A rudimentary knowledge of the anatomy of the nervous system is a prerequisite to discussion of its physiology. This section provides an overview of nervous system anatomy that builds on what has already been discussed about its embryological development. We in turn consider the CNS, PNS, and ANS (see Table 10-1).
The directional terms used to describe brain structures can be somewhat confusing because the human nervous system, unlike that of lower vertebrates, bends during development. Thus, the dorsal surface of the cerebral cortex is also superior, whereas the dorsal surface of the spinal cord is also posterior (Fig. 10-10A).
FIGURE 10-10 Gross anatomy of the CNS.
The CNS consists of the telencephalon, cerebellum, diencephalon, midbrain, pons, medulla, and spinal cord
The CNS can be conveniently divided into five major areas: (1) telencephalon, (2) cerebellum, (3) diencephalon, (4) brainstem (consisting of the midbrain, pons, and medulla), and (5) spinal cord (see Fig. 10-10B). Each of these areas has symmetrical right and left sides.
One of the crowning glories of evolution is the human cerebral cortex, the most conspicuous part of the paired cerebral hemispheres. The human cerebral cortex has a surface area of ~2200 cm2 and is estimated to contain 1.5 to 2 × 1010 neurons. The number of synaptic contacts between these cells is ~3 × 1014. The cortical surface area of mammals increases massively from mouse to monkey to humans in a ratio of 1 : 100 : 1000. The capacity for information processing by this neural machine is staggering and includes a remarkable range of functions: thinking, learning, memory, and consciousness.
The cortex is topographically organized in two ways. First, certain areas of the cortex mediate specific functions. For example, the area that mediates motor control is a well-defined strip of cortex located in the frontal lobe (see Fig. 10-10C). Second, within a portion of cortex that manages a specific function (e.g., motor control, somatic sensation, hearing, or vision), the parts of the body spatially map onto this cortex in an orderly way. We discuss this principle of somatotopy on pp. 400–401.
Another part of the telencephalon is the great mass of axons that stream into and out of the cerebral cortex and connect it with other regions. The corpus callosum and smaller white matter tracts interconnect the two cerebral hemispheres. The volume of axons needed to interconnect cortical neurons increases as a power function of cortical volume, which rises so dramatically from mice to humans. Thus, the relative volume of white matter to gray matter is 5-fold greater in humans than in mice. The final parts of the telencephalon are the basal ganglia, a functionally related group of neuron clusters consisting of the striatum (caudate nucleus and putamen), globus pallidus, amygdala, and hippocampal formation. These are all paired structures. The basal ganglia have indirect connections with motor portions of the cerebral cortex and are involved in motor control. The amygdala participates in the expression of emotion, and the hippocampal formation is crucial in the formation of new memories. Indeed, injury to both hippocampal formations can cause a severe amnestic disorder.
This brain region lies immediately dorsal to the brainstem. Although the cerebellum represents only ~10% of the CNS by volume, it contains ~50% of all CNS neurons. The exceedingly large number of input connections to the cerebellum conveys information from nearly every type of receptor in the nervous system, including visual and auditory input. Combined, these afferent fibers outnumber the efferent projections by an estimated ratio of 40 : 1.
Functionally and by virtue of its connections, the cerebellum can be divided into three parts. Phylogenetically, the vestibulocerebellum (also called the archicerebellum) is the oldest of these three parts, followed by the spinocerebellum (also called the paleocerebellum) and then by the cerebrocerebellum (also called the neocerebellum).
The vestibulocerebellum is closely related to the vestibular system, whose sensors are located in the inner ear and whose way stations are located in the pons and medulla. It helps maintain the body's balance. The spinocerebellum receives strong input from muscle stretch receptors through connections in the spinal cord and brainstem. It helps regulate muscle tone. The cerebrocerebellum, the largest part of the human cerebellum, receives a massive number of projections from sensorimotor portions of the cerebral cortex through neurons in the pons. It coordinates motor behavior. Much of the cerebellum's output reaches the contralateral (i.e., on the opposite side of the body) motor cortex by way of the thalamus. Other efferent projections reach neurons in all three parts of the brainstem.
