Certain aspects of the peripheral nervous system are especially pertinent to a study of the brain and spinal cord. These include the sensory receptors, motor endings, histology of peripheral nerves, and structure of ganglia. The following introductory comments refer to all spinal nerves and to the cranial nerves that are not restricted to the special senses. The structures discussed in this chapter are shown in Figure 3-1, which represents a spinal nerve in the thoracic or upper lumbar region in which neurons for visceral innervation are included.
General sensory endings are scattered profusely throughout the body. They are biological transducers, in which physical or chemical stimuli create action potentials in nerve endings. The resulting nerve impulses, on reaching the central nervous system (CNS), produce reflex responses, awareness of the stimuli, or both. Sensory endings that are superficially located, such as those in the skin, are called exteroceptors; they respond to stimuli for pain, temperature, touch, and pressure. Proprioceptors in muscles, tendons, and joints provide data for reflex adjustments of muscle action and for awareness of position and movement.
Components of Nerves, Roots, and Ganglia
Signals from exteroceptors and proprioceptors are conducted centrally by primary sensory neurons, whose cell bodies are located in
dorsal root ganglia (or in an equivalent cranial nerve ganglion). On entering the spinal cord, the dorsal root fibers divide into ascending and descending branches; these are distributed as necessary for reflex responses (of which some are considered in Chapter 5) and for transmission of sensory data to the brain (pathways are reviewed in Chapter 19).
FIGURE 3-1 Functional components of a “typical” spinal nerve, in this case between levels T1 and L2. Color scheme: Red for somatic motor neurons; blue for primary sensory neurons; green for preganglionic autonomic (sympathetic) neurons; and black for interneurons in the spinal cord and for postganglionic sympathetic neurons.
There is a third class of sensory endings, known as interoceptors, in the viscera. Central conduction occurs through primary sensory neurons like those already noted, except that the peripheral process follows a different route. For a receptor concerned with pain, the sensory axon reaches the sympathetic trunk through a white communicating ramus and continues to a viscus in a branch of the sympathetic trunk. For receptors concerned with the functional regulation of internal organs, some sensory axons may follow similar courses, but the best understood of these “physiological afferent” axons have their cell bodies in cranial nerve ganglia and are connected centrally with the brain stem. There are, therefore, two broad categories of sensory endings and afferent neurons: somatic afferents, for the skin, bones, muscles, and connective tissue that makes up most of the mass of the body (soma), and visceral afferents, for the internal organs of the circulatory, respiratory, alimentary, excretory, and reproductive systems.
There are also two categories of efferent neurons. The cell bodies of somatic efferent neurons (also called motor neurons) are in the ventral gray horns of the spinal cord and motor nuclei of cranial nerves. The axons of ventral horn cells traverse the ventral roots and spinal nerves and terminate in motor end plates on skeletal muscle fibers. The visceral efferent or autonomic system has a special feature, in that at least two neurons participate in transmission from the CNS to smooth muscle, cardiac muscle, or secretory cells (Fig. 3-2).
The sensory endings are supplied by axons that differ in size and other characteristics. This is a matter of some interest because there is a correlation between fiber diameter and the rate of conduction
of the action potential and because functionally different sensory endings are supplied by fibers of specific sizes. A commonly used nomenclature for peripheral nerve fibers, using Roman and Greek letters, is given in Table 2-1. This table includes the functions associated with the categories.
FIGURE 3-2 Comparison of autonomic with somatic innervation.
CUTANEOUS SENSORY ENDINGS
On a structural basis, two classes of cutaneous and other sensory endings are recognized. Nonencapsulated endings are terminal branches of the axon that may either be closely applied to cells or lie freely in the extracellular spaces of connective tissue. Encapsulated endings have distinctive arrangements of nonneuronal cells that completely enclose the terminal parts of the axons. In the following account, the receptors are described according to location, with exteroceptors and some proprioceptors shown in Figures 3-3 and 3-4, respectively.
Most of the skin bears hairs that vary greatly in length, thickness, and abundance from one part of the body to another. Glabrous skin, which lacks hairs, is present on the palmar surfaces of the hands and fingers, the soles, and parts of the face and external genitalia. Hairy and glabrous skin have different patterns of innervation.
