surface membrane of the neuron. A stimulus applied to one part of the neuron initiates an impulse that travels to all other parts of the cell. Neurons commonly have long cytoplasmic processes, known as neurites, that end in close apposition to the surfaces of other cells. The ends of the neurites are called synaptic terminals, and the cell-to-cell contacts they make are known as synapses. The neurites in higher animals usually are specialized to form dendrites and axons, which typically conduct toward and away from the cell body, respectively. Most axons are ensheathed in myelin, which is a lipid-rich material composed of tightly packed membranous layers. The arrival of an impulse at a terminal triggers synaptic transmission. This event normally involves the release of a chemical compound from the neuronal cytoplasm, which evokes some type of response in the postsynaptic cell. At some synapses, the two cells are electrically coupled. Another type of neuron exists that discharges its chemical products into the circulating blood, thereby influencing distant parts of the body. Neurons of the latter type, known as neurosecretory cells, are functionally related to endocrine gland cells.
The central nervous system (CNS) consists of the brain and spinal cord and is protected by the cranium and the vertebral column. Bundles of axons called nerves connect the CNS with
all parts of the body. Nerves are the most conspicuous components of the peripheral nervous system. The cell bodies of neurons in the CNS are in regions known as gray matter. A compact aggregation of gray matter is called a nucleus, not to be confused with the nucleus of a cell. Regions of CNS tissue that contain axons but not neuronal cell bodies are calledwhite matter. In the peripheral nervous system, neuronal cell bodies occur in nodular structures called ganglia (singular: ganglion). This word is also used (commonly but wrongly) for certain nuclei in the CNS.
Development of the Nervous System
The neurons and other cells of the nervous system develop from the dorsal ectoderm of the early embryo. The ectoderm is the layer that also becomes the epidermis, which covers the surface of the body. The first indication of the future nervous system is the neuroectoderm, consisting of the neural plate, which appears in the dorsal midline of the embryo at the 16th day after fertilization. The cells of the neural plate become taller than those of the ordinary ectoderm. This change is induced by the underlying mesodermal cells. The neural plate grows rapidly, and in 2 days, it becomes a neural groove with a neural fold along each side.
A note on times and ages. In clinical practice, pregnancy is timed from the 1st day of the last menstrual period, about 14 days before fertilization. The age of an embryo is stated from the known or estimated time of fertilization. When it is 8 weeks old and all the organs are formed, an embryo is renamed a fetus. The embryonic period is divided into 23 Carnegie stages, based on anatomical development. The neural folds appear at stage 8, when the embryo is 1.0 to 1.5 mm long.
NEURAL TUBE, CREST, AND PLACODES
By the end of the 3rd week (stage 10), the neural folds have begun to fuse with one another, thereby converting the neural groove into a neural tube (Fig. 1-1). This transformation begins in the middle (in what will eventually be the cervical segments of the spinal cord) and proceeds rostrally and caudally. The openings at each end (the rostral and caudalneuropores) close at about the 24th and 27th days, respectively (stages 11 and 12). The neural tube is the forerunner of the brain and spinal cord. The cells lining the tube constitute the neuroepithelium, which will give rise to all the neurons and most of the other cells in the CNS.
FIGURE 1-1 Dorsal view of a human embryo about 22 days after fertilization. Closure of the neural tube is in progress.
Neuroectodermal cells that are not incorporated into the tube form neural crests, which run dorsolaterally along each side of the neural tube. From the neural crests are derived the dorsal root ganglia of spinal nerves, some of the neurons in sensory ganglia of cranial nerves, autonomic ganglia, the nonneuronal cells (neuroglia) of peripheral nerves, and secretory cells of the adrenal medulla. Thus, the cells of the neural crest are notable for their extensive migrations. Many of them even differentiate into cells of nonneural tissue, including the melanocytes of the skin; the calcitonin-secreting cells of the thyroid gland; cells in the carotid and aortic bodies; odontoblasts of teeth; and some of the bones, muscles, and other structures of mesenchymal origin in the head. The connective tissue cells in nerves and ganglia are derived from the local mesoderm.