This brain region consists of the thalamus, the subthalamus, and the hypothalamus, each with a very different function. The thalamus is the main integrating station for sensory information that is bound for the cerebral cortex, where it will reach the level of conscious perception. Control of arousal and certain aspects of memory function also reside in discrete areas of the thalamus. Along with the subthalamus, the thalamus receives projections from the basal ganglia that are important for motor function. Input to the thalamus from the cerebellum (specifically, the cerebrocerebellum) is important for normal motor control. Patients with Parkinson disease, a severe movement disorder, gradually lose the ability to make voluntary movements; in some of these patients, it is possible to improve movement by stimulating certain areas of the subthalamus.
The hypothalamus is the CNS structure that most affects the ANS. It performs this function through strong, direct connections with autonomic nuclei in the brainstem and spinal cord. It also acts as part of the endocrine system in two major ways. First, specialized neurons located within specific nuclei in the hypothalamus synthesize certain hormones (e.g., arginine vasopressin and oxytocin) and transport them down their axons to the posterior pituitary gland, where the hormones are secreted into the blood. Second, other specialized neurons in other nuclei synthesize “releasing hormones” (e.g., gonadotropin-releasing hormone) and release them into a plexus of veins, called a portal system, that carries the releasing hormones to cells in the anterior pituitary. There, the releasing hormones stimulate certain cells (e.g., gonadotrophs) to secrete hormones (e.g., follicle-stimulating hormone or luteinizing hormone) into the bloodstream. We discuss these principles starting on p. 1015 in the second edition of this text. The hypothalamus also has specialized centers that play important roles in controlling body temperature (see p. 1200), hunger (see p. 1001), thirst (see pp. 845–846), and the cardiovascular system. It is the main control center of the ANS.
Brainstem (Midbrain, Pons, and Medulla)
The brainstem lies immediately above, or rostral to, the spinal cord. Like the spinal cord, the midbrain, pons, and medulla have a segmental organization, receive sensory (afferent) information, and send out motor (efferent) signals through paired nerves that are called cranial nerves. The midbrain, pons, and medulla also contain important control centers for the ANS (see Chapter 14). Not only are motor neurons, autonomic neurons, and sensory neurons present at each level, but the caudal brainstem serves as a conduit for a large volume of axons traveling from higher CNS centers to the spinal cord (descending pathways) and vice versa (ascending pathways). Additionally, this portion of the brainstem contains a loosely organized interconnected collection of neurons and fibers called the reticular formation. This neuronal network has diffuse connections with the cortex and other brain regions and affects the level of consciousness or arousal.
The midbrain has somatic motor neurons that control eye movement. These neurons reside in the nuclei for cranial nerve III (CN III) and CN IV. Other midbrain neurons are part of a system, along with the cerebellum and cortex, for motor control. The midbrain also contains groups of neurons that are involved in relaying signals related to hearing and vision.
Just caudal to the midbrain is the pons, which contains the somatic motor neurons that control mastication (nucleus for CN V), eye movement (nucleus for CN VI), and facial muscles (nucleus for CN VII). The pons also receives somatic sensory information from the face, scalp, mouth, and nose (portion of the nucleus for CN V). It is also involved in processing information that is related to hearing and equilibrium (nucleus for CN VIII). Neurons in the ventral pons receive input from the cortex, and these neurons in turn form a massive direct connection with the cerebellum (see above) that is crucial for coordinating motor movements.
The most caudal portion of the brainstem is the medulla. The organization of the medulla is most similar to that of the spinal cord. The medulla contains somatic motor neurons that innervate the muscles of the neck (nucleus of CN XI) and tongue (nucleus of CN XII). Along with the pons, the medulla is involved in controlling blood pressure, heart rate, respiration, and digestion (nuclei of CN IX and X). The medulla is the first CNS way station for information traveling from the special senses of hearing and equilibrium.