HISTOLOGY OF CUTANEOUS INNERVATION
Cutaneous branches of spinal and cranial nerves pass through the subcutaneous connective tissue into the dermis, where the axons spread out horizontally to form three plexuses, which lie in the plane of the skin's surface. The subcutaneous plexus lies in the loose connective tissue deep to the skin, the dermal plexus is within the densely collagenous reticular layer that constitutes the deeper part of the dermis, and the papillary plexus lies in the papillary layer of the dermis, immediately beneath the epidermis. The axons of each plexus send branches into the adjacent tissues. The density of cutaneous innervation varies considerably from one region to another. For example, the
face and hands are more richly innervated than is the dorsal aspect of the trunk.
FIGURE 3-3 Sensory innervation of skin. (A) Plexuses. (B) Peritrichial ending. (C) Merkel ending in epidermis. (D) Pacinian corpuscle. (E) End bulb. (F) Meissner's corpuscle. (G)Ruffini ending.
Free nerve endings occur in the subcutaneous tissue and dermis, and some extend among the cells of the epidermis. They are the terminal branches of group C fibers and the unmyelinated terminal branches of group A fibers, and they are receptive to all modalities of cutaneous sensation. Although they are called “free endings,” these axons are always invested with Schwann cells (the neuroglia of peripheral nerves) and do not contact the extracellular fluid directly. Indeed, it is impossible to identify the exact point of termination of an axon within the skin. The existence of free nerve endings is inferred from the functional sensitivity of regions of skin in which no other types of sensory ending can be recognized.
Merkel endings are found in the germinal layer (stratum basale) of the epidermis. Axonal branches end as flattened expansions, each being closely applied to a Merkel cell. This small cell differs from the other epidermal cells in having an indented nucleus and electron-dense cytoplasmic granules. Merkel cells are found in glabrous skin and in the outer root sheaths of hairs.
Peritrichial nerve endings are cagelike formations of axons that surround hair follicles. A single axon sends branches to many hair follicles, and each follicle is supplied by from 2 to 20 axons. The axons approach the follicle deep to its sebaceous gland and branch in the connective tissue outside the outer root sheath. Some branches encircle the follicle, others run parallel to its long axis, and some end on Merkel cells in the outer root sheath.
Skin contains several types of encapsulated ending. The Ruffini ending, typically about 1 mm long and 20 to 30 µm wide, is an array of terminal branches of a myelinated axon surrounded by capsular cells. The pacinian corpuscle (or Vater-Pacini corpuscle) consists of a single axon that loses its myelin sheath and is encapsulated by several layers of flattened cells with greatly attenuated cytoplasm. These ellipsoidal corpuscles are about 1 mm long and 0.7 mm wide. Ruffini endings and pacinian corpuscles are present in the subcutaneous tissue and dermis of both hairy and glabrous skin. Meissner's tactile corpuscles occur in large numbers in the dermal papillary ridges of the fingertips and are less abundant in other hairless regions. Each Meissner's corpuscle is supplied by three or four myelinated axons whose terminal branches form a complicated knot that is enclosed in a cellular and collagenous capsule. Meissner's corpuscles are about 80 µm by 30 µm in size and are oriented with their long axes perpendicular to the skin's surface. End bulbs vary in size and shape, and several types have been described (e.g., end bulbs of Krause, Golgi-Mazzoni endings, genital corpuscles, mucocutaneous endings), although all may be variants of the same structure. They are commonly spherical, about 50 µm in length, with each containing a coiled, branching axonal terminal in a thin cellular capsule. Most end bulbs occur in mucous membranes (mouth, conjunctiva, anal canal) and in the dermis of glabrous skin close to orifices (lips, external genitalia).
The types of sensation consciously perceived from the skin are called modalities. The different sensations are not always clear cut, but in medical practice, it is customary to recognize five modalities that are easily tested by clinical examination. These are fine (discriminative) touch, vibration, light touch, temperature (warmth or cold), and pain. Sensations of each modality also have quality. For example, pain may have an aching or a burning quality; temperature has quality that varies continuously, from painfully cold to painfully hot. The central pathways that process these sensations are fairly well known (see Chapter 19), but for other modalities (e.g., itch, tickle, rub, firm pressure), they are only poorly understood. Careful testing has revealed that the human skin is a mosaic of spots, each of which responds selectively to only one of the four elementary sensations of touch, warmth, cold, and pain. The response of any one of these spots is always the same, whatever the nature of the stimulus. For example, a feeling of coldness will be experienced from a “cold spot” even if it is heated or injured. The sensitivity is greatest (or in physiologists' parlance, the threshold is lowest) for the specific modality.
Attempts to correlate the modalities of sensation in humans with morphologically identified nerve endings have yielded inconclusive results.