Some peripheral nervous elements are derived from placodes, which are thickened regions
of the ectoderm of the head's surface. Thus, the olfactory neurosensory cells, the sensory cells and associated ganglia of the inner ear, and some of the neurons in the sensory ganglia of cranial nerves are derived from placodes. Some cells of the olfactory placode migrate into the rostral end of the neural tube and become intrinsic neurons of the CNS.
PRODUCTION OF NEURONS AND NEUROGLIA
The first populations of cells produced in the neural tube are neurons. (The old term neuroblasts is inappropriate for these cells because after they are formed, they do not divide again.) Most of the neurons are produced between the 4th and 20th weeks. The young neurons migrate, grow cytoplasmic processes, and form synaptic connections with other neurons.
The number of neurons formed in the neural tube exceeds the number in the adult brain and spinal cord. Large numbers of neurons die in the normal course of development. This occurrence, known as cell death or apoptosis, is seen in many embryonic systems throughout the animal kingdom. In invertebrates, the cell death is genetically programmed. Experimental studies carried out by Hamburger in the 1930s showed that in vertebrates, the cells that died were those that failed to make synaptic connections. In some animals, new neurons are generated throughout life in some parts of the brain, from pluripotent precursor cells. Quantitative histochemical studies have provided no evidence of such activity in the adult human brain.
The neurons in sensory ganglia derived from the neural crest send neurites into peripheral nerves and into the neural tube. By the 8th week of intrauterine life, the centrally directed neurites have extensive synaptic connections with neurons in the spinal cord. The number and complexity of synapses continue to increase until well after birth, as does the generation of neuroglial cells.
Neuroglia, more commonly called glia, comprises the cells of the nervous system that are not neurons. The structures and functions of different glial cell types are dealt with inChapter 2.
The first glial cells, known as radial glia, develop alongside the first neurons, having cytoplasmic processes that extend from the lumen to the outside surface of the neural tube. The processes of radial glia guide the migration of the young neurons. Most astrocytes and oligodendrocytes, however, are generated from the neuroepithelium during the fetal period. Mature glial cells are visible with classical staining methods by 19 weeks, but some can be detected by immunohistochemical techniques as early as 7 weeks. Microglial cells arise from hemopoietic tissue and enter the brain and spinal cord by passing through the walls of blood vessels.
In the peripheral nervous system, neurons (in sensory and autonomic ganglia) and glial cells (satellite cells in ganglia and Schwann cells in nerves) are derived from the neural crest.
FORMATION OF THE BRAIN AND SPINAL CORD
Even before the closure of the neural folds, the neural plate is conspicuously larger at the rostral end of the embryo, and irregularities corresponding to the major divisions of the developing brain are already visible. The remainder of the neural tube becomes the spinal cord. The site of closure of the caudal neuropore corresponds to the upper lumbar segments of the cord. Further caudally, the spinal cord is formed by “secondary neurulation,” which is the coalescence of a chain of vesicles that becomes continuous with the lumen of the neural tube about 3 weeks after the closure of the caudal neuropore. The vesicles are derived from the caudal eminence, a mass of pluripotent cells located dorsal to the developing coccyx.
As described conventionally, three major divisions of the brain appear at the end of the 4th week: the prosencephalon (forebrain), mesencephalon (midbrain), andrhombencephalon (hindbrain). During the 5th week, secondary swellings develop in the prosencephalon and rhombencephalon, so that the number of major parts becomes five: thetelencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon (Fig. 1-2). The same words are used for the corresponding parts of the adult human brain. (In the chick embryo, a favorite subject
for embryological investigation, the swellings in the embryonic brain are known as “brain vesicles,” a term that should not be used in human anatomy.) The early embryonic CNS is also divisible longitudinally into smaller segments known as neuromeres. The neuromeres become
indistinguishable as the complex structure of the brain develops, but segmental organization of the spinal cord persists throughout life.