Continuous with the caudal portion of the medulla is the spinal cord. The spinal cord runs from the base of the skull to the end of the body of the first lumbar vertebra (L1). Thus, it does not run the full length of the vertebral column in adults.
The spinal cord consists of 31 segments that each have a motor and sensory nerve root. (The sensory nerve root of the first cervical segment is very small and can be missing.) These nerve roots combine to form 31 bilaterally symmetrical pairs of spinal nerves. The spinal roots, nerves, and ganglia are part of the PNS (see below).
Sensory information from the skin, muscle, and visceral organs enters the spinal cord through fascicles of axons called dorsal roots (Fig. 10-11A). The point of entry is called the dorsal root entry zone. Dorsal root axons have their cell bodies of origin in the spinal ganglia (i.e., dorsal root ganglia) associated with that spinal segment.
FIGURE 10-11 Spinal cord. A, Each spinal segment has dorsal and ventral nerve roots that carry sensory and motor nerve fibers, respectively. B, The simple “flexor” reflex arc is an illustration of the four functions of the PNS: (1) a receptor transduces a painful stimulus into an action potential, (2) a primary sensory neuron conveys the information to the CNS, (3) the CNS conveys information to the target organ via a motor neuron, and (4) the electrical signals are converted to signals at the motor end plate. C, Ascending pathways, which carry information to more rostral areas of the CNS, are shown on the left. Descending pathways, which carry information in the opposite direction, are shown on the right.
Ventral roots contain strictly efferent fibers (see Fig. 10-11B). These fibers arise from motor neurons (i.e., general somatic efferent neurons) whose cell bodies are located in the ventral (or anterior) gray horns of the spinal cord (gray because they contain mainly cell bodies without myelin) and from preganglionic autonomic neurons (i.e., general visceral efferent neurons) whose cell bodies are located in the intermediolateral gray horns (i.e., between the dorsal and ventral gray horns) of the cord. Most of the efferent fibers are somatic efferents that innervate skeletal muscle to mediate voluntary movement. The other fibers are visceral efferents that synapse with postganglionic autonomic neurons, which in turn innervate visceral smooth muscle or glandular tissue.
Each segment of the spinal cord contains groups of associative neurons in its dorsal gray horns. Some but not all incoming sensory fibers synapse on these associative neurons, which in turn contribute axons to fiber paths that both mediate synaptic interactions within the spinal cord and convey information to more rostral areas of the CNS by way of several conspicuous ascending tracts of axons (see Fig. 10-11C). Similarly, descending tracts of axons from the cerebral cortex and brainstem control the motor neurons whose cell bodies are in the ventral horn, which leads to coordinated voluntary or posture-stabilizing movements. The most important of these descending tracts is called the lateral corticospinal tract; ~90% of its cell bodies of origin are in the contralateral cerebral cortex. These ascending and descending tracts are located in the white portion of the spinal cord (white because it contains mostly myelinated axons). The spatial organization of spinal cord neurons and fiber tracts is complex but orderly and varies somewhat among the 31 segments.
If sensory fibers enter the spinal cord and synapse directly on motor neurons in that same segment, this connection underlies a simple segmental reflex or interaction. If the incoming fibers synapse with neurons in other spinal segments, they can participate in an intersegmental reflex or interaction. Finally, if the incoming signals travel rostrally to the brainstem before they synapse, they constitute a suprasegmental interaction.
The PNS comprises the cranial and spinal nerves, their associated sensory ganglia, and various sensory receptors
The PNS serves four main purposes: (1) it transduces physical or chemical stimuli both from the external environment and from within the body into raw sensory information through receptors; (2) it conveys sensory information to the CNS along axon pathways; (3) it conveys motor signals from the CNS along axon pathways to target organs, primarily skeletal and smooth muscle; and (4) it converts the motor signals to chemical signals at synapses on target tissues in the periphery. Figure 10-11B summarizes these four functions for a simple reflex arc in which a painful stimulus to the foot results in retraction of the foot from the source of the pain.
