nervous system, human

nervous system, human

Introduction

      system that conducts stimuli from sensory receptors to the brain and spinal cord and that conducts impulses back to other parts of the body. As with other higher vertebrates, the human nervous system has two main parts: the central nervous system (the brain and spinal cord) and the peripheral nervous system (the nerves that carry impulses to and from the central nervous system). In humans the brain is especially large and well developed.

Prenatal and postnatal development of the human nervous system
      Almost all nerve cells, or neurons (neuron), are generated during prenatal life, and in most cases they are not replaced by new neurons thereafter. Morphologically, the nervous system first appears about 18 days after conception, with the genesis of a neural plate. Functionally, it appears with the first sign of a reflex activity during the second prenatal month, when stimulation by touch of the upper lip evokes a withdrawal response of the head. Many reflexes of the head, trunk, and extremities can be elicited in the third month.

      During its development the nervous system undergoes remarkable changes to attain its complex organization. In order to produce the estimated 1 trillion neurons present in the mature brain, an average of 2.5 million neurons must be generated per minute during the entire prenatal life. This includes the formation of neuronal circuits comprising 100 trillion synapses (synapse), as each potential neuron is ultimately connected with either a selected set of other neurons or specific targets such as sensory endings. Moreover, synaptic connections with other neurons are made at precise locations on the cell membranes of target neurons. The totality of these events is not thought to be the exclusive product of the genetic code, for there are simply not enough genes to account for such complexity. Rather, the differentiation and subsequent development of embryonic cells into mature neurons and glial cells are achieved by two sets of influences: (1) specific subsets of genes (gene) and (2) environmental stimuli from within and outside the embryo. Genetic influences are critical to the development of the nervous system in ordered and temporally timed sequences. Cell differentiation, for example, depends on a series of signals that regulate transcription, the process in which deoxyribonucleic acid ( DNA) molecules give rise to ribonucleic acid ( RNA) molecules, which in turn express the genetic messages that control cellular activity. Environmental influences derived from the embryo itself include cellular signals that consist of diffusible molecular factors (see below Neuronal development (nervous system, human)). External environmental factors include nutrition, sensory experience, social interaction, and even learning. All of these are essential for the proper differentiation of individual neurons and for fine-tuning the details of synaptic connections. Thus, the nervous system requires continuous stimulation over an entire lifetime in order to sustain functional activity.

Neuronal development
 In the second week of prenatal life, the rapidly growing blastocyst (the bundle of cells into which a fertilized ovum divides) flattens into what is called the embryonic disk. The embryonic disk soon acquires three layers: the ectoderm (outer layer), mesoderm (middle layer), and endoderm (inner layer). Within the mesoderm grows the notochord, an axial rod that serves as a temporary backbone. Both the mesoderm and notochord release a chemical that instructs and induces adjacent undifferentiated ectoderm cells to thicken along what will become the dorsal midline of the body, forming the neural plate. The neural plate is composed of neural precursor cells, known as neuroepithelial cells, which develop into the neural tube (see below Morphological development (nervous system, human)). Neuroepithelial cells then commence to divide, diversify, and give rise to immature neurons and neuroglia, which in turn migrate from the neural tube to their final location. Each neuron forms dendrites and an axon; axons elongate and form branches, the terminals of which form synaptic connections with a select set of target neurons or muscle fibres.

      The remarkable events of this early development involve an orderly migration of billions of neurons (neuron), the growth of their axons (many of which extend widely throughout the brain), and the formation of thousands of synapses (synapse) between individual axons and their target neurons. The migration and growth of neurons are dependent, at least in part, on chemical and physical influences. The growing tips of axons (called growth cones) apparently recognize and respond to various molecular signals, which guide axons and nerve branches to their appropriate targets and eliminate those that try to synapse with inappropriate targets. Once a synaptic connection has been established, a target cell releases a trophic factor (e.g., nerve growth factor) that is essential for the survival of the neuron synapsing with it. Physical guidance cues are involved in contact guidance, or the migration of immature neurons along a scaffold of glial fibres.

      In some regions of the developing nervous system, synaptic contacts are not initially precise or stable and are followed later by an ordered reorganization, including the elimination of many cells and synapses. The instability of some synaptic connections persists until a so-called critical period is reached, prior to which environmental influences have a significant role in the proper differentiation of neurons and in fine-tuning many synaptic connections. Following the critical period, synaptic connections become stable and are unlikely to be altered by environmental influences. This suggests that certain skills and sensory activities can be influenced during development (including postnatal life), and for some intellectual skills this adaptability presumably persists into adulthood and late life.

Morphological development
 By 18 days after fertilization, the ectoderm of the embryonic disk thickens along what will become the dorsal midline of the body, forming the neural plate and, slightly later, the primordial eye, ear, and nose. The neural plate elongates, and its lateral edges rise and unite in the midline to form the neural tube, which will develop into the central nervous system. The neural tube detaches from the skin ectoderm and sinks beneath the surface. At this stage, groupings of ectodermal cells, called neural crests (neural crest), develop as a column on each side of the neural tube. The cephalic (head) portion of the neural tube differentiates into the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain), and the caudal portion becomes the spinal cord. The neural crests develop into most of the elements (e.g., ganglia and nerves) of the peripheral nervous system. This stage is reached at the end of the first embryonic month.

      The cells of the central nervous system originate from the ventricular zone of the neural tube—that is, the layer of neuroepithelial cells lining the central cavity of the tube. These cells differentiate and proliferate into neuroblasts, which are the precursors of neurons, and glioblasts, from which neuroglia develop. With a few exceptions, the neuroblasts, glioblasts, and their derived cells do not divide and multiply once they have migrated from the ventricular zone into the gray and white matter of the nervous system. Most neurons are generated before birth, although not all are fully differentiated. (One exception is the neurons of the olfactory nerve, which are generated continuously throughout life.) This effectively implies that an individual is born with a full complement of nerve cells.

      By mid-fetal life the slender primordial brain of the neural-tube stage differentiates into a globular-shaped brain. Although fully mature size and shape are not obtained until puberty, the main outlines of the brain are recognizable by the end of the third fetal month. This early development is the product of several factors: the formation of three flexures (cephalic, pontine, and cervical); the differential enlargement of various regions, especially the cerebrum and the cerebellum; the massive growth of the cerebral hemispheres over the sides of the midbrain and of the cerebellum at the hindbrain; and the formations of convolutions (sulci and gyri) in the cerebral cortex and folia of the cerebellar cortex. The central and calcarine sulci are discernible by the fifth fetal month, and all major gyri and sulci are normally present by the seventh month. Many minor sulci and gyri appear after birth.

Postnatal changes
      The postnatal growth (growth) of the human brain is rapid and massive, especially during the first two years. By two years after birth, the size of the brain and the proportion of its parts are basically those of an adult. The typical brain of a full-term infant weighs 350 grams (12 ounces) at birth, 1,000 grams at the end of the first year, about 1,300 grams at puberty, and about 1,500 grams at adulthood. This increase is attributable mainly to the growth of preexisting neurons, new glial cells, and the myelination of axons. The trebling of weight during the first year (a growth rate unique to humans) may be an adaptation that is essential to the survival of humans as a species with a large brain. Birth occurs at a developmental stage when the infant is not so helpless as to be unable to survive, yet is small enough to be delivered out of the maternal pelvis. If the brain was much larger (enough, say, to support intelligent behaviour), normal delivery would not be possible.

      Between the ages of 20 and 75, it is estimated that an average of 50,000 neurons atrophy or die each day. In a healthy person, this loss is roughly equal to 10 percent of the original neuronal complement. By the age of 75, the weight of the brain is reduced from its maximum at maturity by about one-tenth, the flow of blood through the brain by almost one-fifth, and the number of functional taste buds by about two-thirds. A loss of neurons does not necessarily imply a comparable loss of function; however, some loss may be compensated for by the formation from viable neurons of new branches of nerve fibres and by the formation of new synapses.

Charles R. Noback

Anatomy of the human nervous system

The central nervous system
 The central nervous system consists of the brain and spinal cord, both derived from the embryonic neural tube. Both are surrounded by protective membranes called the meninges, and both float in a crystal-clear cerebrospinal fluid. The brain is encased in a bony vault, the neurocranium, while the cylindrical and elongated spinal cord lies in the vertebral canal, which is formed by successive vertebrae (vertebral column) connected by dense ligaments.

The brain
 The brain weighs about 1,500 grams (3 pounds) and constitutes about 2 percent of total body weight. It consists of three major divisions: (1) the massive paired hemispheres of the cerebrum, (2) the brainstem, consisting of the thalamus, hypothalamus, epithalamus, subthalamus, midbrain, pons, and medulla oblongata, and (3) the cerebellum.

      The cerebrum, derived from the telencephalon, is the largest, uppermost portion of the brain. It is involved with sensory integration, control of voluntary movement, and higher intellectual functions, such as speech and abstract thought. The outer layer of the duplicate cerebral hemispheres is composed of a convoluted (wrinkled) outer layer of gray matter, called the cerebral cortex. Beneath the cerebral cortex is an inner core of white matter, which is composed of myelinated commissural nerve fibres connecting the cerebral hemispheres via the corpus callosum, and association fibres connecting different regions of a single hemisphere. Myelinated fibres projecting to and from the cerebral cortex form a concentrated fan-shaped band, known as the internal capsule. The internal capsule consists of an anterior limb and a larger posterior limb and is abruptly curved, with the apex directed toward the centre of the brain; the junction is called the genu. The cerebrum also contains groups of subcortical neuronal masses known as basal ganglia.

      The cerebral hemispheres are partially separated from each other by a deep groove called the longitudinal fissure. At the base of the longitudinal fissure lies a thick band of white matter called the corpus callosum. The corpus callosum provides a communication link between corresponding regions of the cerebral hemispheres.

      Each cerebral hemisphere supplies motor function to the opposite, or contralateral, side of the body from which it receives sensory input. In other words, the left hemisphere controls the right half of the body, and vice versa. Each hemisphere also receives impulses conveying the senses of touch (touch reception) and vision, largely from the contralateral half of the body, while auditory (hearing) input comes from both sides. Pathways conveying the senses of smell and taste to the cerebral cortex are ipsilateral (that is, they do not cross to the opposite hemisphere).

      In spite of this arrangement, the cerebral hemispheres are not functionally equal. In each individual, one hemisphere is dominant. The dominant hemisphere controls language, mathematical and analytical functions, and handedness. The nondominant hemisphere controls simple spatial concepts, recognition of faces, some auditory aspects, and emotion. (For further discussion of cerebral dominance, see below Functions of the human nervous system: Higher cerebral functions (nervous system, human).)

Lobes of the cerebral cortex
 The cerebral cortex is highly convoluted; the crest of a single convolution is known as a gyrus, and the fissure between two gyri is known as a sulcus. Sulci and gyri form a more or less constant pattern, on the basis of which the surface of each cerebral hemisphere is commonly divided into four lobes: (1) frontal, (2) parietal, (3) temporal, and (4) occipital. Two major sulci located on the lateral, or side, surface of each hemisphere distinguish these lobes. The central sulcus, or fissure of Rolando, separates the frontal and parietal lobes, and the deeper lateral sulcus, or fissure of Sylvius, forms the boundary between the temporal lobe and the frontal and parietal lobes.

 The frontal lobe, the largest of the cerebral lobes, lies rostral to the central sulcus (that is, toward the nose from the sulcus). One important structure in the frontal lobe is the precentral gyrus, which constitutes the primary motor region of the brain. When parts of the gyrus are electrically stimulated in concious patients (under local anesthesia), they produce localized movements on the opposite side of the body that are interpreted by the patients as voluntary. Injury to parts of the precentral gyrus results in paralysis on the contralateral half of the body. Parts of the inferior frontal lobe (close to the lateral sulcus) constitute the Broca area, a region involved with speech (see below Functions of the human nervous system: Language (nervous system, human)).

      The parietal lobe, posterior to the central sulcus, is divided into three parts: (1) the postcentral gyrus, (2) the superior parietal lobule, and (3) the inferior parietal lobule. The postcentral gyrus receives sensory input from the contralateral half of the body. The sequential representation is the same as in the primary motor area, with sensations from the head being represented in inferior parts of the gyrus and impulses from the lower extremities being represented in superior portions. The superior parietal lobule, located caudal to (that is, below and behind) the postcentral gyrus, lies above the intraparietal sulcus. This lobule is regarded as an association cortex, an area that is not involved in either sensory or motor processing, although part of the superior parietal lobule may be concerned with motor function. The inferior parietal lobule (composed of the angular and supramarginal gyri) is a cortical region involved with the integration of multiple sensory signals.

      In both the parietal and frontal lobes, each primary sensory or motor area is close to, or surrounded by, a smaller secondary area. The primary sensory area receives input only from the thalamus, while the secondary sensory area receives input from the thalamus, the primary sensory area, or both. The motor areas receive input from the thalamus as well as the sensory areas of the cerebral cortex.

      The temporal lobe, inferior to the lateral sulcus, fills the middle fossa, or hollow area, of the skull. The outer surface of the temporal lobe is an association area made up of the superior, middle, and inferior temporal gyri. Near the margin of the lateral sulcus, two transverse temporal gyri constitute the primary auditory area of the brain. The sensation of hearing is represented here in a tonotopic fashion—that is, with different frequencies represented on different parts of the area. The transverse gyri are surrounded by a less finely tuned secondary auditory area. A medial, or inner, protrusion near the ventral surface of the temporal lobe, known as the uncus, constitutes a large part of the primary olfactory area.

      The occipital lobe lies caudal to the parieto-occipital sulcus, which joins the calcarine sulcus in a Y-shaped formation. Cortex on both banks of the calcarine sulcus constitutes the primary visual area, which receives input from the contralateral visual field via the optic radiation. The visual field is represented near the calcarine sulcus in a retinotopic fashion—that is, with upper quadrants of the visual field laid out along the inferior bank of the sulcus and lower quadrants of the visual field represented on the upper bank. Central vision is represented mostly caudally and peripheral vision rostrally.

      Not visible from the surface of the cerebrum is the insular, or central, lobe, an invaginated triangular area on the medial surface of the lateral sulcus; it can be seen in the intact brain only by separating the frontal and parietal lobes from the temporal lobe. The insular lobe is thought to be involved in sensory and motor visceral functions as well as taste perception.

      The limbic lobe is a synthetic lobe located on the medial margin (or limbus) of the hemisphere. Composed of adjacent portions of the frontal, parietal, and temporal lobes that surround the corpus callosum, the limbic lobe is involved with autonomic and related somatic behavioral activities. The limbic lobe receives input from thalamic nuclei that are connected with parts of the hypothalamus and with the hippocampal formation, a primitive cortical structure within the inferior horn of the lateral ventricle.

Cerebral ventricles
 Deep within the white matter of the cerebral hemispheres are cavities filled with cerebrospinal fluid that form the ventricular system. These cavities include a pair of C-shaped lateral ventricles with anterior, inferior, and posterior “horns” protruding into the frontal, temporal, and occipital lobes, respectively. Most of the cerebrospinal fluid is produced in the ventricles, and about 70 percent of it is secreted by the choroid plexus, a collection of blood vessels in the walls of the lateral ventricles. The fluid drains via interventricular foramina, or openings, into a slitlike third ventricle, which, situated along the midline of the brain, separates the symmetrical halves of the thalamus and hypothalamus. From there the fluid passes through the cerebral aqueduct in the midbrain and into the fourth ventricle in the hindbrain. Openings in the fourth ventricle permit cerebrospinal fluid to enter subarachnoid spaces surrounding both the brain and the spinal cord.

Basal ganglia
      Deep within the cerebral hemispheres, large gray masses of nerve cells, called nuclei, form components of the basal ganglia. Four basal ganglia can be distinguished: (1) the caudate nucleus, (2) the putamen, (3) the globus pallidus, and (4) the amygdala. Phylogenetically, the amygdala is the oldest of the basal ganglia and is often referred to as the archistriatum; the globus pallidus is known as the paleostriatum, and the caudate nucleus and putamen are together known as the neostriatum, or simply striatum. Together, the putamen and the adjacent globus pallidus are referred to as the lentiform nucleus, while the caudate nucleus, putamen, and globus pallidus form the corpus striatum.

      The caudate nucleus and the putamen are continuous rostrally and ventrally, and they have similar cellular compositions, cytochemical features, and functions but slightly different connections. The putamen lies deep within the cortex of the insular lobe, while the caudate nucleus has a C-shaped configuration that parallels the lateral ventricle. The head of the caudate nucleus protrudes into the anterior horn of the lateral ventricle, the body lies above and lateral to the thalamus, and the tail is in the roof of the inferior horn of the lateral ventricle. The tail of the caudate nucleus ends in relationship to the amygdaloid nuclear complex, which lies in the temporal lobe beneath the cortex of the uncus.

      There are an enormous number of neurons within the caudate nucleus and putamen; they are of two basic types: spiny and aspiny. Spiny striatal neurons are medium-size cells with radiating dendrites that are studded with spines. Axons (axon) of these cells project beyond the boundaries of the caudate nucleus and putamen. All nerves providing input to the caudate nucleus and the putamen terminate upon the dendritic spines of spiny striatal neurons, and all output is via axons of the same neurons. Chemically, spiny striatal neurons are heterogeneous; that is, most contain more than one neurotransmitter. Gamma-aminobutyric acid (GABA) is the primary neurotransmitter contained in spiny striatal neurons. Other neurotransmitters found in spiny striatal neurons include substance P and enkephalin.