FIGURE 1-2 Major parts of the brain in human embryo at 4 weeks (above, a midline section) and fetus at 8 weeks (below, reconstucted from serial sections). Color scheme: Telencephalon (forebrain), yellow; dienchephalon, blue; mesencephalon (midbrain), orange; rhombencephalon (hindbrain, composed of medulla, pons, and cerebellum), gray. In the embryo, some neuromeres are indicated for the telencephalon (T), diencephalon (D1, D2), mesencephalon (MI, M2), isthmus (Is), and rhombencephalon (RI to R7). The levels of the optic (Op) and otic (Ot) vesicles, which are lateral to the neural tube, are indicated. (These vesicles will become the lens and inner ear, respectively.) In the fetus: Cb, cerebellum; Cx, cerebral cortex; D, diencephalon; E, eye; In, insula; M, mesencephalon; R, rhombencephalon; T, trigeminal ganglion; 5, sensory root of trigeminal nerve; 7, 8, rootlets of facial and vestibulocochlear nerves. (Modified from O'Rahilly R, Müller F. The Embryonic Human Brain. An Atlas of Developmental Stages, 3rd ed. Hoboken, NJ: Wiley-Liss, 2006.)
As cellular proliferation and differentiation proceed in the neural tube, a longitudinal groove called the sulcus limitans appears along the inner aspect of each lateral wall. The sulcus demarcates a dorsal alar plate from a ventral basal plate; they acquire afferent and efferent connections, respectively, and are present from the rostral end of the mesencephalon to the caudal end of the spinal cord. Responding to an inductive effect of the nearby notochord (which marks the position of future vertebrae), the basal plates of the left and right sides become separated by a thin floor plate. Some of the basal plate cells differentiate into motor neurons, with axons that grow out into the developing muscles. The growing axons of neurons of the sensory ganglia enter the alar plate.
FURTHER DEVELOPMENT OF THE BRAIN
As the parts of the brain differentiate and grow, some of the formal embryological names are replaced by others for common usage (Table 1-1). The myelencephalon becomes themedulla oblongata, and the metencephalon develops into the pons and cerebellum. The mesencephalon of the mature brain usually is called the midbrain. The names diencephalonand telencephalon are retained because of the diverse nature of their derivatives. A large mass of gray matter, the thalamus, develops in the diencephalon. Adjacent regions are known as the epithalamus, hypothalamus, and subthalamus, each with distinctive structural and functional characteristics. The left and right halves of the telencephalon are known as the cerebral hemispheres. These undergo the greatest development in the human brain, in respect both to other regions and to the brains of other animals. The telencephalon includes the olfactory system, the corpus striatum (a mass of gray matter with motor functions), an extensive surface layer of gray matter known as the cortex or pallium, and a medullary center of white matter.
The lumen of the neural tube becomes the ventricular system. A lateral ventricle develops in each cerebral hemisphere. The third ventricle is in the diencephalon, and the fourth ventricle is bounded by the medulla, pons, and cerebellum. The third and fourth ventricles are connected by a narrow channel, the cerebral aqueduct, through the midbrain. The lumen also remains narrow in the caudal part of the medulla and throughout the spinal cord, where it becomes the central canal.
Flexures in the neural tube help to accommodate the initially cylindrical brain in what will eventually be a round head. The first to form are the cervical flexure at the junction of the rhombencephalon with the spinal cord and the mesencephalic flexure at the level of the midbrain. The pontine flexure in the metencephalon soon follows. These flexures in the brain (Fig. 1-3) ensure that the optical axes of the eyes (which connect with the prosencephalon) are at right angles to the axis of the vertebral column. This necessary feature of the erect posture of humans contrasts with the posture of quadrupedal animals, in which there is no abrupt bend at the junction of the midbrain with the forebrain.
TABLE 1-1 Development of the Brain
Development of the Meninges
The membranous coverings of the brain and spinal cord first appear in the 4th week as a single mesodermally derived primary (or primitive) meninx. Fluid-filled spaces appear within the primary meninx 1 week later, and subsequent differentiation leads to formation of the three layers that constitute the meninges: the pia mater, closest to the nervous tissue; thearachnoid; and the dura mater, which lines the cranial cavity and spinal canal. The subarachnoid space, which contains cerebrospinal fluid (CSF), is between the inner two meningeal layers.
Summary of Main Regions of the Central Nervous System
Certain features of the main regions are now briefly reviewed, by way of introduction and to provide a first acquaintance with some neuroanatomical terms. Before proceeding to later chapters, the student should know the meanings of all the words used in the following eight paragraphs. There is a glossary at the end of the book. The major divisions of the adult brain are shown in Figure 1-4.