Electrophysiological studies in animals, however, have shown that although no cutaneous receptors have absolute specificity, there is a high degree of selectivity for certain end organs.
An important physiological property of any receptor is adaptation, which is a reduced response to continued stimulation. A slowly adapting receptor reports continuously on the stimulus that activates it. A rapidly adapting receptor reports changes in the stimuli it receives. Meissner's corpuscles are sensitive to mechanical deformation, and they adapt rapidly (i.e., they do not continue to respond to a sustained deformation). These properties, associated with alignment in papillary ridges, allow an array of these receptors to identify with great accuracy the positions and movements of objects touching or moving across the surface of the skin. Thus, Meissner's corpuscles are the sense organs used when feeling the texture of a surface with the tips of the fingers. Merkel endings also respond preferentially to tactile stimuli but are much more slowly adapting than Meissner's corpuscles, so they respond to steady indentation of the surface of the skin. Their sensitivity to this stimulus is enhanced by their location in the epidermis. Pacinian corpuscles also initiate action potentials when they are deformed; they are the most rapidly adapting receptors, so they have a special sensitivity to vibration. The rapid adaptation is attributed to the fluid between the many layers of the corpuscle; a sustained deformation causes a change of shape without mechanically disturbing the axon in the center. The Ruffini ending responds to mechanical stimuli that pull on the collagen fibers attached to its capsule, when pressure on or stretching of the skin causes movement in the subcutaneous tissue. Peritrichial endings respond to mechanical displacement of the hair shaft, so that hair follicles serve as receptor organs for light touch. The various end bulbs are poorly understood but are presumed to respond to tactile stimuli.
For the modalities of warmth and cold (all skin) and touch (hairy skin that does not contain encapsulated endings), it is presumed that the receptors must be free nerve endings derived from the dermal and papillary plexuses. The physiological characteristics of some of these receptors have been ascertained from electrical recordings made from individual axons in peripheral nerves in animals and humans. The receptors for tactile sensation are low threshold mechanoceptors, a category that includes all encapsulated and some free nerve endings.
Painful sensations are received by free nerve endings, termed nociceptors. Three types are recognized. High threshold mechanoreceptors respond only to mechanical stimuli such as stretching or cutting. Polymodal nociceptors respond to both mechanical and thermal (≥45°C) stimuli and to chemical mediators released from injured cells. The third type of nociceptor responds only to chemical mediators and may contribute to the hyperalgesia (lowered pain threshold) associated with inflammation.
SENSORY ENDINGS IN MUSCLES, TENDONS, AND JOINTS
Proprioceptors in the capsules of joints, muscles, and tendons furnish the CNS with information required for the performance of properly coordinated movements through reflex action. In addition, proprioceptive information reaches consciousness so that there is awareness of the position of body parts and of their movements (kinesthetic sense or conscious proprioception). Pain that arises in muscles, tendons, ligaments, and bones is probably detected by free nerve endings in connective tissue. These nociceptive endings respond to physical injury and to local chemical changes such as those caused by inflammation or ischemia.
The proprioceptive organs in skeletal muscles are the neuromuscular spindles, often simply called muscle spindles. They are innervated by both sensory and motor neurons.
Neuromuscular spindles are a fraction of a millimeter wide and up to 6 mm long. They lie in the long axis of the muscle, and their collagenous capsules are continuous with the fibrous septae that separate the muscle fibers. The fibrous septa are in mechanical continuity with the skeletal attachments of the muscle so that the spindles are lengthened whenever a muscle is passively stretched. Spindles are typically located near the tendinous insertions of muscles and are especially numerous in muscles that perform highly skilled movements, such as those of the hand.
FIGURE 3-4 Specialized sensory endings in skeletal muscle and tendon. Sensory axons are shown in shades of blue, fusimotor axons in red, muscle fibers in yellow, and connective tissue in black and gray. (A) A Golgi tendon organ. (B) Neuromuscular spindle in transverse section. (C) Innervation of a muscle spindle.
Each spindle (see Fig. 3-4) consists of a capsule of connective tissue, with two to 14 intrafusal muscle fibers. The latter differ in several respects from the main or extrafusal fibers of the muscle. Intrafusal fibers are considerably smaller than the extrafusal; the equatorial region lacks cross striations and contains many nuclei that are not in the subsarcolemmal position characteristic of mature striated muscle.