      Aspiny striatal neurons have smooth dendrites and short axons confined to the caudate nucleus or putamen. Small aspiny striatal neurons secrete GABA, neuropeptide Y, somatostatin, or some combination of these. The largest aspiny neurons are evenly distributed neurons that also secrete neurotransmitters and are important in maintaining the balance of dopamine and GABA.

      Because the caudate nucleus and putamen receive varied and diverse inputs from multiple sources that utilize different neurotransmitters, they are regarded as the receptive component of the corpus striatum. Most input originates from regions of the cerebral cortex, with the connecting corticostriate fibres containing the excitatory neurotransmitter glutamate. In addition, afferent fibres originating from a large nucleus located in the midbrain called the substantia nigra or from intralaminar thalamic nuclei project to the caudate nucleus or the putamen. Neurons in the substantia nigra are known to synthesize dopamine, but the neurotransmitter secreted by thalamostriate neurons has not been identified. All striatal afferent systems terminate in patchy areas called strisomes; areas not receiving terminals are called the matrix. Spiny striatal neurons containing GABA, substance P, and enkephalin project in a specific pattern onto the globus pallidus and the substantia nigra.

      The globus pallidus, consisting of two cytologically similar wedge-shaped segments, the lateral and the medial, lies between the putamen and the internal capsule. Striatopallidal fibres from the caudate nucleus and putamen converge on the globus pallidus like spokes of a wheel. Both segments of the pallidum receive GABAergic terminals, but in addition the medial segment receives substance P fibres, and the lateral segment receives enkephalinergic projections. The output of the entire corpus striatum (i.e., the caudate nucleus, putamen, and globus pallidus together) arises from GABAergic cells in the medial pallidal segment and in the substantia nigra, both of which receive fibres from the striatum. GABAergic cells in the medial pallidal segment and the substantia nigra project to different nuclei in the thalamus; these in turn influence distinct regions of the cerebral cortex involved with motor function. The lateral segment of the globus pallidus, on the other hand, projects almost exclusively to the subthalamic nucleus, from which it receives reciprocal input. No part of the corpus striatum projects fibres to spinal levels.

      Pathological processes involving the corpus striatum and related nuclei are associated with a variety of specific diseases characterized by abnormal involuntary movements (collectively referred to as dyskinesia) and significant alterations of muscle tone. Parkinson disease (parkinsonism) and Huntington disease are among the more prevalent syndromes; each appears related to deficiencies in the synthesis of particular neurotransmitters.

      The amygdala, located ventral to the corpus striatum in medial parts of the temporal lobe, is an almond-shaped nucleus underlying the uncus. Although it receives olfactory inputs, the amygdala plays no role in olfactory perception. This nucleus also has reciprocal connections with the hypothalamus, the basal forebrain, and regions of the cerebral cortex. It plays important roles in visceral, endocrine, and cognitive functions related to motivational behaviour.

 The brainstem is made up of all the unpaired structures that connect the cerebrum with the spinal cord. Most rostral in the brainstem are structures often collectively referred to as the diencephalon. These structures are the epithalamus, the thalamus, the hypothalamus, and the subthalamus. Directly beneath the diencephalon is the midbrain, or mesencephalon, and beneath the midbrain are the pons and medulla oblongata, often referred to as the hindbrain.

      The epithalamus is represented mainly by the pineal gland, which lies in the midline posterior and dorsal to the third ventricle. This gland synthesizes melatonin and enzymes sensitive to daylight. Rhythmic changes in the activity of the pineal gland in response to daylight suggest that the gland serves as a biological clock.

 The thalamus has long been regarded as the key to understanding the organization of the central nervous system. It is involved in the relay and distribution of most, but not all, sensory and motor signals to specific regions of the cerebral cortex. Sensory signals generated in all types of receptors are projected via complex pathways to specific relay nuclei in the thalamus, where they are segregated and systematically organized. The relay nuclei in turn supply the primary and secondary sensory areas of the cerebral cortex. Sensory input to thalamic nuclei is contralateral for the sensory, or somesthetic, and visual systems, bilateral and contralateral for the auditory system, and ipsilateral for the gustatory and olfactory systems.

      The sensory relay nuclei of the thalamus, collectively known as the ventrobasal complex, receive input from the medial lemniscus (originating in the medulla oblongata), from spinothalamic tracts, and from the trigeminal nerve. Fibres within these ascending tracts that terminate in the central core of the ventrobasal complex receive input from deep sensory receptors, while fibres projecting onto the outer shell receive input from cutaneous receptors. This segregation of deep and superficial sensation is preserved in projections of the ventrobasal complex to the primary sensory area of the cerebral cortex.

      The metathalamus is composed of the medial and lateral geniculate bodies, or nuclei. Fibres of the optic nerve end in the lateral geniculate body, which consists of six cellular laminae, or layers, folded into a horseshoe configuration. Each lamina represents a complete map of the contralateral visual hemifield. Cells in all layers of the lateral geniculate body project via optic radiation to the visual areas of the cerebral cortex. The medial geniculate body receives auditory impulses from the inferior colliculus of the midbrain and relays them to the auditory areas of the temporal lobe. Only the ventral nucleus of the medial geniculate body is laminated and tonotopically organized; this part projects to the primary auditory area and is finely tuned. Other subdivisions of the medial geniculate body project to the belt of secondary auditory cortex surrounding the primary area.

      Most output from the cerebellum projects to specific thalamic relay nuclei in a pattern similar to that for sensory input. The thalamic relay nuclei in turn provide input to the primary motor area of the frontal lobe. This system appears to provide coordinating and controlling influences that result in the appropriate force, sequence, and direction of voluntary motor activities. Output from the corpus striatum, on the other hand, is relayed by thalamic nuclei that have access to the supplementary and premotor areas. The supplementary motor area, located on the medial aspect of the hemisphere, exerts modifying influences upon the primary motor area and appears to be involved in programming skilled motor sequences. The premotor area, rostral to the primary motor area, plays a role in sensorially guided movements.

      Other major thalamic nuclei include the anterior nuclear group, the mediodorsal nucleus, and the pulvinar. The anterior nuclear group receives input from the hypothalamus and projects upon parts of the limbic lobe (i.e., the cingulate gyrus). The mediodorsal nucleus, part of the medial nuclear group, has reciprocal connections with large parts of the frontal lobe rostral to the motor areas. The pulvinar is a posterior nuclear complex that, along with the mediodorsal nucleus, has projections to association areas of the cortex.

      Output ascending from the reticular formation of the brainstem is relayed to the cerebral cortex by intralaminar thalamic nuclei, which are located in laminae separating the medial and ventrolateral thalamic nuclei. This ascending system is involved with arousal mechanisms, maintaining alertness, and directing attention to sensory events.

      The hypothalamus lies below the thalamus in the walls and floor of the third ventricle. It is divided into medial and lateral groups by a curved bundle of axons called the fornix, which originate in the hippocampal formation and project to the mammillary body. The hypothalamus controls major endocrine functions by secreting hormones (i.e., oxytocin and vasopressin) that induce smooth muscle contractions of the reproductive (reproductive system, human), digestive (digestive system, human), and excretory systems; other neurosecretory (neurosecretory cell) neurons convey hormone-releasing factors (e.g., growth hormone, corticosteroids, thyrotropic hormone, and gonadotropic hormone) via a vascular portal system to the adenohypophysis, a portion of the pituitary gland. Specific regions of the hypothalamus are also involved with the control of sympathetic and parasympathetic activities, temperature regulation, food intake, the reproductive cycle, and emotional expression and behaviour (see below Functions of the human nervous system: Emotion and behaviour (nervous system, human)).

Subthalamus
      The subthalamus is represented mainly by the subthalamic nucleus, a lens-shaped structure lying behind and to the sides of the hypothalamus and on the dorsal surface of the internal capsule. The subthalamic region is traversed by fibres related to the globus pallidus. Discrete lesions of the subthalmic nucleus produce hemiballismus, a violent form of dyskinesia in which the limbs are involuntarily flung about.

      The midbrain (mesencephalon) contains the nuclear complex of the oculomotor nerve as well as the trochlear nucleus; these cranial nerves (cranial nerve) innervate muscles that move the eye (eye, human) and control the shape of the lens and the diameter of the pupil. In addition, between the midbrain reticular formation (known here as the tegmentum) and the crus cerebri is a large pigmented nucleus called the substantia nigra. The substantia nigra consists of two parts, the pars reticulata and the pars compacta. Cells of the pars compacta contain the dark pigment melanin; these cells synthesize dopamine and project to either the caudate nucleus or the putamen. By inhibiting the action of large aspiny striatal neurons in the caudate nucleus and the putamen (described above in the section Basal ganglia (nervous system, human)), the dopaminergic cells of the pars compacta influence the output of the neurotransmitter GABA from spiny striatal neurons. The spiny neurons in turn project to the cells of the pars reticulata, which, by projecting fibres to the thalamus, are part of the output system of the corpus striatum.

      At the caudal midbrain, crossed fibres of the superior cerebellar peduncle (the major output system of the cerebellum) surround and partially terminate in a large centrally located structure known as the red nucleus. Most crossed ascending fibres of this bundle project to thalamic nuclei, which have access to the primary motor cortex. A smaller number of fibres synapse on large cells in caudal regions of the red nucleus; these give rise to the crossed fibres of the rubrospinal tract (see the section The spinal cord: Descending spinal tracts (nervous system, human)). The roof plate of the midbrain is formed by two paired rounded swellings, the superior and inferior colliculi. The superior colliculus receives input from the retina and the visual cortex and participates in a variety of visual reflexes, particularly the tracking of objects in the contralateral visual field. The inferior colliculus receives both crossed and uncrossed auditory fibres and projects upon the medial geniculate body, the auditory relay nucleus of the thalamus.

      The pons (metencephalon) consists of two parts: the tegmentum, a phylogenetically older part that contains the reticular formation, and the pontine nuclei, a larger part composed of masses of neurons that lie among large bundles of longitudinal and transverse nerve fibres.

      Fibres originating from neurons in the cerebral cortex (cerebrum) terminate upon the pontine nuclei, which in turn project to the opposite hemisphere of the cerebellum. These massive crossed fibres, called crus cerebri, form the middle cerebellar peduncle and serve as the bridge that connects each cerebral hemisphere with the opposite half of the cerebellum. The fibres originating from the cerebral cortex constitute the corticopontine tract.

      The reticular formation (an inner core of gray matter found in the midbrain, pons, and medulla oblongata) of the pontine tegmentum contains multiple cell groups that influence motor function. It also contains the nuclei of several cranial nerves. The facial nerve and the two components of the vestibulocochlear nerve, for example, emerge from and enter the brainstem at the junction of the pons, medulla, and cerebellum. In addition, motor nuclei of the trigeminal nerve lie in the upper pons. Long ascending and descending tracts that connect the brain to the spinal cord are located on the periphery of the pons.

      The medulla oblongata (myelencephalon), the most caudal segment of the brainstem, appears as a conical expansion of the spinal cord. The roof plate of both the pons and the medulla is formed by the cerebellum and a membrane containing a cellular layer called the choroid plexus, located in the fourth ventricle. cerebrospinal fluid entering the fourth ventricle from the cerebral aqueduct passes into the cisterna magna, a subarachnoid space surrounding the medulla and the cerebellum, via openings in the lateral recesses in the midline of the ventricle.

      At the transition of the medulla to the spinal cord, there are two major decussations, or crossings, of nerve fibres. The corticospinal decussation is the site at which 90 percent of the fibres of the medullary pyramids cross and enter the dorsolateral funiculus of the spinal cord. Signals conveyed by this tract provide the basis for voluntary motor function on the opposite side of the body (see the section The spinal cord: Descending spinal tracts (nervous system, human)). In the other decussation, two groups of ascending sensory fibres in the fasciculus gracilis and the fasciculus cuneatus of the spinal cord terminate upon large nuclear masses on the dorsal surface of the medulla. Known as the nuclei gracilis and cuneatus, these masses give rise to fibres that decussate above the corticospinal tract and form a major ascending sensory pathway known as the medial lemniscus that is present in all brainstem levels. The medial lemniscus projects upon the sensory relay nuclei of the thalamus.

      The medulla contains nuclei associated with the hypoglossal, accessory, vagus, and glossopharyngeal cranial nerves (cranial nerve). In addition, it contains portions of the vestibular nuclear complex, parts of the trigeminal nuclear complex involved with pain and thermal sense, and solitary nuclei related to the vagus, glossopharyngeal, and facial nerves (facial nerve) that subserve the sense of taste.

 The cerebellum (“little brain”) overlies the posterior aspect of the pons and medulla oblongata and fills the greater part of the posterior fossa of the skull. This distinctive part of the brain is derived from the rhombic lips, thickenings along the margins of the embryonic hindbrain. It consists of two paired lateral lobes, or hemispheres, and a midline portion known as the vermis. The cerebellar cortex appears very different from the cerebral cortex in that it consists of small leaflike laminae called folia. The cerebellum consists of a surface cortex of gray matter and a core of white matter containing four paired intrinsic (i.e., deep) nuclei: the dentate, globose, emboliform, and fastigial. Three paired fibre bundles—the superior, middle, and inferior peduncles—connect the cerebellum with the midbrain, pons, and medulla, respectively.

      On an embryological basis the cerebellum is divided into three parts: (1) the archicerebellum, related primarily to the vestibular system, (2) the paleocerebellum, or anterior lobe, involved with control of muscle tone, and (3) the neocerebellum, known as the posterior lobe. Receiving input from the cerebral hemispheres via the middle cerebellar peduncle, the neocerebellum is the part most concerned with coordination of voluntary motor function.

      The three layers of the cerebellar cortex are an outer synaptic layer (also called the molecular layer), an intermediate discharge layer (the Purkinje layer), and an inner receptive layer (the granular layer). Sensory input from all sorts of receptors is conveyed to specific regions of the receptive layer, which consists of enormous numbers of small nerve cells (hence the name granular) that project axons (axon) into the synaptic layer. There the axons excite the dendrites of the Purkinje cells, which in turn project axons to portions of the four intrinsic nuclei and upon dorsal portions of the lateral vestibular nucleus. Because most Purkinje cells are GABAergic and therefore exert strong inhibitory influences upon the cells that receive their terminals, all sensory input into the cerebellum results in inhibitory impulses' being exerted upon the deep cerebellar nuclei and parts of the vestibular nucleus. Cells of all deep cerebellar nuclei, on the other hand, are excitatory (secreting the neurotransmitter glutamate) and project upon parts of the thalamus, red nucleus, vestibular nuclei, and reticular formation.

      The cerebellum thus functions as a kind of computer, providing a quick and clear response to sensory signals. It plays no role in sensory perception, but it exerts profound influences upon equilibrium, muscle tone, and the coordination of voluntary motor function. Because the input and output pathways both cross, a lesion of a lateral part of the cerebellum will have an ipsilateral effect on coordination.

 The spinal cord is an elongated cylindrical structure, about 45 cm (18 inches) long, that extends from the medulla oblongata to a level between the first and second lumbar vertebrae of the backbone. The terminal part of the spinal cord is called the conus medullaris. The spinal cord is composed of long tracts of myelinated nerve fibres (known as white matter) arranged around the periphery of a symmetrical butterfly-shaped cellular matrix of gray matter. The gray matter contains cell bodies, unmyelinated motor neuron fibres, and interneurons connecting either the two sides of the cord or the dorsal and ventral ganglia (ganglion). Many interneurons have short axons (axon) distributed locally, but some have axons that extend for several spinal segments. Some interneurons may modulate or change the character of signals, while others play key roles in transmission and in patterned reflexes. The gray matter forms three pairs of horns throughout most of the spinal cord: (1) the dorsal horns, composed of sensory neurons, (2) the lateral horns, well defined in thoracic segments and composed of visceral neurons, and (3) the ventral horns, composed of motor neurons. The white matter forming the ascending and descending spinal tracts is grouped in three paired funiculi, or sectors: the dorsal or posterior funiculi, lying between the dorsal horns; the lateral funiculi, lying on each side of the spinal cord between the dorsal-root entry zones and the emergence of the ventral nerve roots; and the ventral funiculi, lying between the ventral median sulcus and each ventral-root zone.

      Associated with local regions of the spinal cord and imposing on it an external segmentation are 31 pairs of spinal nerves (spinal nerve), each of which receives and furnishes one dorsal and one ventral root. On this basis the spinal cord is divided into the following segments: 8 cervical (C), 12 thoracic (T), 5 lumbar (L), 5 sacral (S), and 1 coccygeal (Coc). Spinal nerve roots emerge via intervertebral foramina; lumbar and sacral spinal roots, descending for some distance within the subarachnoid space before reaching the appropriate foramina, produce a group of nerve roots at the conus medullaris known as the cauda equina. Two enlargements of the spinal cord are evident: (1) a cervical enlargement (C5 through T1), which provides innervation for the upper extremities, and (2) a lumbosacral enlargement (L1 through S2), which innervates the lower extremities. (The spinal nerves and the area that they innervate are described in the section The peripheral nervous system: Spinal nerves (nervous system, human).)

Cellular laminae
 The gray matter of the spinal cord is composed of nine distinct cellular layers, or laminae, traditionally indicated by Roman numerals. Laminae I to V, forming the dorsal horns, receive sensory input. Lamina VII forms the intermediate zone at the base of all horns. Lamina IX is composed of clusters of large alpha motor neurons, which innervate striated muscle, and small gamma motor neurons, which innervate contractile elements of the muscle spindle. Axons of both alpha and gamma motor neurons emerge via the ventral roots. Laminae VII and VIII have variable configurations, and lamina VI is present only in the cervical and lumbosacral enlargements. In addition, cells surrounding the central canal of the spinal cord form an area often referred to as lamina X.