FIGURE 1-3 Embryonic brain at 7 weeks (stage 20) showing the three flexures in the approximate form of the letter M. The major divisions of the brain are colored: telencephalon (T), yellow; diencephalon (Di), blue; midbrain (M), orange; rhombencephalon, gray; comprising medulla (Me), pons (P), and cerebellum (Cb). (Modified from O'Rahilly R, Müller F. The Embryonic Human Brain. An Atlas of Developmental Stages, 3rd ed. Hoboken, NJ: Wiley-Liss, 2006:221.)
The spinal cord is the least differentiated component of the CNS. The segmental nature of the spinal cord is reflected in a series of paired spinal nerves, each of which is attached to the cord by a dorsal sensory root and a ventral motor root. The central gray matter, in which neuronal cell bodies are located, has a roughly H-shaped outline in transverse section.White matter, which consists of myelinated axons running longitudinally, occupies the periphery of the cord. The spinal gray matter includes neuronal connections that provide for spinal reflexes. The white matter contains axons that convey sensory data to the brain and others that conduct impulses, typically of motor significance, from the brain to the spinal cord.
The fiber tracts of the spinal cord are continued in the medulla, which also contains clusters of neurons called nuclei. The most prominent of these, the inferior olivary nuclei, send fibers to the cerebellum through the inferior cerebellar
peduncles, which attach the cerebellum to the medulla oblongata. Of the smaller nuclei, some are components of cranial nerves.
Abnormal Development of the Nervous System
ANENCEPHALY AND SPINA BIFIDA
Congenital malformations of the CNS include those that result from failure of the neural tube to close normally. Developmental failure occurs also in associated bone and skin. In anencephaly, the neural folds do not fuse at the rostral end of the developing neural tube, so that the forebrain, cranial vault, and much of the scalp are missing. The abnormal brain (the brain stem and, sometimes, the diencephalon) is exposed to the exterior. Anencephaly occurs once in about 1,000 births and is incompatible with sustained life. The equivalent condition at the caudal end of the CNS is myeloschisis (cleft spinal cord), in which there is extensive exposure of nonfunctional nervous tissue in the lumbosacral region. Sometimes these two conditions coexist in the same baby.
Myeloschisis is the severest form of spina bifida. In less severe types, the spinal cord and its adjacent connective tissue ensheathment (the leptomeninges; see Chapter 26) are intact, but the overlying mesodermal derivatives are not. In meningomyelocele, the dura mater, vertebral arches, and skin are missing, and a visible protrusion contains either the caudal part of the spinal cord or its associated nerve roots. If the neural elements remain in the vertebral canal, the lump at the surface is a meningocele, a cyst containing CSF. These types of spina bifida can be corrected surgically, but permanent paralysis or weakness of the lower limbs often persists. Spina bifida occulta is a common condition in which the dura and skin remain intact but one or more bony vertebral arches fail to develop. Usually there are no symptoms other than a dimple, a tuft of hair, or some other minor irregularity of the overlying skin.
Cerebrospinal fluid accumulates in the ventricles of the brain if its normal flow is obstructed (see Chapter 26). Nervous tissue is destroyed by the pressure, and the head can become greatly enlarged. Causes include stenosis of the cerebral aqueduct in the midbrain and the Chiari malformation, in which the medulla and part of the cerebellum are located in the upper cervical spinal canal rather than in the skull. This abnormal anatomy can obstruct the flow of CSF out of the ventricular system, resulting in internal hydrocephalus. Spina bifida is also present in many infants with Chiari malformation. Internal hydrocephalus is treated by installing an alternative pathway for drainage of the ventricular system of the brain.
The pons consists of two distinct parts. The dorsal portion or tegmentum has features shared with the rest of the brain stem. Therefore, it includes ascending and descending tracts, together with some nuclei of cranial nerves. The ventral portion or basal pons is special to this part of the brain stem. Its function is to provide for extensive connections between the cortex of a cerebral hemisphere and that of the contralateral cerebellar hemisphere. These connections contribute to maximal efficiency of motor activities. A pair of middle cerebellar peduncles attaches the cerebellum to the pons.
Similar to other parts of the brain stem, the midbrain contains ascending and descending pathways, together with nuclei for two cranial nerves. A dorsal region, the roof or tectum, is concerned principally with the visual and auditory systems. The midbrain also includes two prominent nuclei, the red nucleus and the substantia nigra, which are concerned with motor control. The cerebellum is attached to the midbrain by the superior cerebellar peduncles.