A muscle spindle is supplied by two sensory axons. One of these is an Aα or Ia fiber (see Table 2-1); the axon loses its myelin sheath as it pierces the capsule, and then it winds spirally around the midportions of the intrafusal muscle fibers in the form of an annulospiral ending. The second, slightly smaller sensory fiber (Aβ or II) branches terminally and ends as varicosities on the intrafusal muscle fibers some distance from the midregion. The latter terminals are called flower spray endings. The annulospiral and flower spray terminals are also known, respectively, as the primary and secondary sensory endings of the spindle.
The extrafusal fibers composing the main mass of a muscle are innervated by large motor cells (alpha motor neurons), whose axons are of Aα size. Smaller motor cells (gamma motor neurons), with Aγ axons, supply the intrafusal muscle fibers within the spindle.
The simplest role of the muscle spindle is that of a receptor for the stretch reflex. Slight stretching of a muscle lengthens the intrafusal fibers, and the sensory endings are stimulated. Action potentials are conducted to the spinal cord, where terminal branches of the sensory axons synapse with alpha motor neurons that supply the main mass of the muscle. The latter thereupon contracts in response to stretch through a two-neuron reflex arc. Stimulation of
the spindles ceases when the muscle contracts because the spindle fibers, in parallel with the other muscle fibers, return to their original lengths. The stretch reflex is in constant use in the adjustment of muscle tone. It also forms the basis of tests for tendon reflexes, such as the knee jerk (extension at the knee on tapping the patellar tendon), which are standard items in clinical examinations.
The spindles also have an important role in muscle action that results from the activity of the brain. The motor fibers that descend from the brain into the spinal cord influence both alpha and gamma motor neurons in the ventral gray horns by synapsing with them directly and through the mediation of interneurons. Contraction of the intrafusal muscle fibers in response to stimulation by gamma motor neurons lengthens the midportions and starts a volley of impulses in the sensory axons. This causes contraction of the regular muscle fibers through reflex stimulation of alpha motor neurons. The gamma reflex loop consists of the gamma motor neuron, muscle spindle, sensory neuron, and alpha motor neuron supplying extrafusal muscle fibers. It is an adjunct to the more direct control of muscles by descending fibers from the brain that control the alpha motor neuron. Activation of the gamma reflex loop can set the length of a muscle before the initiation of a movement.
Golgi tendon organs, also known as neurotendinous spindles, are most numerous near the attachments of tendons to muscles. Each receptor has a thin capsule of connective tissue that encloses a few collagenous fibers of the tendon. The axon of an Aβ or Ib fiber (there may be more than one) breaks up into unmyelinated terminal branches after entering the spindle, and the branches end as varicosities on the intrafusal tendon fibers. This type of sensory ending is stimulated by tension in the tendon, in contrast to the muscle spindle, which responds to changes in the length of the region containing sensory nerve endings. Afferent signals from Golgi tendon organs reach interneurons in the spinal cord, which, in turn, have an inhibitory effect on alpha motor neurons, causing relaxation of the muscle to which the particular tendon is attached. The different functions of the neuromuscular and neurotendinous spindles are in balance in the total integration of spinal reflex activity. As constant monitors of tension, the Golgi tendon organs also provide protection against damage that might result from an excessively strong muscular contraction.
Around the capsules of synovial joints, there are small pacinian corpuscles and formations similar to Ruffini cutaneous endings. They respond, respectively, to the cessation and initiation of movement. Receptors identical to Golgi tendon organs are present in the articular ligaments; they mediate reflex inhibition of muscles when excessive strain is placed on the joint. Free nerve endings are abundant in the synovial membrane, capsule, and periarticular connective tissues. They are believed to respond to potentially injurious mechanical stresses and to mediate the pain that arises in diseased or injured joints.
The various types of proprioceptors provides essential information for neuromuscular control at the subconscious level, including reflexes that involve the spinal cord, brain stem, cerebellum, and cerebral cortex. The roles of specific receptors in conscious proprioception (kinesthesia) are still debated. Observations made with human subjects indicate that the nerves from both joints and muscles carry signals that are consciously perceived as position and movement. Infiltration of a small joint with local anesthetic does not impair these sensations, but damage to major ligaments of a large joint, such as the knee, is followed by diminished position sense. The muscle spindles are considered to be the principal kinesthetic receptors.