      All primary sensory neurons that enter the spinal cord originate in ganglia that are located in openings in the vertebral column called the intervertebral foramina. Peripheral processes of the nerve cells in these ganglia convey sensation from various receptors, and central processes of the same cells enter the spinal cord as bundles of nerve filaments. Fibres conveying specific forms of sensation follow separate pathways. Impulses involved with pain and noxious stimuli largely end in laminae I and II, while impulses associated with tactile sense end in lamina IV or on processes of cells in that lamina. Signals from stretch receptors (i.e., muscle spindles and tendon organs) end in parts of laminae V, VI, and VII; collaterals of these fibres associated with the stretch reflex project into lamina IX.

      Virtually all parts of the spinal gray matter contain interneurons, which connect various cell groups. Many interneurons have short axons distributed locally, but some have axons that extend for several spinal segments. Some interneurons may modulate or change the character of signals, while others play key roles in transmission and in patterned reflexes.

Ascending spinal tracts
      Sensory tracts ascending in the white matter of the spinal cord arise either from cells of spinal ganglia or from intrinsic neurons within the gray matter that receive primary sensory input.

Dorsal column
      The largest ascending tracts, the fasciculi gracilis and cuneatus, arise from spinal ganglion cells and ascend in the dorsal funiculus to the medulla oblongata. The fasciculus gracilis receives fibres from ganglia below thoracic 6, while spinal ganglia from higher segments of the spinal cord project fibres into the fasciculus cuneatus. The fasciculi terminate upon the nuclei gracilis and cuneatus, large nuclear masses in the medulla. Cells of these nuclei give rise to fibres that cross completely and form the medial lemniscus; the medial lemniscus in turn projects to the ventrobasal nuclear complex of the thalamus. By this pathway, the medial lemniscal system conveys signals associated with tactile, pressure, and kinesthetic (or positional) sense to sensory areas of the cerebral cortex.

Spinothalamic tracts
      Fibres concerned with pain, thermal sense, and light touch enter the lateral-root entry zone and then ascend or descend near the periphery of the spinal cord before entering superficial laminae of the dorsal horn—largely parts of laminae I, IV, and V. Cells in these laminae then give rise to fibres of the two spinothalamic tracts. Those fibres crossing in the ventral white commissure (ventral to the central canal) form the lateral spinothalamic tract, which, ascending in the ventral part of the lateral funiculus, conveys signals related to pain and thermal sense. The anterior spinothalamic tract arises from fibres that cross the midline in the same fashion but ascend more anteriorly in the spinal cord; these fibres convey impulses related to light touch. At medullary levels the two spinothalamic tracts merge and cannot be distinguished as separate entities. Many of the fibres, or collaterals, of the spinothalamic tracts terminate upon cell groups in the reticular formation, while the principal tracts convey sensory impulses to relay nuclei in the thalamus.

Spinocerebellar tracts
      Impulses from stretch receptors are carried by fibres that synapse upon cells in deep laminae of the dorsal horn or in lamina VII. The posterior spinocerebellar tract arises from the dorsal nucleus of Clarke and ascends peripherally in the dorsal part of the lateral funiculus. The anterior spinocerebellar tract ascends on the ventral margin of the lateral funiculus. Both tracts transmit signals to portions of the anterior lobe of the cerebellum and are involved in mechanisms that automatically regulate muscle tone without reaching consciousness.

Descending spinal tracts
      Tracts descending to the spinal cord are involved with voluntary motor function, muscle tone, reflexes and equilibrium, visceral innervation, and modulation of ascending sensory signals. The largest, the corticospinal tract, originates in broad regions of the cerebral cortex. Smaller descending tracts, which include the rubrospinal tract, the vestibulospinal tract, and the reticulospinal tract, originate in nuclei in the midbrain, pons, and medulla oblongata. Most of these brainstem nuclei themselves receive input from the cerebral cortex, the cerebellar cortex, deep nuclei of the cerebellum, or some combination of these.

      In addition, autonomic tracts, which descend from various nuclei in the brainstem to preganglionic sympathetic and parasympathetic neurons in the spinal cord, constitute a vital link between the centres that regulate visceral functions and the nerve cells that actually effect changes.

Corticospinal tract
 The corticospinal tract originates from pyramid-shaped cells in the premotor, primary motor, and primary sensory cortex and is involved in skilled voluntary activity. Containing about one million fibres, it forms a significant part of the posterior limb of the internal capsule and is a major constituent of the crus cerebri in the midbrain. As the fibres emerge from the pons, they form compact bundles on the ventral surface of the medulla, known as the medullary pyramids. In the lower medulla about 90 percent of the fibres of the corticospinal tract decussate and descend in the dorsolateral funiculus of the spinal cord. Of the fibres that do not cross in the medulla, approximately 8 percent cross in cervical spinal segments. As the tract descends, fibres and collaterals branch off at all segmental levels, synapsing upon interneurons in lamina VII and upon motor neurons in lamina IX. Approximately 50 percent of the corticospinal fibres terminate within cervical segments.

      At birth, few of the fibres of the corticospinal tract are myelinated; myelination takes place during the first year after birth, along with the acquisition of motor skills. Because the tract passes through, or close to, nearly every major division of the neuraxis, it is vulnerable to vascular and other kinds of lesions. A relatively small lesion in the posterior limb of the internal capsule, for example, may result in contralateral hemiparesis, which is characterized by weakness, spasticity, greatly increased deep tendon reflexes, and certain abnormal reflexes.

Rubrospinal tract
      The rubrospinal tract arises from cells in the caudal part of the red nucleus, an encapsulated cell group in the midbrain tegmentum. Fibres of this tract decussate at midbrain levels, descend in the lateral funiculus of the spinal cord (overlapping ventral parts of the corticospinal tract), enter the spinal gray matter, and terminate on interneurons in lamina VII. Through these crossed rubrospinal projections, the red nucleus exerts a facilitating influence on flexor alpha motor neurons and a reciprocal inhibiting influence on extensor alpha motor neurons. Because cells of the red nucleus receive input from the motor cortex (via corticorubral projections) and from globose and emboliform nuclei of the cerebellum (via the superior cerebellar peduncle), the rubrospinal tract effectively brings flexor muscle tone under the control of these two regions of the brain.

Vestibulospinal tract
      The vestibulospinal tract originates from cells of the lateral vestibular nucleus, which lies in the floor of the fourth ventricle. Fibres of this tract descend the length of the spinal cord in the ventral and lateral funiculi without crossing, enter laminae VIII and IX of the anterior horn, and terminate upon both alpha and gamma motor neurons, which innervate ordinary muscle fibres and fibres of the muscle spindle (see below Functions of the human nervous system: Movement (nervous system, human)). Cells of the lateral vestibular nucleus receive facilitating impulses from labyrinthine receptors in the utricle of the inner ear and from fastigial nuclei in the cerebellum. In addition, inhibitory influences upon these cells are conveyed by direct projections from Purkinje cells in the anterior lobe of the cerebellum. Thus, the vestibulospinal tract mediates the influences of the vestibular end organ and the cerebellum upon extensor muscle tone.

      A smaller number of vestibular projections, originating from the medial and inferior vestibular nuclei, descend ipsilaterally in the medial longitudinal fasciculus only to cervical levels. These fibres exert excitatory and inhibitory effects upon cervical motor neurons.

Reticulospinal tract
      The reticulospinal tracts arise from relatively large but restricted regions of the reticular formation of the pons and medulla oblongata—the same cells that project ascending processes to intralaminar thalamic nuclei and are important in the maintenance of alertness and the conscious state. The pontine reticulospinal tract arises from groups of cells in the pontine reticular formation, descends ipsilaterally as the largest component of the medial longitudinal fasciculus, and terminates among cells in laminae VII and VIII. Fibres of this tract exert facilitating influences upon voluntary movements, muscle tone, and a variety of spinal reflexes. The medullary reticulospinal tract, originating from reticular neurons on both sides of the median raphe, descends in the ventral part of the lateral funiculus and terminates at all spinal levels upon cells in laminae VII and IX. The medullary reticulospinal tract inhibits the same motor activities that are facilitated by the pontine reticulospinal tract. Both tracts receive input from regions of the motor cortex.

Autonomic tracts
      Descending fibres involved with visceral and autonomic activities emanate from groups of cells at various levels of the brainstem. For example, hypothalamic nuclei project to visceral nuclei in both the medulla oblongata and the spinal cord; in the spinal cord these projections terminate upon cells of the intermediolateral cell column in thoracic, lumbar, and sacral segments. Preganglionic parasympathetic neurons originating in the oculomotor nuclear complex in the midbrain project not only to the ciliary ganglion but also directly to spinal levels. Some of these fibres reach lumbar segments of the spinal cord, most of them terminating in parts of laminae I and V. Pigmented cells in the isthmus, an area of the rostral pons, form a blackish-blue region known as the locus ceruleus; these cells distribute the neurotransmitter norepinephrine to the brain and spinal cord. Fibres from the locus ceruleus descend to spinal levels without crossing and are distributed to terminals in the anterior horn, the intermediate zone, and the dorsal horn. Other noradrenergic cell groups in the pons, near the motor nucleus of the facial nerve, project uncrossed noradrenergic fibres that terminate in the intermediolateral cell column (that is, lamina VII of the lateral horn). Postganglionic sympathetic neurons associated with this system have direct effects upon the cardiovascular system (human cardiovascular system). Cells in the nucleus of the solitary tract project crossed fibres to the phrenic nerve nucleus (in cervical segments three through five), the intermediate zone, and the anterior horn at thoracic levels; these innervate respiratory muscles.

Ed.

The peripheral nervous system
 The peripheral nervous system is a channel for the relay of sensory and motor impulses between the central nervous system on one hand and the body surface, skeletal muscles, and internal organs on the other hand. It is composed of (1) spinal nerves, (2) cranial nerves, and (3) certain parts of the autonomic nervous system. As in the central nervous system, peripheral nervous pathways are made up of neurons (neuron) (that is, nerve cell bodies and their axons and dendrites) and synapses (synapse), the points at which one neuron communicates with the next. The structures commonly known as nerves (or by such names as roots, rami, trunks, and branches) are composed of orderly arrangements of the axonal and dendritic processes of many nerve cell bodies.

      The cell bodies of peripheral neurons are often found grouped into clusters called ganglia (ganglion). On the basis of the type of nerve cell bodies found in ganglia, they may be classified as either sensory or motor. Sensory ganglia are oval swellings located on the dorsal roots of spinal nerves and on the roots of certain cranial nerves. The sensory neurons making up these ganglia are unipolar. Shaped much like a golf ball on a tee, they have round or slightly oval cell bodies with concentrically located nuclei, and they give rise to a single fibre that undergoes a T-shaped bifurcation, one branch going to the periphery and the other entering the brain or spinal cord. There are no synaptic contacts between neurons in a sensory ganglion.

      Motor ganglia are associated with neurons of the autonomic nervous system, the part of the nervous system that controls and regulates the internal organs. Many motor ganglia are located in the sympathetic trunks, two long chains of ganglia stretching along each side of the vertebral column from the base of the skull to the coccyx; these are referred to as paravertebral ganglia. Prevertebral motor ganglia are located near internal organs innervated by their projecting fibres, while terminal ganglia are found on the surfaces or within the walls of the target organs themselves. Motor ganglia have multipolar cell bodies, which have irregular shapes and eccentrically located nuclei and which project several dendritic and axonal processes. Preganglionic fibres originating from the brain or spinal cord enter motor ganglia, where they synapse on multipolar cell bodies. These postganglionic cells, in turn, send their processes to visceral structures.

Spinal nerves
      Sensory input from the body surface, from joint, tendon, and muscle receptors, and from internal organs passes centrally through the dorsal roots of the spinal cord. Fibres from motor cells in the spinal cord exit via the ventral roots and course to their peripheral targets (autonomic ganglia or skeletal muscle). Each spinal nerve is formed by the joining of a dorsal root and a ventral root, and it is the basic structural and functional unit of the peripheral nervous system.

Structural components of spinal nerves
      There are 31 pairs of spinal nerves; in descending order from the most rostral end of the spinal cord, there are 8 cervical (designated C1–C8), 12 thoracic (T1–T12), 5 lumbar (L1–L5), 5 sacral (S1–S5), and 1 coccygeal (Coc1). Each spinal nerve exits the vertebral canal (vertebral column) through an opening called the intervertebral foramen. The first spinal nerve (C1) exits the vertebral canal between the skull and the first cervical vertebra; consequently, spinal nerves C1–C7 exit above the correspondingly numbered vertebrae. Spinal nerve C8, however, exits between the 7th cervical and first thoracic vertebrae, so that, beginning with T1, all other spinal nerves exit below their corresponding vertebrae.

      Just outside the intervertebral foramen, two branches, known as the gray and white rami communicantes, connect each spinal nerve with the sympathetic trunk. These rami, along with the sympathetic trunk and more distal ganglia, are involved with the innervation of visceral structures. In addition, small meningeal branches leave each spinal nerve and gray ramus and reenter the vertebral canal, where they innervate the dura mater (the outermost of the meninges) and blood vessels.

 More peripherally, each spinal nerve divides into ventral and dorsal rami. All dorsal rami (with the exception of those from C1, S4, S5, and Coc1) have medial and lateral branches, which innervate deep back muscles and overlying skin. The medial and lateral branches of the dorsal rami of spinal nerves C2–C8 supply both the muscles and the skin of the neck. Those of T1–T6 are mostly cutaneous (that is, supplying only the skin), while those from T7–T12 are mainly muscular. Dorsal rami from L1–L3 have both sensory and motor fibres, while those from L4–L5 are only muscular. Dorsal rami of S1–S3 may also be divided into medial and lateral branches, serving deep muscles of the lower back as well as cutaneous areas of the lower buttocks and perianal area. Undivided dorsal rami from S4, S5, and Coc1 also send cutaneous branches to the gluteal and perianal regions.

      Ventral rami of the spinal nerves carry sensory and motor fibres for the innervation of the muscles, joints, and skin of the lateral and ventral body walls and the extremities. Both dorsal and ventral rami also contain autonomic fibres.

Functional types of spinal nerves
      Because spinal nerves contain both sensory fibres (from the dorsal roots) and motor fibres (from the ventral roots), they are known as mixed nerves. When individual fibres of a spinal nerve are identified by their specific function, they may be categorized as one of four types: (1) general somatic afferent, (2) general visceral afferent, (3) general somatic efferent, and (4) general visceral efferent. The term somatic refers to the body wall (broadly defined to include skeletal muscles as well as the surface of the skin), and visceral refers to structures composed of smooth muscle, cardiac muscle, glandular epithelium, or a combination of these. Efferent fibres carry motor information to skeletal muscle and to autonomic ganglia (and then to visceral structures), and afferent fibres carry sensory information from them.

      General somatic afferent receptors are sensitive to pain, thermal sensation, touch and pressure, and changes in the position of the body. (Pain and temperature sensation coming from the surface of the body is called exteroceptive, while sensory information arising from tendons, muscles, or joint capsules is called proprioceptive (proprioception).) General visceral afferent receptors are found in organs of the thorax, abdomen (abdominal cavity), and pelvis; their fibres convey, for example, pain information from the digestive tract. Both types of afferent fibre project centrally from cell bodies in dorsal-root ganglia.

      General somatic efferent fibres originate from large ventral-horn cells and distribute to skeletal muscles in the body wall and in the extremities. General visceral efferent fibres also arise from cell bodies located within the spinal cord, but they exit only at thoracic and upper lumbar levels or at sacral levels (more specifically, at levels T1–L2 and S2–S4). Fibres from T1–L2 enter the sympathetic trunk, where they either form synaptic contacts within a ganglion, ascend or descend within the trunk, or exit the trunk and proceed to ganglia situated closer to their target organs. Fibres from S2–S4, on the other hand, leave the cord as the pelvic nerve and proceed to terminal ganglia located in the target organs. Postganglionic fibres arising from ganglia in the sympathetic trunk rejoin the spinal nerves and distribute to blood vessels, sweat glands (sweat gland), and the arrector pili muscles of the skin, while postganglionic fibres arising from prevertebral and terminal ganglia innervate viscera of the thorax, abdomen, and pelvis.

      Cervical levels C1–C4 are the main contributors to the group of nerves called the cervical plexus; in addition, small branches of the plexus link C1 and C2 with the vagus nerve, C1 and C2 with the hypoglossal nerve, and C2–C4 with the accessory nerve. Sensory branches of the cervical plexus are the lesser occipital nerve (to the scalp behind the ear), the great auricular nerve (to the ear and to the skin over the mastoid and parotid areas), transverse cervical cutaneous nerves (to the lateral and ventral neck surfaces), and supraclavicular nerves (along the clavicle, shoulder, and upper chest). Motor branches of the plexus serve muscles that stabilize and flex the neck, muscles that stabilize the hyoid bone (to assist in actions like swallowing), and muscles that elevate the upper ribs.

      Originating from C4, with small contributions from C3 and C5, are the phrenic nerves, which carry sensory information from parts of the pleura of the lungs and pericardium of the heart as well as motor impulses to muscles of the diaphragm.

      Cervical levels C5–C8 and thoracic level T1 contribute to the formation of the brachial plexus; small nerve bundles also arrive from C4 and T2. Spinal nerves from these levels converge to form superior (C5 and C6), middle (C7), and inferior (C8 and T1) trunks, which in turn split into anterior and posterior divisions. The divisions then form cords (posterior, lateral, and medial), which provide motor, sensory, and autonomic fibres to the shoulder and upper extremity.