Like the CNS, the PNS can be divided into somatic and autonomic parts. The somatic division includes the sensory neurons and axons that innervate the skin, joints, and muscle as well as the motor axons that innervate skeletal muscle. The somatic division of the PNS primarily deals with the body's external environment, either to gather information about this environment or to interact with it through voluntary motor behavior. The ANS, discussed in the next section and in Chapter 14, is a functionally distinct part of both the CNS and PNS (see Table 10-1). The autonomic portion of the PNS consists of the motor and sensory axons that innervate smooth muscle, the exocrine glands, and other viscera. This division mainly deals with the body's internal environment.
Three important aspects of the PNS are discussed in other chapters. Sensory transduction is reviewed in Chapter 15, synaptic transmission in Chapters 8 and 13, and peripheral neuronal circuits in Chapter 16. Here, we focus primarily on the system of axons that is such a prominent feature of the PNS.
Axons in the PNS are organized into bundles called peripheral nerves (Fig. 10-12). These nerves contain, in a large nerve such as the sciatic nerve, tens of thousands of axons. Individual axons are surrounded by loose connective tissue called the endoneurium. Within the nerve, axons are bundled together in small groups called fascicles, each one covered by a connective tissue sheath known as the perineurium. The perineurium contributes structural stability to the nerve. Fascicles are grouped together and surrounded by a matrix of connective tissue called the epineurium. Fascicles within a nerve anastomose with neighboring fascicles. Axons shift from one fascicle to another along the length of the nerve, but they tend to remain in roughly the same general area within the nerve over long distances. The interlocking meshwork of fascicles adds further mechanical strength to the nerve. Axons range in diameter from <1 to 20 µm. Because axons are extremely fragile, adaptations that enhance mechanical stability are very important. Nervous tissue in the PNS is designed to be much tougher, physically, than that in the CNS. The PNS must be mechanically flexible, tolerant of minor physical trauma, and sustainable by a blood supply that is less dependable than the one providing for the CNS. A spinal cord transplanted to the lower part of the leg would not survive the running of a 100-m dash.
FIGURE 10-12 Peripheral nerve.
Axons in peripheral nerves are closely associated with Schwann cells. In the case of a myelinated axon, a Schwann cell forms a myelinated wrap around a single adjacent axon, a single internodal myelin segment between 250 and 1000 µm in length. Many such internodal myelin segments, and thus many Schwann cells, are necessary to myelinate the entire length of the axon. In an unmyelinated nerve, the Schwann cell surrounds but does not wrap multiple times around axons. Unmyelinated axons outnumber myelinated axons by about 2 : 1 in typical human nerves. Diseases that affect the PNS can disrupt nerve function by causing either loss of myelin or axonal injury.
The functional organization of a peripheral nerve is best illustrated by a typical thoracic spinal nerve and its branches. Every spinal nerve is formed by the dorsal and ventral roots joining together and emerging from the spinal cord at that segmental level (see Fig. 10-11). The dorsal roots coalesce and display a spindle-shaped swelling called the spinal or dorsal root ganglion, which contains the cell bodies of the sensory axons in the dorsal roots. Individual neurons are called dorsal root ganglion cells or spinal ganglion cells and are typical unipolar neurons that give rise to a single process that bifurcates in a T-like manner into a peripheral and central branch (see Fig. 10-3). The central branch carries sensory information into the CNS and the peripheral branch terminates as a sensory ending. The peripheral process, which brings information toward the cell body, meets one definition of a dendrite; however, it has all the physiological and morphological features of a peripheral axon.
Spinal nerves divide into several branches that distribute motor and sensory axons to the parts of the body associated with that segment. Axons conveying autonomic motor or autonomic sensory signals also travel in these branches. These branches are said to be “mixed” because they contain both efferent and afferent axons. Further nerve division occurs as axons travel to supply their targets, such as the skin, muscle, or blood vessels. In the case of thoracic spinal nerves, the subdivision is orderly and has a similar pattern for most of the nerves. In the cervical and lumbosacral areas, however, the spinal nerves from different segments of the spinal cord intermingle to form a nerve plexus. The subsequent course of the nerves in the upper and lower extremities is complex. The pattern of cutaneous innervation of the body is shown in Figure 10-13. The area of cutaneous innervation provided by a single dorsal root and its ganglion is called a dermatome. Severing a single dorsal root does not produce anesthesia in that dermatome because of overlap between the cutaneous innervation provided by adjacent dorsal roots. The sole exception to this rule is the C2 root, sectioning of which causes a patch of analgesia on the back of the head; neither C3 nor the trigeminal nerve innervates skin in this area. Also note that no dermatomes are shown for the first cervical and the coccygeal segments because the dermatomes are small or, in the case of the first cervical segment, may be missing.