SENSORY ENDINGS IN VISCERA
Except for pacinian corpuscles, most of which are in mesenteries, the sensory endings in viscera consist mainly of nonencapsulated terminal branches of axons, some of which are quite complicated. In general, visceral afferents function in physiological visceral reflexes; in the sensations of fullness of the stomach, rectum, and bladder; and in pain caused by visceral
dysfunction or disease. Afferent fibers for pain generally travel in different nerves from those involved in functional control and have different connections in the CNS (see Chapter 24).
The nervous system acts on muscle fibers and secretory cells. Control of these nonneural cells is effected by a mechanism similar to that of chemical synaptic transmission between neurons (see Chapter 2). At the neuroeffector endings, axons terminate in relation to skeletal, cardiac, and smooth muscle fibers and to the cells of exocrine and endocrine glands. Many endocrine organs are controlled, directly or indirectly, by hypothalamic neurosecretory neurons that discharge their products into blood vessels for subsequent delivery to the target cells.
MOTOR END PLATES
The motor end plates, or myoneural junctions, on extrafusal and intrafusal fibers of skeletal striated muscles are synaptic structures with two components: the ending of a motor axon and the subjacent part of the muscle fiber. The axon of an alpha motor neuron divides terminally to supply variable numbers of muscle fibers. A motor unit consists of one motor neuron and the muscle fibers that it innervates. The number of muscle fibers in a motor unit varies from fewer than 10 to several hundred, depending on the size and function of the muscle. Small muscles, such as the extraocular and intrinsic hand muscles, must contract with greater precision, so their motor units include only a few muscle fibers. Large motor units occur in the muscles of the trunk and proximal parts of the limbs; they are necessary for sudden and powerful movements, with many muscle fibers contracting simultaneously.
FIGURE 3-5 Motor end plates. (Gold chloride technique, X800; courtesy of Drs. R. Mitchell and A. S. Wilson.)
Each branch of the motor nerve fiber gives up its myelin sheath on approaching a muscle fiber and ends as several branchlets that constitute the neural component of the end plate (Fig. 3-5). The end plate is typically 40 to 60 µm in diameter and is usually located midway along the length of the muscle fiber. The neurolemmal sheath (consisting of the nucleated cytoplasmic parts of Schwann cells) continues around the terminal branches of the motor axon but does not intervene between the nerve ending and the muscle fiber. The nerve fiber is surrounded outside the neurolemma by a thin sheath of endoneurial connective tissue, which blends at the motor end plates with the endomysium (the connective tissue that ensheaths each muscle fiber).
The axonal endings within the end plates contain mitochondria and synaptic vesicles. The latter contain acetylcholine, which is the neurotransmitter in motor end plates. Each axonal branchlet occupies a groove or “synaptic gutter” on the surface of the muscle fiber. The intervening synaptic cleft is 20 to 50 nm wide. The plasma membrane and associated basement membrane, which together constitute the sarcolemma of the muscle fiber, have a wavy outline where they appose the nerve terminal, with the irregularities known as junctional folds. This folded region of the sarcolemma, the subneural
apparatus, is demonstrable histochemically by its content of acetylcholinesterase, the enzyme that inactivates acetylcholine.
Acetylcholine, which is released from the synaptic vesicles when action potentials travel along the axon, binds to acetylcholine receptor molecules in the folded sarcolemma of the subneural apparatus. An adequate train of impulses releases enough acetylcholine to depolarize the postsynaptic membrane, and the resulting action potential is carried into the muscle fiber (by invaginations of the sarcolemma that constitute the transverse tubular system) to the contractile myofibrils.
POSTGANGLIONIC AUTONOMIC ENDINGS
The presynaptic effector nerve endings on smooth muscle, cardiac muscle, and secretory cells are swellings, usually called varicosities, along the courses and at the tips of unmyelinated axons. These swellings contain accumulations of mitochondria and clusters of synaptic vesicles. The terminals are applied to the effector cells, sometimes as closely as they are in skeletal muscle, but there are no obvious postsynaptic structural specializations. Whereas noradrenergic terminals of the sympathetic nervous system contain electron-dense synaptic vesicles, cholinergic terminals (typically parasympathetic) contain small electron-lucent vesicles. Other types of synaptic vesicles are also seen frequently, and immunohistochemical studies indicate that most autonomic nerve endings contain one or more peptides in addition to the two classical neurotransmitters.