 Nerves to shoulder and pectoral muscles include the dorsal scapular (to the rhomboid muscles), suprascapular (to supraspinatus and infraspinatus), medial and lateral pectoral (to pectoralis minor and major (pectoralis muscle)), long thoracic (to serratus anterior), thoracodorsal (to latissimus dorsi), and subscapular (to teres major and subscapular). The axillary nerve carries motor fibres to the deltoid (deltoideus muscle) and teres minor muscles as well as sensory fibres to the lateral surface of the shoulder and upper arm. The biceps (biceps muscle), brachialis, and coracobrachialis muscles, as well as the lateral surface of the forearm, are served by the musculocutaneous nerve.

      The three major nerves of the arm, forearm, and hand are the radial, median, and ulnar. The radial nerve innervates the triceps (triceps muscle), anconeus, and brachioradialis muscles, eight extensors of the wrist and digits, and one abductor (abductor muscle) of the hand; it is also sensory to part of the hand. The median nerve branches in the forearm to serve the palmaris longus, two pronator muscles, four flexor (flexor muscle) muscles, thenar muscles, and lumbrical muscles; most of these serve the wrist and hand. The ulnar nerve serves two flexor muscles and a variety of small muscles of the wrist and hand.

      Cutaneous innervation of the upper extremity originates, via the brachial plexus, from spinal cord levels C3–T2. The shoulder is served by supraclavicular branches (C3, C4) of the cervical plexus, while the anterior and lateral aspects of the arm and forearm have sensory innervation via the axillary (C5, C6) nerve as well as the dorsal (C5, C6), lateral (C5, C6), and medial (C8, T1) antebrachial cutaneous nerves. These same nerves have branches that wrap around to serve portions of the posterior and medial surfaces of the extremity. The palm of the hand is served by the median (C6–C8) and ulnar (C8, T1) nerves. The ulnar nerve also wraps around to serve medial areas of the dorsum, or back, of the hand. An imaginary line drawn down the midline of the ring finger represents the junction of the ulnar-radial distribution on the back of the hand and the ulnar-median distribution on the palm. A small part of the thumb and the distal thirds of the index, middle, and lateral surface of the ring finger are served by the median nerve. The inner arm and the armpit is served by the intercostobrachial and the posterior and medial brachial cutaneous nerves (T1–T2).

      Spinal nerves from lumbar levels L1–L4 contribute to the formation of the lumbar plexus, which, along with the sacral plexus, provides motor, sensory, and autonomic fibres to gluteal and inguinal regions and to the lower extremities. Lumbar roots are organized into dorsal and ventral divisions.

      Minor cutaneous and muscular branches of the lumbar plexus include the iliohypogastric, genitofemoral, and ilioinguinal (projecting to the lower abdomen and to inguinal and genital regions) and the lateral femoral cutaneous nerve (to skin on the lateral thigh). Two major branches of the lumbar plexus are the obturator and femoral nerves. The obturator enters the thigh through the obturator foramen; motor branches proceed to the obturator internus and gracilis muscles as well as the adductor (adductor muscle) muscles, while sensory branches supply the articular capsule of the knee joint. An accessory obturator nerve supplies the pectineus muscle of the thigh and is sensory to the hip joint.

      The sartorius (sartorius muscle) muscle and medial and anterior surfaces of the thigh are served by branches of the anterior division of the femoral nerve. The posterior division of the femoral nerve provides sensory fibres to the inner surface of the leg (saphenous nerve), to the quadriceps (quadriceps femoris muscle) muscles (muscular branches), to the hip and knee joints, and to the articularis genu muscle.

  The ventral rami of L5 and S1–S3 form the sacral plexus, with contributions from L4 and S4. Branches from this plexus innervate gluteal muscles, muscles forming the internal surface of the pelvic basin (including those forming the levator ani (levator muscle)), and muscles that run between the femur and pelvis to stabilize the hip joint (such as the obturator, piriformis, and quadratus femoris muscles). These muscles lend their names to the nerves that innervate them. Cutaneous branches from the plexus serve the buttocks, perineum, and posterior surface of the thigh.

      The major nerve of the sacral plexus, and the largest nerve in the body, is the sciatic (sciatic nerve). Formed by the joining of ventral and dorsal divisions of the plexus, it passes through the greater sciatic foramen and descends in back of the thigh. There, sciatic branches innervate the biceps femoris (biceps muscle), semitendinosus and semimembranosus muscles, and part of the adductor magnus muscle. In the popliteal fossa (just above the knee), the sciatic nerve divides into the tibial nerve and the common fibular (or peroneal) nerve. The tibial nerve (from the dorsal division) continues distally in the calf and innervates the gastrocnemius (gastrocnemius muscle) muscle, deep leg muscles such as the popliteus, soleus (soleus muscle), and tibialis posterior, and the flexor (flexor muscle) muscles, lumbrical muscles, and other muscles of the ankle and plantar aspects of the foot. The peroneal nerve, from the ventral division, travels to the anterior surface of the leg and innervates the tibialis anterior, the fibularis muscles, and extensor muscles that elevate the foot and fan the toes. Cutaneous branches from the tibial and common fibular nerves serve the outer sides of the leg and the top and bottom of the foot and toes.

Coccygeal plexus
      The ventral rami of S4, S5, and Coc1 form the coccygeal plexus, from which small anococcygeal nerves arise to innervate the skin over the coccyx (tailbone) and around the anus.

Cranial nerves (cranial nerve)
 Cranial nerves can be thought of as modified spinal nerves, since the general functional fibre types found in spinal nerves are also found in cranial nerves (cranial nerve) but are supplemented by special afferent or efferent fibres. Fibres conveying olfaction (in cranial nerve I) and taste (in cranial nerves VII, IX, and X) are classified as special visceral afferent, while the designation of special somatic afferent is applied to fibres conveying vision (cranial nerve II) and equilibrium and hearing (cranial nerve VIII). Skeletal muscles that arise from the branchial arches are innervated by fibres of cranial nerves V, VII, IX, and X; these are classified as special visceral efferent fibres.

      The 12 pairs of cranial nerves are identified either by name or by Roman or Arabic numeral.

Olfactory nerve (CN I or 1)
      Bipolar cells in the nasal mucosa give rise to axons that enter the cranial cavity through foramina in the cribriform plate of the ethmoid bone. These cells and their axons, totaling about 20 to 24 in number, make up the olfactory nerve. Once in the cranial cavity, the fibres terminate in a small oval structure resting on the cribriform plate called the olfactory bulb. As stated above, the functional component of olfactory fibres is special visceral afferent. Injury or disease of the olfactory nerve may result in anosmia, an inability to detect odours; it may also dull the sense of taste.

optic nerve (CN II or 2)
      Rods (rod) and cones (cone) in the retina of the eye receive information from the visual fields and, through intermediary cells, convey this input to retinal ganglion cells. Ganglion cell axons converge at the optic disc, pass through the sclera, and form the optic nerve. A branch from each eye enters the skull via the optic foramen, and they join to form the optic chiasm. At the chiasm, fibres from the nasal halves of each retina cross, while those from the temporal halves remain uncrossed. In this way the optic tracts, which extend from the chiasm to the thalamus, contain fibres conveying information from both eyes. Injury to one optic nerve therefore results in total blindness of that eye, while damage to the optic tract on one side results in partial blindness in both eyes.

      Optic fibres also participate in accommodation of the lens and in the pupillary light reflex. Since the subarachnoid space around the brain is continuous with that around the optic nerve, increases in intracranial pressure can result in papilledema, or damage to the optic nerve, as it exits the bulb of the eye.

Oculomotor nerve (CN III or 3)
      The oculomotor nerve arises from two nuclei in the rostral midbrain. These are (1) the oculomotor nucleus, the source of general somatic efferent fibres to superior, medial, and inferior recti muscles, to the inferior oblique muscle, and to the levator palpebrae superious muscle, and (2) the Edinger-Westphal nucleus, which projects general visceral efferent preganglionic fibres to the ciliary ganglion.

      The oculomotor nerve exits the ventral midbrain, pierces the dura mater (meninges), courses through the lateral wall of the cavernous sinus, and exits the cranial cavity via the superior orbital fissure. Within the orbit it branches into a superior ramus (to the superior rectus and levator muscles) and an inferior ramus (to the medial and inferior rectus muscles, the inferior oblique muscles, and the ciliary ganglion). Postganglionic fibres from the ciliary ganglion innervate the sphincter pupillae muscle of the iris as well as the ciliary muscle.

      Oculomotor neurons project primarily to orbital muscles on the same side of the head. A lesion of the oculomotor nerve will result in paralysis of the three rectus muscles and the inferior oblique muscle (causing the eye to rotate downward and slightly outward), paralysis of the levator palpebrae superious muscle (drooping of the eyelids), and paralysis of the sphincter pupillae and ciliary muscles (so that the iris will remain dilated and the lens will not accommodate).

Trochlear nerve (CN IV or 4)
      The fourth cranial nerve is unique for three reasons. First, it is the only cranial nerve to exit the dorsal side of the brainstem. Second, fibres from the trochlear nucleus cross in the midbrain before they exit, so that trochlear neurons innervate the contralateral (opposite side) superior oblique muscle of the eye. Third, trochlear fibres have a long intracranial course before piercing the dura mater.

      The trochlear nucleus is located in the caudal midbrain; the functional component of these cells is general somatic efferent. After exiting at the dorsal side of the midbrain, the trochlear nerve loops around the midbrain, pierces the dura mater, and passes through the lateral wall of the cavernous sinus. It then enters the orbit through the superior orbital fissure and innervates only the superior oblique muscle, which rotates the eye downward and slightly outward. Damage to the trochlear nerve will result in a loss of this eye movement and may produce double vision (diplopia).

Trigeminal nerve (CN V or 5)
      The trigeminal nerve is the largest of the cranial nerves. It has both motor and sensory components, the sensory fibres being general somatic afferent and the motor fibres being special visceral efferent. Most of the cell bodies of sensory fibres are located in the trigeminal ganglion, which is attached to the pons by the trigeminal root. These fibres convey pain and thermal sensations from the face, oral and nasal cavities, and parts of the dura mater and nasal sinuses, sensations of deep pressure, and information from sensory endings in muscles. Trigeminal motor fibres, projecting from nuclei in the pons, serve the muscles of mastication (chewing). Lesions of the trigeminal nerve result in sensory losses over the face or in the oral cavity. Damage to the motor fibres results in paralysis of the masticatory muscles; as a result, the jaw may hang open or deviate toward the injured side when opened. Trigeminal neuralgia, or tic douloureux, is an intense pain originating mainly from areas supplied by sensory fibres of the maxillary and mandibular branches of this nerve.

      The trigeminal ganglion gives rise to three large nerves: the ophthalmic, maxillary, and mandibular.

Ophthalmic nerve
      The ophthalmic nerve passes through the wall of the cavernous sinus and enters the orbit via the superior orbital fissure. Branches in the orbit are (1) the lacrimal nerve, serving the lacrimal gland, part of the upper eyelid, and the conjunctiva, (2) the nasociliary nerve, serving the mucosal lining of part of the nasal cavity, the tentorium cerebelli and some of the dura mater of the anterior cranial fossa, and skin on the dorsum and tip of the nose, and (3) the frontal nerve, serving the skin on the upper eyelid, the forehead, and the scalp above the eyes up to the vertex of the head.

Maxillary nerve
      The maxillary nerve courses through the cavernous sinus below the ophthalmic nerve and passes through the foramen rotundum into the orbital cavity. Branches of the maxillary nerve are (1) the meningeal branches, which serve the dura mater of the middle cranial fossa, (2) the alveolar nerves, serving the upper teeth and gingiva and the lining of the maxillary sinus, (3) the nasal and palatine nerves, which serve portions of the nasal cavity and the mucosa of the hard and soft palate, and (4) the infraorbital, zygomaticotemporal, and zygomaticofacial nerves, serving the upper lip, the lateral surfaces of the nose, the lower eyelid and conjunctiva, and the skin on the cheek and the side of the head behind the eye.

Mandibular nerve
      The mandibular nerve exits the cranial cavity via the foramen ovale and serves (1) the meninges and parts of the anterior cranial fossae (meningeal branches), (2) the temporomandibular joint, skin over part of the ear, and skin over the sides of the head above the ears (auriculotemporal nerve), (3) oral mucosa, the anterior two-thirds of the tongue, gingiva adjacent to the tongue, and the floor of the mouth (lingual nerve), and (4) the mandibular teeth (inferior alveolar nerve). Skin over the lateral and anterior surfaces of the mandible and the lower lip is served by cutaneous branches of the mandibular nerve.

      Trigeminal motor fibres exit the cranial cavity via the foramen ovale along with the mandibular nerve. They serve the muscles of mastication (chewing) (temporalis, masseter, medial and lateral pterygoid), three muscles involved in swallowing (anterior portions of the digastric muscle, the mylohyoid muscle, and the tensor veli palatini), and the tensor tympani, a muscle that has a damping effect on loud noises by stabilizing the tympanic membrane.

Abducens nerve (CN VI or 6)
      From its nucleus in the caudal pons, the abducens nerve exits the brainstem at the pons-medulla junction, pierces the dura mater, passes through the cavernous sinus close to the internal carotid artery, and exits the cranial vault via the superior orbital fissure. In the orbit the abducens nerve innervates the lateral rectus muscle, which turns the eye outward. Damage to the abducens nerve results in a tendency for the eye to deviate medially, or cross. Double vision may result on attempted lateral gaze. The nerve often is affected by increased intracranial pressure.

facial nerve (CN VII or 7)
      The facial nerve is composed of a large root that innervates facial muscles and a small root (known as the intermediate nerve) that contains sensory and autonomic fibres.

      From the facial nucleus in the pons, facial motor fibres enter the internal auditory meatus, pass through the temporal bone, exit the skull via the stylomastoid foramen, and fan out over each side of the face in front of the ear. Fibres of the facial nerve are special visceral efferent; they innervate the small muscles of the external ear, the superficial muscles of the face, neck, and scalp, and the muscles of facial expression.

      The intermediate nerve contains autonomic (parasympathetic) as well as general and special sensory fibres. Preganglionic autonomic fibres, classified as general visceral efferent, project from the superior salivatory nucleus in the pons. Exiting with the facial nerve, they pass to the pterygopalatine ganglion via the greater petrosal nerve (a branch of the facial nerve) and to the submandibular ganglion by way of the chorda tympani nerve (another branch of the facial nerve, which joins the lingual branch of the mandibular nerve). Postganglionic fibres from the pterygopalatine ganglion innervate the nasal and palatine glands and the lacrimal gland, while those from the submandibular ganglion serve the submandibular and sublingual salivary glands. Among the sensory components of the intermediate nerve, general somatic afferent fibres relay sensation from the caudal surface of the ear, while special visceral afferent fibres originate from taste buds in the anterior two-thirds of the tongue, course in the lingual branch of the mandibular nerve, and then join the facial nerve via the chorda tympani branch. Both somatic and visceral afferent fibres have cell bodies in the geniculate ganglion, which is located on the facial nerve as it passes through the facial canal in the temporal bone.

      Injury to the facial nerve at the brainstem produces a paralysis of facial muscles known as Bell palsy as well as a loss of taste sensation from the anterior two-thirds of the tongue. If damage occurs at the stylomastoid foramen, facial muscles will be paralyzed but taste will be intact.

vestibulocochlear nerve (CN VIII or 8)
      This cranial nerve has a vestibular part, which functions in balance, equilibrium, and orientation in three-dimensional space, and a cochlear part, which functions in hearing. The functional component of these fibres is special somatic afferent; they originate from receptors located in the temporal bone.

      Vestibular receptors are located in the semicircular canals of the ear, which provide input on rotatory movements (angular acceleration), and in the utricle and saccule, which generate information on linear acceleration and the influence of gravitational pull. This information is relayed by the vestibular fibres, whose bipolar cell bodies are located in the vestibular (Scarpa) ganglion. The central processes of these neurons exit the temporal bone via the internal acoustic meatus and enter the brainstem alongside the facial nerve.

      Auditory receptors of the cochlear division are located in the organ of Corti and follow the spiral shape (about 2.5 turns) of the cochlea. Air movement against the eardrum initiates action of the ossicles of the ear, which, in turn, causes movement of fluid in the spiral cochlea. This fluid movement is converted by the organ of Corti into nerve impulses that are interpreted as auditory information. The bipolar cells of the spiral, or Corti, ganglion branch into central processes that course with the vestibular nerve. At the brainstem, cochlear fibres separate from vestibular fibres to end in the dorsal and ventral cochlear nuclei.

      Lesions of the vestibular root result in eye movement disorders ( nystagmus), unsteady gait with a tendency to fall toward the side of the lesion, nausea, and vertigo. Damage to the cochlea or cochlear nerve results in complete deafness, ringing in the ear ( tinnitus), or both.

      The ninth cranial nerve, which exits the skull through the jugular foramen, has both motor and sensory components. Cell bodies of motor neurons, located in the nucleus ambiguus in the medulla oblongata, project as special visceral efferent fibres to the stylopharyngeal muscle. The action of the stylopharyngeus is to elevate the pharynx, as in gagging or swallowing. In addition, the inferior salivatory nucleus of the medulla sends general visceral efferent fibres to the otic ganglion via the lesser petrosal branch of the ninth nerve; postganglionic otic fibres innervate the parotid salivary gland.