The cerebellum is especially large in the human brain. Receiving data from most of the sensory systems and the cerebral cortex, the cerebellum eventually influences motor neurons that
supply the skeletal musculature. The functions of the cerebellum are to produce changes in muscle tone in relation to equilibrium, locomotion, and posture and to coordinate the timing, force, and extent of contraction of muscles being used for skilled movements. The cerebellum operates at a subconscious level.
FIGURE 1-4 Regions of the mature central nervous system, as seen in sagittal section. (Photograph courtesy of Dr. D. G. Montemurro.)
The diencephalon forms the central core of the cerebrum. The largest component of the diencephalon, the thalamus, consists of several regions or nuclei, some of which receive data from sensory systems and project to sensory areas of the cerebral cortex. Part of the thalamus has connections with cortical areas that are concerned with complex mental processes. Other regions participate in neural circuits related to emotions, and certain thalamic nuclei are incorporated into pathways from the cerebellum and corpus striatum to motor areas of the cerebral cortex. The epithalamus includes small tracts and nuclei, together with the pineal gland, an endocrine organ. The hypothalamus has an important controlling influence over the sympathetic and parasympathetic systems, which supply internal organs, exocrine glands, and blood vessels. In addition, neurosecretory cells in the hypothalamus synthesize hormones that enter the bloodstream. Some act on the kidneys and other organs; others influence the hormonal output of the anterior lobe of the pituitary gland through a special portal system of blood vessels. Some of the neurosecretory cells in the hypothalamus and in the immediately adjacent part of the telencephalon are derived from the olfactory placode, not from the epithelium of the neural tube. These neurons contain and secrete a polypeptide known as gonadotrophin-releasing hormone (GnRH). They migrate along the terminal nerve into the forebrain. The terminal nerve is a tiny cranial nerve (sometimes given number zero) rostral to the olfactory nerves. The subthalamusincludes sensory tracts that proceed to the thalamus, axons that originate in the cerebellum and corpus striatum, and the subthalamic nucleus, which has motor functions. Theretina is a derivative of the diencephalon; therefore, the optic nerve and the visual system are intimately related to this part of the brain.
TELENCEPHALON (CEREBRAL HEMISPHERES)
The telencephalon includes the cerebral cortex, corpus striatum, and cerebral white matter. The cerebral cortex is much folded, with ridges (gyri) separated by grooves (sulci). Major sulci separate the frontal, parietal, occipital, and temporal lobes of the cerebral hemisphere, which are named after the overlying bones of the skull. Different modalities of sensation and motor functions are represented in distinct areas of the cortex, and there are also large expanses of association cortex, in which the highest levels of neural function take place, including those inherent in intellectual activity.
The corpus striatum is a large mass of gray matter with motor functions situated near the base of each hemisphere. It consists of the caudate and lentiform nuclei, which are parts of a system known as the basal ganglia, discussed in Chapters 12 and 23. The cerebral white matter (medullary center) consists of fibers that connect cortical areas of the same hemisphere, fibers that cross the midline (most are in a large commissure known as the corpus callosum) to connect cortical areas of the two hemispheres, and fibers that pass in both directions between cortex and subcortical parts of the CNS. Fibers of the last category converge to form the compact internal capsule in the region of the thalamus and corpus striatum.
Size of the Human Brain
At birth, the average brain weighs about 400 g. Further increase in size is attributable to continuing formation of synaptic connections, production of neuroglial cells, and thickening of the myelin sheaths around axons. The most rapid growth of the brain occurs in utero and during the first 20 postnatal weeks. By age 3 years, the average weight (1,200 g) of the brain is almost that of an adult, although slow growth continues until age 18 years. After age 50 years, there is a slow decline in brain size. This decrease in size does not lead to intellectual deterioration unless there is considerable atrophy caused by disease.
The weight of the mature brain varies with age and stature. The normal range in adult men is 1,100 to 1,700 g (mean, 1,360 g). The lower figures for adult women (1,050-1,550 g; mean, 1,275 g) are mainly attributable to the smaller stature of women compared with men. There is no evidence of a relation between brain weight, within normal limits, and a person's level of intelligence.
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