An autoimmune disease is one in which there is production of antibodies that bind to cells or proteins that are normal components of the person's own body. In myasthenia gravis, such antibodies combine with the acetylcholine receptors at motor end plates, thereby blocking the normal action of acetylcholine. In many cases, the antibody-producing cells are derived from a benign tumor of the thymus. All skeletal muscles become weak and easily fatigued, so the first signs of the disease appear in constantly used muscles, such as those that move the eyes and eyelids and those of respiration. Symptomatic relief is provided by drugs that inhibit acetylcholinesterase, allowing higher concentrations of the transmitter to accumulate in the synaptic cleft. Treatments that suppress the immune system (e.g., removal of the thymus, use of corticosteroids and other drugs) are also valuable in the management of patients with myasthenia gravis.
Spinal ganglia are swellings on the dorsal roots of spinal nerves, located in the intervertebral foramina, just proximal to the union of dorsal and ventral roots. Spinal ganglia contain the cell bodies of primary sensory neurons, mainly in a large peripheral zone. The center of the ganglion is occupied by the proximal parts of the neurites. Dorsal root ganglia and ganglia of cranial nerves involved with general sensation have the same histological structure.
The neurons in sensory ganglia are at first bipolar, but the two neurites soon unite to form a single process. (The term pseudounipolar is often applied to the sensory ganglion cell, but this is a truly unipolar neuron after the two processes of the bipolar embryonic cell have fused.) The neurite divides into peripheral and central branches; the former terminates in a sensory ending, and the latter enters the spinal cord through a dorsal root. Action potentials pass directly from the peripheral to the central branch, bypassing the cell body. Both branches have the structural and electrophysiological characteristics of axons.
The spherical cell bodies in a sensory ganglion vary from 20 to 100 µm in diameter; their processes are similarly of graded size, ranging from small unmyelinated fibers in group C to the largest myelinated fibers in group A (see Table 2-1). The large neurons are for proprioception and discriminative touch; those of intermediate size are concerned with light touch, pressure, pain, and temperature; the smallest neurons transmit impulses for pain and temperature.
Each cell body is closely invested by a layer of satellite cells that is continuous with the Schwann cell sheath that surrounds the axon. External to this, the neurons are supported by connective tissue that contains collagen fibers and blood vessels.
Autonomic ganglia include those of the sympathetic trunks along the sides of the vertebral bodies, collateral or prevertebral ganglia in plexuses of the thorax and abdomen (e.g., the cardiac, celiac, and mesenteric plexuses), and certain ganglia near viscera. The principal cells of autonomic ganglia are multipolar neurons 20 to 45 µm in diameter. The cell body is surrounded by satellite cells similar to those of spinal ganglia. Several dendrites extend and branch outside the capsule of satellite cells and receive synaptic contacts from preganglionic axons. The thin, unmyelinated axons (group C fibers) of the principal cells leave the ganglia and eventually supply smooth muscle and gland cells in some viscera, cardiac muscle, the enteric plexuses, blood vessels throughout the body, and sweat glands and arrector pili muscles in the skin. Autonomic ganglia also contain small interneuronswith short dendrites that are postsynaptic to the preganglionic axons and presynaptic to dendrites of principal cells.
ARRANGEMENT AND ENSHEATHMENT OF NERVE FIBERS
The constituent fibers of all but the smallest peripheral nerves are arranged in bundles or fascicles, and three connective tissue sheaths are recognized (Fig. 3-6). The entire nerve is surrounded by the epineurium. This is composed of ordinary connective tissue, and it also fills the spaces between the fascicles. Undulations in the epineurial collagen fibers around each fascicle allow for stretching of the nerve that accompanies flexion of joints and other movement. A nerve root within the vertebral canal does not have an epineurium; this ensheathing layer is acquired as the nerve pierces the dura mater on its way through an intervertebral foramen. (The dura mater is the outermost of the three meninges; these layers of connective tissue that envelop the brain and spinal cord are described in Chapter 26.)
A common disorder involving spinal or cranial nerve ganglia is herpes zoster (or shingles), in which a viral infection of the ganglion causes pain and other sensory disturbances and a skin eruption in the area of distribution of the affected dorsal root or cranial nerve. The cutaneous inflammation is caused partly by spontaneous antidromic conduction of impulses in the group C fibers of the nerve. These release from their terminals peptides, including substance P (SP) and calcitonin gene-related peptide (CGRP). SP and CGRP dilate small arteries and make small veins permeable, causing exudation of plasma.
The sheath that encloses each small bundle of fibers in a nerve consists of several layers of flattened cells, collectively known as the perineurium. Within the perineurium, individual nerve fibers have a delicate covering of connective tissue that constitutes the endoneurium, or sheath of Henle. The cells of all three connective tissue layers of peripheral nerves are derived from mesodermal cells rather than from the neuroectoderm. Within the endoneurium, the axons are intimately ensheathed by neuroglial cells (Schwann cells), which are derived from the neural crest and constitute the neurolemma (also spelled neurilemma) or sheath of Schwann.