      Among the sensory components of the glossopharyngeal nerve, special visceral afferent fibres convey taste sensation from the back third of the tongue via lingual branches of the nerve. General visceral afferent fibres from the pharynx, the back of the tongue, parts of the soft palate and eustachian tube, and the carotid body and carotid sinus have their cell bodies in the superior and inferior ganglia, which are situated, respectively, within the jugular foramen and just outside the cranium. Sensory fibres in the carotid branch detect increased blood pressure in the carotid sinus and send impulses into the medulla that ultimately reduce heart rate and arterial pressure; this is known as the carotid sinus reflex.

vagus nerve (CN X or 10)
      The vagus nerve has the most extensive distribution in the body of all the cranial nerves, innervating structures as diverse as the external surface of the eardrum and internal abdominal organs. The root of the nerve exits the cranial cavity via the jugular foramen. Within the foramen is the superior ganglion, containing cell bodies of general somatic afferent fibres, and just external to the foramen is the inferior ganglion, containing visceral afferent cells.

      Pain and temperature sensations from the eardrum and external auditory canal and pain fibres from the dura mater of the posterior cranial fossa are conveyed on general somatic afferent fibres in the auricular and meningeal branches of the nerve. Taste buds on the root of the tongue and on the epiglottis contribute special visceral afferent fibres to the superior laryngeal branch. General visceral afferent fibres conveying sensation from the lower pharynx, larynx, trachea, esophagus, and organs of the thorax and abdomen (abdominal cavity) to the left (splenic) flexure of the colon converge to form the posterior (right) and anterior (left) vagal nerves. Right and left vagal nerves are joined in the thorax by cardiac, pulmonary, and esophageal branches. In addition, general visceral afferent fibres from the larynx below the vocal folds join the vagus via the recurrent laryngeal nerves, while comparable input from the upper larynx and pharynx is relayed by the superior laryngeal nerves and by pharyngeal branches of the vagus. A vagal branch to the carotid body usually arises from the inferior ganglion.

      Motor fibres of the vagus nerve include special visceral efferent fibres arising from the nucleus ambiguus of the medulla oblongata and innervating pharyngeal constrictor muscles and palatine muscles via pharyngeal branches of the vagus as well as the superior laryngeal nerve. All laryngeal musculature (excluding the cricothyroid but including the muscles of the vocal folds) are innervated by fibres arising in the nucleus ambiguus. Cells of the dorsal motor nucleus in the medulla distribute general visceral efferent fibres to plexuses or ganglia serving the pharynx, larynx, esophagus, and lungs (lung). In addition, cardiac branches arise from plexuses in the lower neck and upper thorax, and, once in the abdomen, the vagus gives rise to gastric, celiac, hepatic, renal, intestinal, and splenic branches or plexuses.

      Damage to one vagus nerve results in hoarseness and difficulty in swallowing or speaking. Injury to both nerves results in increased heart rate, paralysis of pharyngeal and laryngeal musculature, atonia of the esophagus and intestinal musculature, vomiting, and loss of visceral reflexes. Such a lesion is usually life-threatening, as paralysis of laryngeal muscles may result in asphyxiation.

Accessory nerve (CN XI or 11)
      The accessory nerve is formed by fibres from the medulla oblongata (known as the cranial root) and by fibres from cervical levels C1–C4 (known as the spinal root). The cranial root originates from the nucleus ambiguus and exits the medulla below the vagus nerve. Its fibres join the vagus and distribute to some muscles of the pharynx and larynx via pharyngeal and recurrent laryngeal branches of that nerve. For this reason, the cranial part of the accessory nerve is, for all practical purposes, part of the vagus nerve.

      Fibres that arise from spinal levels exit the cord, coalesce and ascend as the spinal root of the accessory nerve, enter the cranial cavity through the foramen magnum, and then immediately leave through the jugular foramen. The accessory nerve then branches into the sternocleidomastoid muscle, which tilts the head toward one shoulder with an upward rotation of the face to the opposite side, and the trapezius muscle, which stabilizes and shrugs the shoulder.

Hypoglossal nerve (CN XII or 12)
      The hypoglossal nerve innervates certain muscles that control movement of the tongue. From the hypoglossal nucleus in the medulla oblongata, general somatic efferent fibres exit the cranial cavity through the hypoglossal canal and enter the neck in close proximity to the accessory and vagus nerves and the internal carotid artery. The nerve then loops down and forward into the floor of the mouth and branches into the tongue musculature from underneath. Hypoglossal fibres end in intrinsic tongue muscles, which modify the shape of the tongue (as in rolling the edges), as well as in extrinsic muscles that are responsible for changing its position in the mouth.

      A lesion of the hypoglossal nerve on the same side of the head results in paralysis of the intrinsic and extrinsic musculature on the same side. The tongue atrophies and, on attempted protrusion, deviates toward the side of the lesion.

Duane E. Haines

 The autonomic nervous system is the part of the peripheral nervous system that regulates the basic visceral processes needed for the maintenance of normal bodily functions. It operates independently of voluntary control, although certain events, such as stress, fear, sexual excitement, and alterations in the sleep-wake cycle, change the level of autonomic activity.

      The autonomic system usually is defined as a motor system that innervates three major types of tissue: cardiac muscle, smooth muscle, and glands (gland). However, it also relays visceral sensory information to the central nervous system and processes it so that alterations can be made in the activity of specific autonomic motor outflows, such as those that control the heart, blood vessels, and other visceral organs. It also stimulates the release of certain hormones involved in energy metabolism (e.g., insulin, glucagon, and epinephrine (epinephrine and norepinephrine) [also called adrenaline]) or cardiovascular functions (e.g., renin and vasopressin). These integrated responses maintain the normal internal environment of the body in an equilibrium state called homeostasis.

      The autonomic system consists of two major divisions: the sympathetic nervous system and the parasympathetic nervous system. These often function in antagonistic ways. The motor outflow of both systems is formed by two serially connected sets of neurons. The first set, called preganglionic neurons, originates in the brainstem or the spinal cord, and the second set, called ganglion cells or postganglionic neurons, lies outside the central nervous system in collections of nerve cells called autonomic ganglia. Parasympathetic ganglia tend to lie close to or within the organs or tissues that their neurons innervate, whereas sympathetic ganglia are located at more distant sites from their target organs. Both systems have associated sensory fibres that send feedback into the central nervous system regarding the functional condition of target tissues.

      A third division of the autonomic system, the enteric nervous system, consists of a collection of neurons embedded within the wall of the gastrointestinal tract and its derivatives. This system controls gastrointestinal motility and secretion.

Sympathetic nervous system
 The sympathetic nervous system normally functions to produce localized adjustments (such as sweating (sweat) as a response to an increase in temperature (body heat)) and reflex adjustments of the cardiovascular system. Under conditions of stress, however, the entire sympathetic nervous system is activated, producing an immediate, widespread response called the fight-or-flight response. This response is characterized by the release of large quantities of epinephrine (epinephrine and norepinephrine) from the adrenal gland, an increase in heart rate, an increase in cardiac output, skeletal muscle vasodilation, cutaneous and gastrointestinal vasoconstriction, pupillary dilation, bronchial dilation, and piloerection. The overall effect is to prepare the individual for imminent danger.

      Sympathetic preganglionic neurons originate in the lateral horns of the 12 thoracic and the first 2 or 3 lumbar segments of the spinal cord. (For this reason the sympathetic system is sometimes referred to as the thoracolumbar outflow.) The axons of these neurons exit the spinal cord in the ventral roots and then synapse on either sympathetic ganglion cells or specialized cells in the adrenal gland called chromaffin cells.

Sympathetic ganglia (ganglion)
      Sympathetic ganglia can be divided into two major groups, paravertebral and prevertebral (or preaortic), on the basis of their location within the body. Paravertebral ganglia generally are located on each side of the vertebrae and are connected to form the sympathetic chain, or trunk. There are usually 21 or 22 pairs of these ganglia—3 in the cervical region, 10 or 11 in the thoracic region, 4 in the lumbar region, and 4 in the sacral region—and a single unpaired ganglion lying in front of the coccyx, called the ganglion impar. The three cervical sympathetic ganglia are the superior cervical ganglion, the middle cervical ganglion, and the cervicothoracic ganglion (also called the stellate ganglion). The superior ganglion innervates viscera of the head, and the middle and stellate ganglia innervate viscera of the neck, thorax (i.e., the bronchi and heart), and upper limbs. The thoracic sympathetic ganglia innervate the trunk region, and the lumbar and sacral sympathetic ganglia innervate the pelvic floor and lower limbs. All the paravertebral ganglia provide sympathetic innervation to blood vessels in muscle and skin, arrector pili muscles attached to hairs, and sweat glands (sweat gland).

 The three preaortic ganglia are the celiac, superior mesenteric, and inferior mesenteric. Lying on the anterior surface of the aorta, preaortic ganglia provide axons that are distributed with the three major gastrointestinal arteries arising from the aorta. Thus, the celiac ganglion innervates the stomach, liver, pancreas, and the duodenum, the first part of the small intestine; the superior mesenteric ganglion innervates the small intestine; and the inferior mesenteric ganglion innervates the descending colon, sigmoid colon, rectum, urinary bladder, and sexual organs.

Neurotransmitters (neurotransmitter) and receptors
      Upon reaching their target organs by traveling with the blood vessels that supply them, sympathetic fibres terminate as a series of swellings close to the end organ. Because of this anatomical arrangement, autonomic transmission takes place across a junction rather than a synapse. “Presynaptic” sites can be identified because they contain aggregations of synaptic vesicles and membrane thickenings; postjunctional membranes, on the other hand, rarely possess morphological specializations, but they do contain specific receptors for various neurotransmitters. The distance between pre- and postsynaptic elements can be quite large compared with typical synapses. For instance, the gap between cell membranes of a typical chemical synapse is 30–50 nanometres, while in blood vessels the distance is often greater than 100 nanometres or, in some cases, 1–2 micrometres (1,000–2,000 nanometres). Owing to these relatively large gaps between autonomic nerve terminals and their effector cells, neurotransmitters (neurotransmitter) tend to act slowly; they become inactivated rather slowly as well. To compensate for this inefficiency, many effector cells, such as those in smooth and cardiac muscle, are connected by low-resistance pathways that allow for electrotonic coupling of the cells. In this way, if only one cell is activated, multiple cells will respond and work as a group.

      At a first approximation, chemical transmission in the sympathetic system appears simple: preganglionic neurons use acetylcholine as a neurotransmitter, whereas most postganglionic neurons utilize norepinephrine (noradrenaline)—with the major exception that postganglionic neurons innervating sweat glands use acetylcholine. On closer inspection, however, neurotransmission is seen to be more complex, because multiple chemicals are released, and each functions as a specific chemical code affecting different receptors on the target cell. In addition, these chemical codes are self-regulatory, in that they act on presynaptic receptors located on their own axon terminals.

      The chemical codes are specific to certain tissues. For example, most sympathetic neurons that innervate blood vessels secrete both norepinephrine and neuropeptide Y; sympathetic neurons that innervate the submucosal neural plexus of the gut contain both norepinephrine and somatostatin; and sympathetic neurons that innervate sweat glands contain calcitonin gene-related peptide, vasoactive intestinal polypeptide, and acetylcholine. In addition, other chemicals besides the neuropeptides mentioned above are released from autonomic neurons along with the so-called classical neurotransmitters, norepinephrine and acetylcholine. For instance, some neurons synthesize a gas, nitric oxide, that functions as a neuronal messenger molecule. Thus, neural transmission in the autonomic nervous system involves the release of combinations of different neuroactive agents that affect both pre- and postsynaptic receptors.

      Neurotransmitters released from nerve terminals bind to specific receptors, which are specialized macromolecules embedded in the cell membrane. The binding action initiates a series of specific biochemical reactions in the target cell that produce a physiological response. In the sympathetic nervous system, for example, there are five types of adrenergic receptors (receptors binding epinephrine): α1, α2, β1, β2, and β3. These adrenoceptors are found in different combinations in various cells throughout the body. Activation of α1- adrenoceptors in arterioles causes blood-vessel constriction, whereas stimulation of α2 autoreceptors (receptors located in sympathetic presynaptic nerve endings) functions to inhibit the release of norepinephrine. Other types of tissue have unique adrenoceptors. Heart rate and myocardial contractility, for example, are controlled by β1-adrenoceptors; bronchial smooth muscle relaxation is mediated by β2-adrenoceptors; and the breakdown of fat (lipolysis) is controlled by β3-adrenoceptors.

      Cholinergic receptors (receptors binding acetylcholine) also are found in the sympathetic system (as well as the parasympathetic system). Nicotinic cholinergic receptors stimulate sympathetic postganglionic neurons, adrenal chromaffin cells, and parasympathetic postganglionic neurons to release their chemicals. Muscarinic receptors are associated mainly with parasympathetic functions and are located in peripheral tissues (e.g., glands and smooth muscle). Peptidergic receptors exist in target cells as well.

      The length of time that each type of chemical acts on its target cell is variable. As a rule, peptides cause slowly developing, long-lasting effects (one or more minutes), whereas the classical transmitters produce short-term effects (about 25 milliseconds).

Parasympathetic nervous system
 The parasympathetic nervous system primarily modulates visceral organs such as glands. Responses are never activated en masse as in the fight-or-flight sympathetic response. While providing important control of many tissues, the parasympathetic system, unlike the sympathetic system, is not crucial for the maintenance of life.

      The parasympathetic nervous system is organized in a manner similar to the sympathetic nervous system. Its motor component consists of preganglionic and postganglionic neurons. The preganglionic neurons are located in specific cell groups (also called nuclei) in the brainstem or in the lateral horns of the spinal cord at sacral levels (segments S2–S4). (Because parasympathetic fibres exit from these two sites, the system is sometimes referred to as the craniosacral outflow.) Preganglionic axons emerging from the brainstem project to parasympathetic ganglia that are located in the head (ciliary, pterygopalatine [also called sphenopalatine], and otic ganglia) or near the heart (cardiac ganglia), embedded in the end organ itself (e.g., the trachea, bronchi, and gastrointestinal tract), or situated a short distance from the urinary bladder (pelvic ganglion). Both pre- and postganglionic neurons secrete acetylcholine as a neurotransmitter, but, like sympathetic ganglion cells, they also contain other neuroactive chemical agents that function as cotransmitters.

      The third cranial nerve (oculomotor nerve) contains parasympathetic nerve fibres that regulate the iris and lens of the eye. From their origin in the Edinger-Westphal nucleus of the midbrain, preganglionic axons travel to the orbit and synapse on the ciliary ganglion. The ciliary ganglion contains two types of postganglionic neurons: one innervates smooth muscle of the iris and is responsible for pupillary constriction, and the other innervates ciliary muscle and controls the curvature of the lens.

      Various secretory glands located in the head are under parasympathetic control. These include the lacrimal gland, which supplies tears to the cornea of the eye; salivary glands (sublingual, submandibular, and parotid glands), which produce saliva; and nasal mucous glands, which secrete mucus throughout the nasal air passages. The parasympathetic preganglionic neurons that regulate these functions originate in the reticular formation of the medulla oblongata. One group of parasympathetic preganglionic neurons belongs to the superior salivatory nucleus and lies in the rostral part of the medullary reticular formation. These neurons send axons out of the medulla in a separate branch of the seventh cranial nerve ( facial nerve) called the intermediate nerve. Some of the axons innervate the pterygopalatine ganglion, and others project to the submandibular ganglion. Pterygopalatine ganglion cells innervate the vasculature of the brain and eye as well as the lacrimal gland, nasal glands, and palatine glands, while neurons of the submandibular ganglion innervate the submandibular and sublingual salivary glands. A second group of parasympathetic preganglionic neurons belongs to the inferior salivatory nucleus, located in the caudal part of the medullary reticular formation. Neurons of this group send axons out of the medulla in the ninth cranial (glossopharyngeal) nerve and to the otic ganglion. From this site, postganglionic fibres travel to and innervate the parotid salivary gland.

      Preganglionic parasympathetic fibres of the 10th cranial (vagus (vagus nerve)) nerve arise from two different sites in the medulla oblongata. Neurons that slow heart rate arise from a part of the ventral medulla called the nucleus ambiguus, while those that control functions of the gastrointestinal tract arise from the dorsal vagal nucleus. After exiting the medulla in the vagus nerve and traveling to their respective organs, the fibres synapse on ganglion cells embedded in the organs themselves. The vagus nerve also contains visceral afferent fibres that carry sensory information from organs of the neck ( larynx, pharynx, and trachea), chest ( heart and lungs (lung)), and gastrointestinal tract into a visceral sensory nucleus located in the medulla called the solitary tract nucleus.

Enteric nervous system
      The enteric nervous system is composed of two plexuses, or networks of neurons, embedded in the wall of the gastrointestinal tract (alimentary canal). The outermost plexus, located between the inner circular and outer longitudinal smooth-muscle layers of the gut, is called the Auerbach, or myenteric, plexus. Neurons of this plexus regulate peristaltic (peristalsis) waves that move digestive products from the oral to the anal opening. In addition, myenteric neurons control local muscular contractions that are responsible for stationary mixing and churning. The innermost group of neurons is called the Meissner, or submucosal, plexus. This plexus regulates the configuration of the luminal surface, controls glandular secretions, alters electrolyte and water transport, and regulates local blood flow.

      Three functional classes of intrinsic enteric neurons are recognized: sensory neurons, interneurons, and motor neurons. Sensory neurons, activated by either mechanical or chemical stimulation of the innermost surface of the gut, transmit information to interneurons located within the Auerbach and the Meissner plexi, and the interneurons relay the information to motor neurons. Motor neurons in turn modulate the activity of a variety of target cells, including mucous glands, smooth muscle cells, endocrine cells, epithelial cells, and blood vessels.