FIGURE 10-13 Dermatomes. A dermatome is the area of cutaneous sensory innervation that a single spinal segment provides.
The ANS innervates effectors that are not under voluntary control
The nervous system regulates some physiological mechanisms in a way that is independent or autonomous of voluntary control. Control of body temperature is an example of a fundamental process that most individuals cannot consciously regulate. Other examples include blood pressure and heart rate. The absence of voluntary control means that the ANS has little cortical representation.
The ANS has three divisions: sympathetic, parasympathetic, and enteric. The sympathetic and parasympathetic divisions have both CNS and PNS parts. The enteric division lies entirely within the PNS. The parasympathetic and sympathetic efferent systems are composed of two-neuron pathways. The cell body of the first neuron is located in the CNS and that of the second in the PNS. The sympathetic and parasympathetic divisions innervate most visceral organs and have a yin-yang functional relationship. The enteric division regulates the rhythmic contraction of intestinal smooth muscle and also regulates the secretory functions of intestinal epithelial cells. It receives afferent input from the gut wall and is subject to modulation by the two other divisions of the ANS.
All the divisions have both efferent and afferent connections, although the efferent actions of the ANS are usually emphasized. We consider the ANS in detail in Chapter 14.
Peripheral Nerve Disease
The symptoms of peripheral nerve disease, or neuropathy, are numbness (i.e., a sensory deficit) and weakness (i.e., a motor deficit). Such symptoms may arise from disturbances in many parts of the nervous system. How, then, can one tell whether a problem is the result of disease in the PNS?
Motor axons directly innervate and have “trophic” effects on skeletal muscle. If the axon is cut or dies, this trophic influence is lost and the muscle undergoes denervation atrophy. In addition, individual muscle fibers may twitch spontaneously (fibrillation). The cause of fibrillation is still debated, but it may be related to the observation that acetylcholine receptors spread beyond the neuromuscular junction and become “supersensitive” to their agonist. If true, these observations imply continuing exposure to acetylcholine, even if it is in smaller quantities. Schwann cells at denervated junctions may be the source of acetylcholine. When a motor axon is first damaged but has not yet lost continuity with the muscle fibers that it innervates, these muscle cells may twitch in unison. These small twitches can be seen under the skin and are called fasciculations. They are probably due to spontaneous action potentials in dying or injured motor neurons or their axons.
When the PNS is affected by a diffuse or generalized disease (e.g., the result of a metabolic problem or toxin), all peripheral nerves are involved, but symptoms arise first in the longest nerves of the body (i.e., those traveling from the spinal cord to the feet). This predilection for affecting the longest nerves often causes a “stocking pattern” defect in sensation and sometimes in strength. If both the feet and hands are affected, the process is called a “stocking and glove” defect. With progression of the disease, the level of involvement moves centripetally (i.e., up the leg, toward the trunk), and the sensory or motor dysfunction comes to involve more proximal portions of the legs and arms. One of the most common causes of this diffuse pattern of PNS involvement is the sensorimotor polyneuropathy associated with diabetes. Other causes include chronic renal failure (uremia), thiamine deficiency (often seen with alcohol abuse), and heavy-metal poisoning.
If a patient exhibits weakness or sensory loss that is associated with muscle fibrillation and atrophy and a stocking or stocking and glove pattern of sensory disturbance, a PNS problem is likely. Patients with peripheral neuropathy may also complain of tingling sensations (paresthesias) or pain in areas of the body supplied by the diseased nerves.