MYELINATED NERVE FIBERS
A nerve fiber consists of the axon, the myelin sheath (of fibers in groups A and B), and the neurolemma (sheath of Schwann). The axon is no different from a long axon in the CNS. Its cytoplasm (axoplasm) contains neurofilaments, microtubules, patches of smooth-surfaced endoplasmic reticulum, and mitochondria. The plasma membrane of an axon is called
the axolemma. The neurolemma and the myelin sheath are components of Schwann cells. The ultrastructure of myelin and its mode of formation from the Schwann cell membrane are described and illustrated in Chapter 2. The neurolemma consists of the cytoplasm of the Schwann cell, outside the myelin sheath. Most of the cytoplasm is in the region of the ellipsoidal nucleus, but traces of cytoplasm and the plasma membrane closely surround the myelin sheath.
FIGURE 3-6 The connective tissue sheaths in a transversely sectioned nerve. This is a biopsy of human sural nerve. Fat cells are black (from treatment with osmium tetroxide), and other structures are blue, from staining of the thin resin-embedded section with alkaline toluidine blue. (Courtesy of Dr. William McDonald.)
The myelin sheath is interrupted at intervals by nodes of Ranvier. The distance between nodes varies from 100 µm to about 1 mm, depending on the length and thickness of the fiber, and there is one Schwann cell for each internode. Funnel-shaped clefts in myelin sheaths, the incisures of Schmidt-Lanterman, can be seen by light microscopy in longitudinal sections of nerves. In electron micrographs, these incisures are shown to be zones in which there are spaces between the layers, with occasional retention of Schwann cell cytoplasm between the membranes. This may aid the passage of materials through the myelin sheath to the axon.
The myelin sheath electrically insulates the internodal parts of the axon. At each node, however, the cytoplasmic portions of the adjoining Schwann cells have irregular edges, and there is a narrow space between the two cells through which the axolemma at the node is in contact with extracellular fluid (see Fig. 2-7E). Voltage-gated sodium channels are present in the axolemma only at nodes. This arrangement allows action potentials to skip electrically (instantaneously) from node to node. This rapid transmission of action potentials along a myelinated fiber is called saltatory conduction (from the Latin saltare, to jump). The most rapidly conducting myelinated fibers in a nerve are those with the largest diameters and the longest internodes.
Nerves contain many axons that do not have myelin sheaths. A single Schwann cell envelops several (up to 15) such axons, as shown in Figure 2-7F. The cell and its included axons constitute a Remak fiber. Each axon is surrounded by a single layer of the glial cell's plasma membrane. It is, therefore, unmyelinated, and there are no nodes of Ranvier. The nerve impulse is a self-propagating action potential along the axolemma, without the accelerating factor of node-to-node
or saltatory conduction. This accounts for the slow rate of conduction that is characteristic of unmyelinated (group C) axons.
Peripheral Nerve Diseases and Injuries
Peripheral neuropathy is a common cause of sensory loss and motor weakness. Loss of myelin is a typical feature of affected nerves. Distal parts of nerves are affected first, with symptoms in the hands and feet. There are many causes of peripheral neuropathy, including autoimmunity, nutritional deficiencies, toxic substances of various kinds (including ethanol), and metabolic disorders (notably, diabetes mellitus).
Nerve injuries may or may not cause transection of axons, with resulting loss of function. There may be failure of conduction in axons that have been injured but not transected. Patients with this condition, known as neurapraxia, usually recover quite quickly, but sometimes neurapraxia is permanent for unknown reasons. As explained in Chapter 2, severed axons regenerate vigorously in the peripheral nervous system, but many are misdirected to inappropriate places. Damage to a nerve by a penetrating wound may be followed by an incapacitating disorder known as causalgia. Severe pain is present in the affected limb, together with changes in skin texture. The symptoms of causalgia may be attributable, at least in part, to the formation in the injured nerve of abnormal excitatory contacts between sympathetic and sensory axons. The pain can often be relieved by surgical removal of the sympathetic ganglia that supply the affected skin.