 Extrinsic neural pathways also are involved in the control of gastrointestinal functions. Three types exist: intestinofugal, sensory, and motor. Intestinofugal neurons reside in the gut wall; their axons travel to the preaortic sympathetic ganglia and control reflex arcs that involve large portions of the gastrointestinal tract. Sensory neurons relay information regarding distention and acidity to the central nervous system. There are two types of sensory neurons: sympathetic neurons, which originate from dorsal-root ganglia found at the thoracic and lumbar levels; and parasympathetic neurons, which originate in the nodose ganglion of the vagus nerve or in dorsal-root ganglia at sacral levels S2–S4. The former innervate the gastrointestinal tract from the pharynx to the left colic flexure, and the latter innervate the distal colon and rectum. Each portion of the gastrointestinal tract receives a dual sensory innervation: pain sensations travel via sympathetic afferent fibres, and sensations that signal information regarding the chemical environment of the gut travel by way of parasympathetic fibres and are not consciously perceived.

      The third extrinsic pathway, exercising motor control over the gut, arises from parasympathetic preganglionic neurons found in the dorsal vagal nucleus of the medulla oblongata and from sympathetic preganglionic neurons in the lateral horns of the spinal cord. These pathways provide modulatory commands to the intrinsic enteric motor system and are nonessential in that basic functions can be maintained in their absence.

      Through the pathways described above, the parasympathetic system activates digestive processes while the sympathetic system inhibits them. The sympathetic system inhibits digestive processes by two mechanisms: (1) contraction of circular smooth muscle sphincters located in the distal portion of the stomach (pyloric sphincter), small intestine (ileo-cecal sphincter), and rectum (internal anal sphincter), which act as valves to prevent the oral-to-anal passage (as well as reverse passage) of digestive products; and (2) inhibition of motor neurons throughout the length of the gut. In contrast, the parasympathetic system provides messages only to myenteric motor neurons.

Arthur D. Loewy

Functions of the human nervous system
      The human nervous system differs from that of other mammals chiefly in the great enlargement and elaboration of the cerebral hemispheres. Much of what is known of the functions of the human brain is derived from observations of the effects of disease or by the results of experimentation on animals, particularly the monkey. Such sources of information are clearly inadequate for the elucidation of the nervous activity underlying many properties of the human brain—particularly speech and mental processes. It is not surprising, therefore, that knowledge of the functions of this uniquely complex system, although rapidly expanding, is far from complete.

      In the following account of the functions of the human nervous system, there are numerous references to tracts and to less-well-defined connections between different regions of the brain and spinal cord. The identification of these pathways is not always a simple matter; indeed, in humans, many are incompletely known or are simply conjectural.

      A great deal of information about the human nervous system has been obtained by observing the effects of axonal (axon) destruction. If a nerve fibre is severed, the length of axon farthest from the cell body, or soma, will be deprived of the axonal flow of metabolites and will begin to deteriorate. The myelin sheath will also degenerate, so that, for some months after the injury, breakdown products of myelin will be seen under the microscope with special stains. This method is obviously of limited application in humans, as it requires precise lesions and subsequent examination before the myelin has been completely removed.

      The staining of degenerated axons and of the terminals that form synapses with other neurons (neuron) is also possible through the use of silver impregnation, but the techniques are laborious and results sometimes difficult to interpret. That a damaged neuron should show degenerative changes, however difficult to detect, is not unexpected, but the interdependence of neurons is sometimes shown by transneuronal degeneration. Neurons deprived of major input from axons that have been destroyed may themselves atrophy. This phenomenon is called anterograde degeneration. In retrograde degeneration, similar changes may occur in neurons that have lost the main recipient of their outflow.

      These anatomical methods are occasionally applicable to human disease. They can also be used postmortem when lesions of the central nervous system have been deliberately made—for example, in the surgical treatment of intractable pain. Other techniques can be used only in experiments on animals, but these are not always relevant to humans. For example, normal biochemical constituents labeled with a radioactive isotope can be injected into neurons and then transported the length of the axon, where they can be detected by picking up the radioactivity on an X-ray plate.

      An observation technique dependent on retrograde axonal flow has been used extensively to demonstrate the origin of fibre tracts. In this technique, the enzyme peroxidase is taken up by axon terminals and is transported up the axon to the soma, where it can be shown by appropriate staining.

      The staining of neurotransmitter substances is possible in postmortem human material as well as in animals. Success, however, is dependent on examining relatively fresh or frozen material, and results may be greatly affected by previous treatment with neurologically active medications.

      Electrical stimulation of a region of the nervous system generates nerve impulses in centres receiving input from the site of stimulation. This method, using microelectrodes, has been widely used in animal studies; however, the precise path followed by the artificially generated impulse may be difficult to establish.

Receptors (receptor)
      Receptors are biological transducers that convert energy from both external and internal environments into electrical impulses. They may be massed together to form a sense organ, such as the eye or ear, or they may be scattered, as are those of the skin and viscera. Receptors are connected to the central nervous system by afferent nerve fibres. The region or area in the periphery from which a neuron within the central nervous system receives input is called its receptive field. Receptive fields are changing and not fixed entities.

      Receptors are of many kinds and are classified in many ways. Steady-state receptors, for example, generate impulses as long as a particular state such as temperature remains constant. Changing-state receptors, on the other hand, respond to variation in the intensity or position of a stimulus. Receptors are also classified as exteroceptive (reporting the external environment), interoceptive (sampling the environment of the body itself), and proprioceptive (sensing the posture and movements of the body). Exteroceptors report the senses of sight, hearing, smell, taste, and touch (touch reception). Interoceptors report the state of the bladder, the alimentary canal, the blood pressure, and the osmotic pressure of the blood plasma. Proprioceptors report the position and movements of parts of the body and the position of the body in space.

      Receptors are also classified according to the kinds of stimulus to which they are sensitive. Chemical receptors, or chemoreceptors, are sensitive to substances taken into the mouth (taste or gustatory receptors), inhaled through the nose (smell or olfactory receptors), or found in the body itself (detectors of glucose or of acid-base balance in the blood). Receptors of the skin are classified as thermoreceptors, mechanoreceptors, and nociceptors—the last being sensitive to stimulation that is noxious, or likely to damage the tissues of the body.

      Thermoreceptors are of two types, warmth and cold. Warmth fibres are excited by rising temperature and inhibited by falling temperature, and cold fibres respond in the opposite manner.

      Mechanoreceptors are also of several different types. Sensory nerve terminals around the base of hairs are activated by very slight movement of the hair, but they rapidly adapt to continued stimulation and stop firing. In hairless skin both rapidly and slowly adapting receptors provide information about the force of mechanical stimulation. The Pacinian corpuscles, elaborate structures found in the skin of the fingers and in other organs, are layers of fluid-filled membranes forming structures just visible to the naked eye at the terminals of axons. The precise function of the corpuscles is not fully known, but they are probably activated by rapidly changing or alternating stimuli such as vibration.

      All receptors report two features of stimulation, its intensity and its location. Intensity is signaled by the frequency of nerve impulse discharge of a neuron and also by the number of afferent nerves reporting the stimulation. As the strength of a stimulus increases, the rate of change in electrical potential of the receptor increases, and the frequency of nerve impulse generation likewise increases.

      The location of a stimulus, whether in the external or internal environment, is readily determined by the nervous system. Localization of stimuli in the environment depends to a great extent on pairs of receptors, one on each side of the body. For example, children learn very early in life that a loud sound is probably coming from a nearer source than a weak sound. They localize the sound by noticing the difference in intensity and the minimal difference in time of arrival at the ears, increasing these differences by turning the head.

      Localization of a stimulus on the skin depends upon the arrangement of nerve fibres in the skin and in the deep tissues beneath the skin, as well as upon the overlap of receptive fields. Most mechanical stimuli indent the skin, stimulating nerve fibres in the connective tissue below the skin. Any point on the skin is supplied by at least 3, and sometimes up to 40, nerve fibres, and no two points are supplied by precisely the same pattern of fibres.

      Finer localization is achieved by what is called surround inhibition. In the retina, for example, there is an inhibitory area around the excited area. This mechanism accentuates the excited area. Surround excitation, on the other hand, is characterized by an excitatory area around an inhibitory area. In both cases contrast is enhanced and discrimination sharpened.

      In seeking information about the environment, the nervous system presents the most-sensitive receptors to a stimulating object. At its simplest, this action is reflex. In the retina a small region about the size of a pinhead, called the fovea, is particularly sensitive to colour. When a part of the periphery of the visual field is excited, a reflex movement of the head and eyes focuses the light rays upon that part of the fovea. A similar reflex turns the head and eyes in the direction of a noise. As the English physiologist Charles Sherrington (Sherrington, Sir Charles Scott) said in 1900, “In the limbs and mobile parts, when a spot of less discriminative sensitivity is touched, instinct moves the member, so that it brings to the object the part where its own sensitivity is delicate.”

reflex actions
      Of the many kinds of neural activity, there is one simple kind in which a stimulus leads to an immediate action. This is reflex activity. The word reflex (from Latin reflexus, “reflection”) was introduced into biology by a 19th-century English neurologist, Marshall Hall (Hall, Marshall), who fashioned the word because he thought of the muscles as reflecting a stimulus much as a wall reflects a ball thrown against it. By reflex, Hall meant the automatic response of a muscle or several muscles to a stimulus that excites an afferent nerve. The term is now used to describe an action that is an inborn central nervous system activity, not involving consciousness, in which a particular stimulus, by exciting an afferent nerve, produces a stereotyped, immediate response of muscle or gland.

      The anatomical pathway of a reflex is called the reflex arc. It consists of an afferent (or sensory) nerve, usually one or more interneurons within the central nervous system, and an efferent (motor, secretory, or secreto-motor) nerve.

      Most reflexes have several synapses in the reflex arc. The stretch reflex is exceptional in that, with no interneuron in the arc, it has only one synapse between the afferent nerve fibre and the motor neuron (see below Movement: The regulation of muscular contraction (nervous system, human)). The flexor reflex, which removes a limb from a noxious stimulus, has a minimum of two interneurons and three synapses.

      Probably the best-known reflex is the pupillary light reflex. If a light is flashed near one eye, the pupils of both eyes contract. Light is the stimulus; impulses reach the brain via the optic nerve; and the response is conveyed to the pupillary musculature by autonomic nerves that supply the eye. Another reflex involving the eye is known as the lacrimal reflex. When something irritates the conjunctiva or cornea of the eye, the lacrimal reflex causes nerve impulses to pass along the fifth cranial nerve (trigeminal) and reach the midbrain. The efferent limb of this reflex arc is autonomic and mainly parasympathetic. These nerve fibres stimulate the lacrimal glands of the orbit, causing the outpouring of tears. Other reflexes of the midbrain and medulla oblongata are the cough and sneeze reflexes. The cough reflex is caused by an irritant in the trachea and the sneeze reflex by one in the nose. In both, the reflex response involves many muscles; this includes a temporary lapse of respiration in order to expel the irritant.

      The first reflexes develop in the womb. By seven and a half weeks after conception, the first reflex can be observed; stimulation around the mouth of the fetus causes the lips to be turned toward the stimulus. By birth, sucking and swallowing reflexes are ready for use. Touching the baby's lips induces sucking, and touching the back of its throat induces swallowing.

      Although the word stereotyped is used in the above definition, this does not mean that the reflex response is invariable and unchangeable. When a stimulus is repeated regularly, two changes occur in the reflex response—sensitization and habituation. Sensitization is an increase in response; in general, it occurs during the first 10 to 20 responses. Habituation is a decrease in response; it continues until, eventually, the response is extinguished. When the stimulus is irregularly repeated, habituation does not occur or is minimal.

      There are also long-term changes in reflexes, which may be seen in experimental spinal cord transections performed on kittens. Repeated stimulation of the skin below the level of the lesion, such as rubbing the same area for 20 minutes every day, causes a change in latency (the interval between the stimulus and the onset of response) of certain reflexes, with diminution and finally extinction of the response. Although this procedure takes several weeks, it shows that, with daily stimulation, one reflex response can be changed into another. Repeated activation of synapses increases their efficiency, causing a lasting change. When this repeated stimulation ceases, synaptic functions regress, and reflex responses return to their original form.

      Although a reflex response is said to be rapid and immediate, some reflexes, called recruiting reflexes, can hardly be evoked by a single stimulus. Instead, they require increasing stimulation to induce a response. The reflex contraction of the bladder, for example, requires an increasing amount of urine to stretch the muscle and to obtain muscular contraction.

      Reflexes can be altered by impulses from higher levels of the central nervous system. For example, the cough reflex can be suppressed easily, and even the gag reflex (the movements of incipient vomiting resulting from mechanical stimulation of the wall of the pharynx) can be suppressed with training.

      The so-called conditioned reflexes are not reflexes at all but complicated acts of learned behaviour. Salivation is one such conditioned reflex; it occurs only when a person is conscious of the presence of food or when one imagines food.

Movement (locomotion)
      Movements of the body are brought about by the harmonious contraction and relaxation of selected muscles (muscle). Contraction occurs when nerve impulses are transmitted across neuromuscular junctions (neuromuscular junction) to the membrane covering each muscle fibre. Most muscles are not continuously contracting but are kept in a state ready to contract. The slightest movement or even the intention to move results in widespread activity of the muscles of the trunk and limbs.

      Movements may be intrinsic to the body itself and carried out by muscles of the trunk and body cavity. Examples are those involved in breathing, swallowing, laughing, sneezing, urinating, and defecating. Such movements are largely carried out by smooth muscles of the viscera ( alimentary canal and bladder, for example); they are innervated by efferent sympathetic and parasympathetic nerves. Other movements relate the body to the environment, either for moving or for signaling to other individuals. These are carried out by the skeletal muscles of the trunk and limbs. Skeletal muscles are attached to bones and produce movement at the joints. They are innervated by efferent motor nerves and sometimes by efferent sympathetic and parasympathetic nerves.

      Every movement of the body has to be correct for force, speed, and position. These aspects of movement are continuously reported to the central nervous system by receptors sensitive to position, posture, equilibrium, and internal conditions of the body. These receptors are called proprioceptors, and those proprioceptors that keep a continuous report on the position of limbs are the muscle spindles and tendon organs.

      Movements can be organized at several levels of the nervous system. At the lowest level are movements of the viscera, some of which do not involve the central nervous system, being controlled by neurons of the autonomic nervous system within the viscera themselves. Movements of the trunk and limbs occur at the next level of the spinal cord. If the spinal cord is severed so that no nerve impulses arrive from the brain, certain movements of the trunk and limbs below the level of the injury can still occur. At a higher level, respiratory movements are controlled by the lower brainstem. The upper brainstem controls muscles of the eye (eye, human), the bladder, and basic movements of walking and running. At the next level is the hypothalamus. It commands certain totalities of movement, such as those of vomiting, urinating (urination) and defecating (defecation), and curling up and falling asleep. At the highest level is gray matter of the cerebral hemispheres, both the cortex and the subcortical basal ganglia. This is the level of conscious control of movements.

Peter W. Nathan

Sensory receptors
      Only a minority of the nerve fibres supplying a muscle are ordinary motor fibres that actually make it contract. The rest are either afferent sensory fibres telling the central nervous system what the muscle is doing or specialized motor fibres regulating the behaviour of the sensory nerve endings. If the constant feedback of proprioceptive information from the muscles, tendons, and joints is cut off, movements can still occur, but they cannot be adjusted to suit changing conditions; nor can new motor skills be developed. As stated above, the sensory receptors chiefly concerned with body movement are the muscle spindles and tendon organs. The muscle spindle is vastly more complicated than the tendon organ, so that, although it has been much more intensively studied, it is less well understood.

Tendon organs
      The tendon organ consists simply of an afferent nerve fibre that terminates in a number of branches upon slips of tendon where the tendons join onto muscle fibres. By lying in series with muscle, the tendon organ is well placed to signal muscular tension. In fact, the afferent fibre of the tendon organ is sufficiently sensitive to generate a useful signal on the contraction of a single muscle fibre. In this way tendon organs provide a continuous flow of information on the level of muscular contraction.

Muscle spindles
      The familiar knee-jerk reflex, tested routinely by physicians, is a spinal reflex in which a brief, rapid tap on the knee excites muscle spindle afferent neurons, which then excite the motor neurons of the stretched muscle via a single synapse in the spinal cord. In this simplest of reflexes, which is not transmitted through interneurons of the spinal cord, the delay (approximately 0.02 second) primarily occurs in the conduction of impulses to and from the spinal cord.

      Information provided by muscle spindles is also utilized by the cerebellum and the cerebral cortex in ways that continue to elude detailed analysis. One example is kinesthesia, or the subjective sensory awareness of the position of limbs in space. It might be supposed (as it long was) that sensory receptors in joints, not the muscles, provide kinesthetic signals, since people are very aware of joint angle and not at all of the length of the various muscles involved. In fact, kinesthesia depends largely upon the integration within the cerebral cortex of signals from the muscle spindles.

      New features of the structure and function of the muscle spindle continue to be discovered. Within it are several specialized muscle fibres, known as intrafusal muscle fibres (from Latin fusus, “spindle”). The muscle spindle is several millimetres long, and approximately five intrafusal muscle fibres run throughout its length. They are considerably thinner and shorter than ordinary skeletal muscle fibres, although they show similar contractions and have the same histological appearance. The characteristic central swelling of the spindle (giving it a shape reminiscent of the spindle of a spinning wheel) is produced by fluid contained in a capsule surrounding the central millimetre of the intrafusal fibres.

      Classically, the nerve terminals are considered to be of three kinds: primary sensory endings, secondary sensory endings, and plate motor endings. There are approximately equal numbers of primary and secondary sensory endings, so they may be considered equally important. However, the primary, or annulo-spiral, ending has traditionally attracted the most attention, largely through its prominent appearance and the simplicity of its chief reflex action, the tendon jerk. It consists of a large axon, which branches to wind spirals around the equatorial region of every intrafusal fibre. The secondary ending is supplied by a smaller axon. It has less-dramatic “flower spray” terminals lying primarily upon the smaller intrafusal fibres to one side of the primary endings. The reflex action of the secondary endings is incompletely understood. The plate motor endings lie toward the ends of the intrafusal fibres. They are fairly similar to the motor end plates of the skeletal, or extrafusal, muscle fibres.

      The working of this elaborate piece of biological machinery is not yet fully understood. The muscle spindle lies parallel with the main muscle fibres and so sends a signal whenever the muscle changes its length. Both types of sensory endings increase their discharge of impulses when the muscle is stretched and reduce their firing when the muscle is slackened. The primary ending differs from the secondary ending in two important respects: first, it is much more sensitive to changing length of the muscle; second, it is much more sensitive to small stimuli than large ones. Together, these properties explain the exquisite sensitivity of the primary sensory ending to the stimulus of a tendon tap, which has little effect on the secondary ending or on the tendon organ. The essential principle is that the ability of the muscle spindle to signal a wide range of movement is increased by its having two separate output channels of different sensitivity.

      Most of the intrafusal fibres of the muscle spindle receive specialized fusimotor nerve fibres. These are much smaller than the motor axons innervating extrafusal muscle fibres and are given the name gamma (γ) efferents. Because their only function is to regulate the behaviour of the muscle spindles, their stimulation produces no significant contraction of the muscle as a whole. The γ efferents are of two functionally distinct kinds with different effects on the afferent fibres—especially on the primary ending. One type, the dynamic fusimotor axon, increases the normal sensitivity of the primary ending to movement; the other type, the static fusimotor axon, decreases its sensitivity, causing it to behave much more like a secondary ending. Thus, the two types of efferent fibre provide a means whereby the sensitivity of the muscle spindle to external stimuli may be regulated over a very wide range. Stimulation of both types also increases the rate of firing of the afferent fibres when the length of the muscle is constant; this is called a biasing action. It is thought that they produce these different effects by supplying different types of intrafusal fibre.

      In addition to receiving specialized fusimotor fibres, the muscle spindle may also receive, though on a less-regular basis, branches of ordinary extrafusal motor axons. Called alpha (α) efferents, these fibres have either a static or a dynamic effect. The physiologically important point is that most of the motor supply to the muscle spindles is largely independent of that of the ordinary muscle fibres, and only a small part is obligatorily coupled with them. The specific mechanisms by which the sensitivity of the spindle is regulated remain obscure; they may differ from muscle to muscle and for movements of different kinds.

Peter B.C. Matthews

Basic organization of movement

Stretch reflexes
      Primary afferent fibres are responsible for the stretch reflex, in which pulling the tendon of a muscle causes the muscle to contract. As noted above, the basis for this simple spinal reflex is a monosynaptic excitation of the motor neurons of the stretched muscle. At the same time, however, motor neurons of the antagonist muscle (the muscle that moves the limb in the opposite direction) are inhibited. This action is mediated by an inhibitory interneuron interposed between the afferent neuron and the motor neuron. These reflexes have a transitory, or phasic, action even though the afferent impulses continue unabated; this is probably because they become submerged in more-complex delayed reflex responses elicited by the same and other afferent inputs.

      Traditionally, it was thought that the stretch reflex provided uniquely for the automatic reflex control of standing, so that if the body swayed, then the stretched muscle would automatically take up the load and the antagonist would be switched off. This is now recognized to be only a part of the process, since more-powerful, slightly delayed reflex responses occur not only in the stretched muscle but also in others that help restore balance but have not themselves been stretched. Some of these responses seem to be spinal reflexes, but in humans, with their large brains, there is evidence that others are transcortical reflexes, in which the afferent impulse is transmitted rapidly up to the motor areas of the cerebral cortex to influence the level of ongoing voluntary motor impulses.

Reciprocal innervation
      Any cold, hot, or noxious stimulus coming in contact with the skin of the foot contracts the flexor muscle of that limb, relaxes the extensor muscles of the same limb, and extends the opposite limb. The purpose of these movements is to remove one limb from harm while shifting weight to the opposite limb. These movements constitute the first and immediate response to a stimulus, but a slower and longer-lasting reflex response is also possible. For example, noxious stimulation of the deep tissues of the limb can cause a prolonged discharge of impulses conducted by nonmyelinated afferent fibres to the spinal cord. The result is prolonged flexion of the damaged limb or at least a pattern of posture and movement favouring flexion. These effects last far longer than the original discharges from the afferent neurons of the damaged region—often continuing not for minutes but for weeks or months.

      The flexor and extensor reflexes are only two examples of the sequential ordering of muscular contraction and relaxation. Underlying this basic organization is the principle of reciprocal innervation—the contraction of one muscle or group of muscles with the relaxation of muscles that have the opposite function. In reciprocal innervation, afferent nerve fibres from the contracting muscle excite inhibitory interneurons in the spinal cord; the interneurons, by inhibiting certain motor neurons, cause an antagonist muscle to relax.

      Reciprocal innervation is apparent in eye movements. On looking to the right, the right lateral rectus and left medial rectus muscles of the eye contract, while the antagonist left lateral rectus and right medial rectus muscles relax. One eye cannot be turned without turning the other eye in the same direction (except in the movement of convergence, when both eyes turn medially toward the nose in looking at a near object).

      Reciprocal innervation does not underlie all movement. For example, in order to fix the knee joint, antagonist muscles must contract simultaneously. In the movement of walking, there is both reciprocal innervation and simultaneous contraction of different sets of muscles. Because this basic organization of movement takes place at lower levels of the nervous system, the training of skilled movements such as walking requires the suppression of some lower-level reflexes as well as a proper arrangement of the reciprocal inhibition and simultaneous contraction of antagonist muscles.

      Posture is the position and carriage of the limbs and the body as a whole. Except when lying down, the first postural requirement is to counteract the pull of gravity, which pulls the body toward the ground. This force induces stretch reflexes to keep the lower limbs extended and the back upright. The muscles are not kept contracted all the time, however. As the posture changes and the centre of gravity shifts, different muscles are stretched and contracted. Another important reflex is the extensor thrust reflex of the lower limb. Pressure on the foot stretches the ligaments of the sole, which causes reflex contraction of both flexor and extensor muscles, making the leg into a rigid pillar. As soon as the sole of the foot leaves the ground, the reflex response ceases, and the limb is free to move again.

      The body is balanced when the centre of gravity is above the base formed by the feet. When the centre of gravity moves outside this base, the body starts to fall and has to bring the centre back to the base. Striding forward in walking depends on leaning forward so that the centre of gravity moves in front of the feet. When a baby is learning to walk, he must either take a step forward or fall down. Both happen; eventually the former happens more frequently than the latter.

      In addition to continuous postural adjustment for the changing centre of gravity, all movements require that certain parts of the body be fixed so that other parts can be supported as they move. For instance, when manipulating objects with the fingers, the forearm and arm are fixed. This does not mean that they do not move; they move so as to support the fine movements of the fingers. This changing postural fixation is carried out automatically and unconsciously. Before any movement occurs, the essential posture is arranged, and it continues to be adjusted throughout the movement.

Lower-level mechanisms of movement (locomotion)
      The success of English physiologist Charles Sherrington (Sherrington, Sir Charles Scott) in opening up the physiology and pathology of movement by the study of reflexes caused a lack of interest in any other concept of movements, particularly in English-speaking countries. It was the German physiologist Erich Walter von Holst who, around the mid-20th century, first showed that many series of movements of invertebrates and vertebrates are organized not reflexly but endogenously. His general hypothesis was that within the gray matter there are networks of local neurons that generate alternating or cyclical patterns of movement. Von Holst proposed that these are the mechanisms of rhythmically repeated movements such as those of locomotion, breathing, scratching, feeding, and chewing.

      In fish, Von Holst demonstrated that the movements of the fins in swimming that need careful and correct timing and coordination continued even after the sensory dorsal roots of the spinal cord had been cut, so that there could be no sensory input to trigger reflexes. In these animals, command neurons in the lower medulla oblongata switch on the rhythmic movement built into the spinal cord, so that even when the brain has been cut out, the motor impulses and rhythmic movements continue.

      Von Holst's theory differs from previous concepts in that it attributes little or no importance to the role of feedback from the parts of the body being moved. Instead, it proposes, as the essential mechanism of repetitive movements, certain central pacemakers or oscillators. The role of feedback, according to this theory, is merely to modulate the central oscillator. This is seen in the above example of swimming movements in fish and even in purring rhythms in cats, which continue after dorsal roots have been cut.

      In certain kinds of movement, the input of dorsal roots is essential, but the movement needs to be defined in every case. For example, stepping movements of certain vertebrates, of which the mechanisms are within the spinal cord, can occur only with intact dorsal roots.

      Higher levels of the brain can set spinal centres in motion, stop them, and change the amplitude and frequency of repetitive movements. In the case of humans, when the spinal cord is cut off from the brain by disease or trauma, the movements that occur are uncontrolled. The movements of locomotion, seen in lower vertebrates, do not occur. This is because the cerebral hemispheres in humans have taken over the organization of movements that in lower species are organized at lower levels of the central nervous system, such as the reticular formation of the brainstem and the spinal cord.

      Within the centre of the brainstem, the reticular formation consists of vast numbers of neurons and their interconnections. The majority of the neurons have motor functions, and many of their fibres branch. This branching allows a single fibre to affect several different levels of the spinal cord. For example, one nerve fibre may excite motor neurons of the neck and of various regions of the back. This is one way in which commands from the higher neural level are sent to several segments of the spinal cord.

      The movements of breathing are instigated and regulated by chemoreceptors in blood vessel walls, which sense carbon dioxide tension in the blood plasma. The essential drive or central rhythm generator consists of pacemaker neurons in the reticular formation of the pons and throughout the medulla oblongata. These neurons show rhythmic changes in electrical potential, which are relayed by reticulospinal tracts to the spinal neurons concerned with respiration.

      Other movements intrinsic to the body are those needed for urination and defecation. Cats and dogs from which the cerebral cortex has been removed urinate and defecate in a normal manner. This is because nuclei in the midbrain near those that organize the movements of locomotion control these movements, so that urination and defecation occur whenever there are enough waste products to be expelled. This is also the condition of the healthy human baby. But as the infant grows up, he learns to fit these events into the social circumstances of living, which requires higher-level control by the cerebral hemispheres.

Higher-level mechanisms of movement
      Because of the many differences in the movements used in standing, coughing, laughing, or playing a scale on the piano, it is convenient to think of movements as lower and more automatic or as higher and less automatic. According to this concept, movements are not placed in totally different categories but are regarded as different in degree.

Cerebral hemispheres
      Basic organizations of movement, such as reciprocal innervation, are organized at levels of the central nervous system lower than the cerebral hemispheres—at both the spinal and the brainstem level. Examples of brainstem reflexes are turning of the eyes and head toward a light or sound. The same movements, of course, also can be organized consciously when one decides to turn the head and eyes to look. The cerebral hemispheres themselves can organize certain series of movements, called programmed movements, that need to be performed so rapidly that there is no time for correction of error by local feedback. For this reason the program is arranged before the movements begin. Examples of such movements are those of a pianist performing a trill or of an athlete hitting a ball.

      Most of the movements organized by the cerebral cortex are carried out automatically. But when a new series of movements is being learned, or when a movement is difficult, the attributes usually associated with the higher levels of the brain—such as planning, internal speech, remembering, and learning—are used. (For the role of the cerebral hemispheres in these higher mental activities, see below Higher cerebral functions (nervous system, human).)

 The primary motor area is the motor strip of the precentral gyrus. Immediately behind it is the postcentral gyrus, also called the primary sensory area. Each of these areas displays a maplike correspondence with various body parts, the legs represented near the top of the hemispheres and the arms and face lower on the cortical surface. Each of these areas is to some extent both motor and sensory. The motor region, for example, receives input from the skin, joints, and muscles via the postcentral gyrus behind and the thalamus below.

      Experiments in monkeys have shown that the motor strip is able to arrange activity of muscles to produce the correct force for the loading conditions of the limbs. To do this, the motor strip continually receives information from the primary sensory area both before and during the movement. Cutaneous areas having the greatest tactile acuity have the largest representation in the primary sensory area; these areas are connected to equally large areas in the primary motor area.

      In front of the motor strip is an area known as the premotor cortex or area. When it is stimulated in a monkey, the animal turns its head and eyes as though it is looking in a particular direction. This cortical area, then, organizes the guiding of movements by vision and hearing.

      The secondary motor area is at the lower end of the precentral gyrus. It is secondary not only because it was discovered after the primary motor area but also because it does not function in a discrete manner like the primary area. Stimulation of this small area produces movements of large parts of the body. It is also a sensory area, as sensations in the parts of the body being moved are felt during stimulation.

      On the medial surface of the hemisphere, in front of the motor strip, is the supplementary motor area. Stimulation of this area can produce vocalization or interrupt speech. Large movements of both sides of the body—often symmetrical movements of the two limbs—also may occur. Stimulation also produces movements of the opposite side of the body, such as raising the upper limb and turning the head and eyes as if looking at something opposite. In experiments on monkeys, when the animal chooses to respond to one kind of sensation rather than to another, it is the supplementary area that is active rather than the precentral area. In these animals—it is unknown for humans—the fibres descending from the supplementary motor area run to the spinal cord and terminate throughout its whole length. Fibres also are sent to the precentral gyri of both hemispheres, the reticular formation of the pons, the hypothalamus, the midbrain, and many other masses of cerebral gray matter such as the caudate nucleus and the globus pallidus. The supplementary motor area is upstream from the primary motor area; it initiates movements, whereas the motor strip of the precentral gyrus is part of the apparatus for carrying them out.

      Other regions of the cerebral hemisphere from which movements are produced by electrical stimulation are the insula and the surface of the temporal lobe. The insula is a region below the frontal and temporal lobes that, when stimulated, causes movements of the face, larynx, and neck. Stimulation of the anterior end of one temporal lobe causes movements of the head and body toward the other side.

      Fibres from the anterior part of the cingulate gyrus are involved in the control of urination and defecation. The organization of these functions also depends on regions anterior to the cingulate gyrus in the medial wall of the frontal lobe. These regions form a part of the limbic lobe, which is responsible, along with their autonomic components, for some emotional states.

      Movements closely guided by vision have their own pathways. Occipital visual areas send fibres to the pons and from there to the cerebellum. Also just in front of the visual cortex in the parietal lobe are neurons organizing certain types of eye movement. In the monkey, these neurons are at rest during steady gaze, becoming active when the animal turns its eyes to look at something. The fact that the movements constitute a high level of motor behaviour is shown by the activation of these neurons only when the animal is attempting to satisfy an appetite by using its upper limbs and hands; using the limbs for other purposes does not activate them. The neurons are also active when the animal is carrying out the movements of grooming, which also satisfies an innate drive.

      One of the main pathways for cortically directed movement of the limbs is the corticospinal tract. This tract developed among animals that used their forelimbs for exploring and affecting the environment as well as for locomotion. It is largest in humans. Fibres of the tract go to various regions of the brainstem and the spinal cord that organize movement. Excitation via the corticospinal tract is then brought to many muscles, all of them presumably working together in a coordinated manner. This is achieved by the anatomical arrangement of the motor neurons and by the termination of the corticospinal tract on interneurons, which convey a coordinated pattern of stimulation to the motor neurons.

      The corticospinal tract is not merely a pathway to medullary and spinal motor neurons. Activity in this tract can suppress the input from cutaneous areas while facilitating proprioceptive input. This is probably an important mechanism in the organization of movement. The corticospinal neurons themselves receive constant input from the cerebellum needed for internal feedback. Much of this input originates in the muscles, joints, and skin of the body parts being moved.

      Although a cycle of simple repetitive movements can be organized without sensory feedback, more-sophisticated movements require feedback as well as what is called feed-forward control. This is provided by the cerebellum. Many parts of the brain have to be kept informed of movements in order to detect error and continually correct the movement. The cerebellum continuously receives input from the trunk, limbs, eyes, ears, and vestibular apparatus, maintaining in turn a continuous transfer of information to the motor parts of the thalamus and to the cerebral cortex.

      As a movement is being prepared, a replica of the instructions is sent to the cerebellum, which sends back its own information to the cerebral cortex. The cortex, meanwhile, sends information about the movement to various afferent neurons that are about to receive information from receptors in the body parts where the movement is about to begin. This comparison between instructions sent and movement performed is a fundamental requirement of all complicated movements. The discharge of impulses from motor to sensory regions is called the corollary discharge. The mechanisms involving the cerebellum do not come to consciousness. There are no sensory consequences of damage to the cerebellum, for the cerebellum is a motor structure.

      As series of movements are learned and improved with practice, a replica of the movement is probably retained in the cerebral hemispheres. (The mechanisms of this postulated replica are as yet unknown.) Whenever the learned movements are repeated, they are formed and guided by the replica. This hypothesis of controlling movement by previously practiced patterns was developed by von Holst. He gave the name “efference” to the totality of motor impulses necessary for a movement, and he proposed that, whenever the efference is produced, it leaves an image of itself somewhere in the central nervous system. He called this image the efference copy. According to von Holst's theory, as the movement is repeated, afferent impulses, called the re-afference, return to the brain from receptors activated by muscular activity. There is then a comparison between the efference copy and the re-afference. When they are identical, the movement is “correct” in relation to its previous performance. When the re-afference differs from the efference copy, corrections have to be made so as to bring the present pattern of movement back to the original image left in the brain.