If the proximal stump of a transected nerve is not connected to a distal stump, the axons go on regenerating and, with associated glial cells, form a neuroma in which there are many abnormal contacts between the surfaces of axons and other cells. The neuroma may account for painful sensations that are perceived as coming from an amputated limb, known as phantom limb pain. Phantom limb sensations also include feelings of size, position, and movement. They are experienced not only by amputees but also by about one third of people born without one of their limbs. Genetically determined circuitry in the CNS may, therefore, provide for conscious awareness of a map of the parts of the body that normally exist.
A nerve may be pressed on where it passes over a bony prominence or through a restricted aperture; for example, the ulnar nerve is subject to pressure at the elbow, and the median nerve can be squeezed in the carpal tunnel at the wrist. The resulting entrapment syndrome includes motor and sensory disturbances in the area of distribution of the nerve. The major plexuses, especially the brachial plexus, may be compressed (as in crutch palsy). Nerve roots are more fragile than nerves because they lack an epineurium. They may be irritated or compressed by inflamed meninges, by abnormally protruding parts of intervertebral disks (spondylosis), or by bony irregularities (spinal osteoarthritis). Clinical manifestations of nerve root lesions include weakness and wasting of muscles as well as pain in the affected cutaneous areas. The distribution of axons from segmental sensory nerve roots to the skin is discussed in association with the spinal cord inChapter 5.
The thinnest unmyelinated axons are those of the olfactory nerves. Here, each mesaxon envelops a bundle consisting of many unmyelinated axons. A somewhat similar arrangement exists in the enteric nervous system, which consists of ganglia and nerves in the wall of the alimentary canal and its associated organs. Olfactory ensheathing cells and enteric glial cells differ from the Schwann cells of ordinary nerves, and they contain some chemical components that are otherwise characteristic of astrocytes of the CNS (see Chapter 2).
Arroyo EJ, Scherer SS. On the molecular architecture of myelinated fibers. Histochem Cell Biol 2000;113:1-18.
Bunge MB, Wood PM, Tynan LB, et al. Perineurium originates from fibroblasts: demonstration in vitro with a retroviral marker. Science 1989;243:229-231.
Ferrell WR, Gandevia SC, McCloskey DI. The role of joint receptors in human kinesthesia when intramuscular receptors cannot contribute. J Physiol (Lond) 1987;386:63-71.
Fu SY, Gordon T. The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 1997;14:67-116.
Halata Z, Grim M, Christ B. Origin of spinal cord meninges, sheaths of peripheral nerves, and cutaneous receptors including Merkel cells: an experimental study with avian chimeras. Anat Embryol 1990;182:529-537.
Houk JC. Reflex control of muscle. In: Adelman A, ed. Encyclopedia of Neuroscience, vol 2. Boston: Birkhauser, 1987:1030-1031.
Iggo A, Andres KH. Morphology of cutaneous receptors. Annu Rev Neurosci 1982;5:1-31.
Janig W. Causalgia and reflex sympathetic dystrophy: in which way is the sympathetic nervous system involved? Trends Neurosci 1985;8:471-477.
Luff SE. Ultrastructure of sympathetic axons and their structural relationship with vascular smooth muscle. Anat Embryol 1996;193:515-531.
Matthews PBC. Where does Sherrington's muscular sense originate? Annu Rev Neurosci 1982;5:189-218.
Melzack R, Israel R, Lacroix R, et al. Phantom limbs in people with congenital limb deficiency or amputation in early childhood. Brain 1997;120:1603-1620.
Risling M, Dalsgaard C-J, Cukierman A, et al. Electron microscopic and immunohistochemical evidence that unmyelinated ventral root axons make U-turns or enter the spinal pia mater. J Comp Neurol 1984;225:53-63.
Schott GD. Mechanisms of causalgia and related clinical conditions: the role of the central and of the sympathetic nervous systems. Brain 1986;109:717-738.
Stolinski C. Structure and composition of the outer connective tissue sheaths of peripheral nerve. J Anat 1995;186:123-130.
Sunderland S. Nerves and Nerve Injuries, 2nd ed. Edinburgh: Churchill-Livingstone, 1978.
Swash M, Fox KP. Muscle spindle innervation in man. J Anat 1972;112:61-80.
Terenghi G. Peripheral nerve regeneration and neurotrophic factors. J Anat 1999;194:1-14.
Valeriani M, Restuccia D, Dilazzaro V, et al. Central nervous system modifications in patients with lesion of the anterior cruciate ligament of the knee. Brain 1996;119:1751-1762.
Winkelmann RK. Cutaneous sensory nerves. Semin Dermatol 1988;17:236-268.