      If the cerebellum is damaged or degenerates, any error between the movement being performed and the efference copy will no longer be corrected, and the postural adjustments sent from the cerebral hemispheres will no longer be implemented. The force and extent of movements also will be abnormal, the movement going too far or not far enough. The various muscles may not come into play at the right time, and there will be a disturbance in the relationship of antagonist muscles, so that the accurate arrival on target will be replaced by oscillation.

Basal ganglia
      Most of what is known about the contribution of the basal ganglia has been obtained from studying abnormal conditions that occur when these nuclei are affected by disease. In Parkinson disease (parkinsonism) there is a loss of the pigmented neurons of the substantia nigra, which release the neurotransmitter dopamine at synapses in the basal ganglia. Individuals with this disease have a certain type of muscle stiffness called rigidity, a typical tremor, flexed posture, and difficulty in maintaining equilibrium. They have difficulty in initiating movements, including walking, and they cannot put adequate force into fast movements. They have particular difficulty in changing from one movement to its opposite, in carrying out two movements simultaneously, and in stopping one movement while starting another.

      The organization of posture, which is based on vestibular, proprioceptive, and visual input to the globus pallidus, is severely damaged when this region of the basal ganglia degenerates. Because a changing posture of the various parts of the body is a prerequisite of every movement, degeneration of this region upsets all movement. Visual reflexes contributing to motion also act through the globus pallidus. One patient may be unable to go forward if he has to pass through a narrow door, and another may not be able to do so if he has to go into a wide expanse such as a field.

Peter W. Nathan

The vestibular system
 Humans have evolved sophisticated sensory receptors to detect features of the environment in which they live. In addition to the special senses such as hearing and sight, there are unobtrusive sensory systems such as the vestibular system, which is sensitive to acceleration.

       acceleration can be considered as occurring in two forms—linear and angular. One familiar type of linear acceleration is gravity. Because this environmental feature, unlike any other encountered by an organism, is always present, highly sophisticated systems have developed to detect gravity and enable humans to maintain their position relative to Earth. A common form of angular acceleration is that induced by rotation, such as a turning of the head. Through the vestibular apparatus these forces are detected, and appropriate motor activities are organized to counter the postural perturbations that they induce.

Sensory receptors (receptor)
      The vestibular sensory organ is a paired structure located symmetrically on either side of the head within the inner ear. Inside each end organ are the hair cells, the detection units for both linear and angular acceleration. Extending from each hair cell are fine, hairlike cilia; displacement of the cilia alters the electrical potential of the cell. Bending the cilia in one direction causes the cell membrane to depolarize, while hyperpolarization is induced by movement in the opposite direction. Changes in membrane potential induce alteration in the firing of nerve impulses by the afferent neurons supplying each hair cell.

      The two types of acceleration are detected by two types of vestibular end organ. Linear acceleration is sensed by a pair of organs—the saccule and utricle—while there are three receptor organs—called semicircular canals—in each vestibular apparatus for the detection of angular acceleration.

Saccule and utricle
      Each saccule and utricle has a single cluster, or macula, of hair cells located in the vertical and horizontal planes, respectively. Resting upon the hair cells is a gelatinous membrane in which are embedded calcareous granules called otoliths. Changes in linear acceleration alter the pressure on the otoliths, causing displacement of the cilia and providing an adequate stimulus for membrane depolarization. Within each macula the hair cells are arranged in two groups oriented in opposite directions, so that the receptor functions in a push-pull fashion within each organ. Since many of the nerve fibres traveling from the hair cells to the brain are constantly active, this arrangement makes the receptors a highly sensitive detection system for both vertical and horizontal linear acceleration.

Semicircular canals
      The angular acceleration detectors within the semicircular canals function in a different way. The three canals—which in fact are considerably more than a semicircle in circumference—are oriented at approximately right angles to one another. Two are vertically placed, and one is at about 30° to the horizontal. In this arrangement the anterior canal of one side of the head is in the plane of the posterior canal of the other side. A ridge, or crista, covered by sensory hair cells is located at the end of each canal within an expanded chamber called the ampulla. Rotation of the canals about an imaginary axis passing through the centre of each semicircle causes endolymphatic fluid to flow toward or away from the crista, generating a force that bends the cilia by displacement of a gelatinous plate resting upon the hairs. The cells of the vertical canals are oriented in such a way that centrifugal movement away from the cristae depolarizes the hair cell membranes of the vertical canals, while the opposite applies to the horizontal canal.

Nerve supply
      As in the case of the utricle and saccule, some of the nerve fibres conveying information from the cells are constantly active. The hair cells receive nerve impulses from the brain (via efferent fibres) and send them to the central nervous system (via afferent fibres). Excitatory efferent fibres increase the sensitivity of the hair cells, while inhibitory fibres decrease sensitivity. This system gives the semicircular canals a plasticity that is essential to maintaining optimal activity under different environmental conditions—including such extraordinary states as space travel.

      The vestibular apparatus is supplied by neurons that make up the vestibular portion of the vestibulocochlear (vestibulocochlear nerve), or eighth cranial, nerve. The somata, or cell bodies, of the afferent fibres lie in the vestibular ganglia near the end organ. Most of the nerve fibres pass from there to vestibular nuclei in the pons, while others pass directly to the cerebellum. The efferent fibres of the vestibular nerve arise from nuclei in the pons.

Vestibular functions
      For vision to be effective, the retinal image must be stationary. This can be achieved only by maintaining the position of the eyes relative to the earth and using this as a stable platform for following a moving object. The vestibular system plays a critical part in this, mainly through complex and incompletely understood connections between the vestibular apparatus and the musculature of the eyes. Rotation of the head in any direction is detected by the semicircular canals, and a velocity signal is then passed via the vestibular nuclei to the somatic and extraocular muscles. In the case of the eye muscles, the velocity signal reaching the brainstem is in some way integrated with impulses signaling the position of the eyes, thus ensuring that the eyes maintain their position relative to space and the observed object. This integration partly occurs in the vestibular nuclei, the source of secondary neurons destined for the extraocular muscle nuclei of both sides.

      When the head is oscillated, the eyes maintain their position in space but move in relation to the head. This so-called vestibulo-ocular reflex operates in both horizontal and vertical planes owing to the arrangement of the three semicircular canals, and it maintains such stability that the observed object does not oscillate until quite high velocities are attained. The other components of the vestibular system, the saccule and utricle, also contribute to the vestibulo-ocular reflex. Under normal circumstances the otolith receptors cause torsional movement of the eyes. For example, tilting the head toward one shoulder results in counterrolling of the eyes, thereby stabilizing the image upon the retina. The two components of the vestibulo-ocular reflex interact, enabling appropriate eye movements to be generated when both linear and angular accelerations are changing.

      While the vestibulo-ocular reflex is the best understood of the vestibulo-motor connections, information from the vestibular receptors is also known to be passed via vestibular and other brainstem nuclei to the somatic musculature of the trunk and limbs. Through these pathways, body posture is adjusted to counter acceleration forces applied to the vestibule. These reflexes are so important in maintaining vertical posture that severe short-term consequences on posture are seen if the vestibulocochlear nerve is cut.

      Besides maintaining input for the generation of motor reflexes, vestibular impulses reach consciousness and create a powerful sensation. A person being rotated knows when he is accelerating even in the absence of an object upon which he can fix his eyes. This occurs because acceleration is the adequate stimulus for the semicircular canals. Similarly, information detected by the otoliths is brought readily to consciousness; for example, a person is aware when a darkened elevator accelerates up or down. The pathways to the cerebral cortex, which mediate conscious sensation, are not fully known, but there is evidence that areas of the parietal and temporal lobes receive connections via the thalamus.

      An important aspect of vestibular physiology is the interaction of vestibular impulses, which signal changes of position, and impulses from other sensory receptors that signal changes in bodily movement. For example, when the head turns to one side about a vertical axis, not only is the horizontal canal of that side stimulated and that of the other side inhibited, but receptors in the neck joints and muscles are also stimulated, and the retina indicates movement if fixation is not maintained perfectly. This information is fed to the brain via sensory pathways in the spinal cord and various visual sensory systems. Therefore, within the vestibular nuclei of the pons, neurons that respond to acceleration signals from the semicircular canals receive impulses from other sources as well. Other information from visual and spinal sensory systems pass to the cerebellum, which also receives direct impulses from the vestibular apparatus that bypass the vestibular nuclei. In this way the cerebellum has the opportunity to compare signals and assess the degree of mismatch between them. (Motion sickness is often generated by a mismatch between the various inputs signaling orientation within space. People will frequently be seasick if they are below the deck of a boat and the visual system signals no movement while the vestibular system indicates motion.) The vestibulo-ocular reflex also may be underactive, so that for a given head movement the eyes do not deviate sufficiently within the orbit and the observed object does not remain stationary upon the retina. Thus, the image slips and cannot be seen clearly during movement. The cerebellum has the opportunity to detect this mismatch between the required position of the eyes with respect to the environment and the movement actually achieved. Through inhibitory connections to the vestibular nuclei, the cerebellum can then adjust the vestibulo-ocular reflex so that a more appropriate movement of the eyes is achieved with the next acceleration signal. In other words, there is a continual updating of the vestibulo-ocular reflex via the cerebellum or structures associated with it.

      A similar situation also obtains for somatosensory input from the spinal cord. A dramatic demonstration of short-term adaptation via the visual system occurs when someone wears glasses with prism lenses that reverse the perception of the environment in the horizontal plane, making everything appear upside down. The person is at first unable to move about because any rotation of the head results in apparent movement of the environment in the wrong direction. However, over a few days normal mobility gradually returns. During this time, the vestibulo-ocular reflex is at first diminished in amplitude and then is reversed. Removal of the prisms results in a rapid return to the normal state. These experiments are a powerful demonstration of the plasticity of the vestibulo-ocular reflex, which can continue functioning throughout life in spite of the various insults that befall it.

Peter Rudge

Functions of the autonomic system
      The autonomic nervous system is regulated by cell groups in the brain that process visceral information arriving in specific neural networks, integrate that information, and then issue specific regulatory instructions through the appropriate autonomic outflows. Each end organ is processed in a unique way by functionally specific sets of neurons in which there is often coordination of both the sympathetic and parasympathetic nervous systems.

The eye (eye, human)
      In order for the eye (eye, human) to function properly, specific autonomic functions must maintain adjustment of four types of smooth muscle: (smooth muscle) (1) smooth muscle of the iris, which controls the amount of light that passes through the pupil to the retina, (2) ciliary muscle on the inner aspect of the eye, which controls the ability to focus on nearby objects, (3) smooth muscle of arteries providing oxygen to the eye, and (4) smooth muscle of veins that drain blood from the eye and affect intraocular pressure. In addition, the cornea must be kept moist by secretion from the lacrimal gland.

      When bright light is shined into an eye, the pupils of both eyes constrict. This response, called the light reflex, is regulated by three structures: the retina, the pretectum, and the midbrain. In the retina is a three-neuron circuit consisting of light-sensitive photoreceptors (rods (rod)), bipolar cells, and retinal ganglion cells. The latter transmit luminosity information to the pretectum, where particular types of neurons relay the information to parasympathetic preganglionic neurons located in the Edinger-Westphal nucleus of the midbrain. The axons of these neurons exit the ventral surface of the midbrain and synapse in the ciliary ganglion. From there, parasympathetic postganglionic neurons innervate the pupillary sphincter muscle, causing constriction.

      In order to bring a nearby object into focus, several changes must occur in both the external and internal muscles of the eyes. The initial stimulus for accommodation is a blurred visual image that first reaches the visual cortex. Through a series of cortical connections, the blurred image reaches two specialized motor centres. One of these, located in the frontal cortex, sends motor commands to neurons in the oculomotor nucleus controlling the medial rectus muscles; this causes the eyes to converge. The other motor centre, located in the temporal lobe, functions as the accommodation area. Via multineuronal pathways, it activates specific parasympathetic pathways arising from the ciliary ganglion. This pathway causes the ciliary muscle to contract, thereby reducing tension on the lens and allowing it to become more rounded so the image of the near object can be focused on the central part of the retina. At the same time, the iris, also under control of the oculomotor parasympathetic system, constricts to further enhance the resolution of the lens.

The urinary system (renal system)
      Functions of the urinary (urinary bladder) bladder depend entirely on the autonomic nervous system. For example, urine is retained by activation of sympathetic pathways originating from lateral horns in spinal segments T11–L2; these cause contraction of smooth muscle that forms the internal urinary sphincter. The external urinary sphincter, which works in concert with the internal sphincter, is made up of skeletal muscle controlled by motor fibres of the pudendal nerve. These fibres, arising from ventral horns of segments S2–S4, provide tonic excitation of the external sphincter. Because they are under voluntary control, micturition (urination) is initiated by higher brain centres. Voluntary inhibition of the sacral motor outflow results in relaxation of the external urinary sphincter. Simultaneously, an increase in abdominal pressure, caused by contraction of muscles of the abdominal wall, initiates the flow of urine. This is followed by a reflex inhibition of sympathetic outflow, resulting in relaxation of the internal urinary sphincter, and by activation of parasympathetic outflow to smooth muscle that causes the bladder to contract and expel the urine.

      While the autonomic nervous system is not crucial to functions of the kidney, the fine-tuning of certain processes, such as water maintenance, electrolyte balance, and the production of the vasoactive hormones renin and erythropoietin, is regulated by sympathetic fibres.

The reproductive system (reproductive system, human)
      The sexual response in both males and females can be defined by three physiological events. The first stage begins with psychogenic impulses in higher neural centres, which travel through multineuronal pathways and cause excitation of sacral parasympathetic outflow innervating vascular tissues of the penis or clitoris. This results in dilation of these arteries and erection of the penis or clitoris.

      The second stage involves secretion of glandular fluids, which is mediated by sympathetic neurons arising in the T12–L2 levels of the lateral horns. In the male, this stage involves contraction of the epididymis, vas deferens, seminal vesicles (seminal vesicle), and prostate gland, with the overall effect of moving fluids into the urethra; at the same time, sympathetic activation causes a closure of the internal urinary sphincter to prevent retrograde ejaculation of semen into the bladder. In the female, the response involves mucous secretions of the greater vestibular glands, resulting in lubrication of the vaginal orifice.

      The third phase involves a muscular response in which somatic efferent fibres in the pudendal nerve produce rhythmic contractions of the bulbocavernous and ischiocavernosus muscles in the male, causing ejaculation. In the female, homologous muscles of the pelvic floor undergo rhythmic contractions controlled by somatic efferent neurons from the S2–S4 ventral horns.

The endocrine system (endocrine system, human)
      The adrenal glands (adrenal gland), which lie above the kidney, are composed of the cortex and the medulla. The adrenal cortex synthesizes and secretes steroid hormones that are essential for life, but it is not under autonomic control. The adrenal medulla, on the other hand, is innervated by sympathetic preganglionic neurons. Within the adrenal medulla are chromaffin cells, which are homologous to sympathetic neurons and, like sympathetic neurons, are developed from embryonic neural crest cells. Chromaffin cells produce epinephrine (epinephrine and norepinephrine) (adrenaline) and, to a much lesser extent, norepinephrine as well as other chemicals such as chromogranins, enkephalins, and neuropeptide Y—all of which are released into the bloodstream and act as hormones. Epinephrine in particular affects many different types of tissues throughout the body and has a particularly potent effect on cells that possess β-adrenoceptors.

      The release of epinephrine prevents hypoglycemia (low blood sugar) through the following mechanism. By binding to α2-adrenoceptors embedded in the hormone-releasing cells of the pancreas, epinephrine inhibits the release of insulin. Since insulin promotes the absorption of glucose from the bloodstream into liver, skeletal muscle, and fat cells, inhibition of its release results in a greater amount of glucose that is available for entry into the brain. In addition, by binding to certain β-adrenoceptors, epinephrine stimulates the release of glucagon, a pancreatic peptide hormone that acts in the liver to convert glycogen to glucose. Under emergency conditions, epinephrine causes even more widespread effects on glucose metabolism. Glycogen in the liver and skeletal muscle is broken down to glucose; fat held in adipose cells is converted to fatty acids and glycerol; and production of glucose and ketone bodies (e.g., β-hydroxybutyric acid and acetoacetic acid) is increased in the liver. All of these substances can be used as energy sources for the body.

The cardiovascular system (human cardiovascular system)
      The function of the cardiovascular system (human cardiovascular system) is to maintain an adequate supply of oxygen to all tissues of the body. In order to maintain this function, the autonomic system must process visceral information and coordinate neural elements that innervate the heart, blood vessels, and respiration. In addition, certain hormones such as angiotensin II and vasopressin are released and act in concert with the autonomic nervous system.

Reflex pathways
      The cardiovascular system is regulated by sets of neurons that form two major types of reflex circuit. One type is triggered by mechanoreceptors (mechanoreception) found in the major arteries near the heart and in the heart itself. Receptors (mechanoreception) sensitive to high pressure are located in the wall of the aortic arch and the carotid sinuses. These receptors are innervated by the aortic branch of the vagus nerve and by a branch of the glossopharyngeal nerve. Both branches send information regarding increases in arterial blood pressure into the medulla oblongata and synapse in the nucleus of the solitary tract. Another group of mechanoreceptors provides information about venous pressure and volume; these are low-pressure receptors located in the walls of the major veins as they enter the heart and within the walls of the atria. Low-pressure afferents also relay sensory information to the solitary tract.

      Mechanoreceptors trigger what is called the baroreceptor reflex, which causes a decrease in the discharge of sympathetic vasomotor and cardiac outflows whenever an increase in blood pressure occurs. In addition, the baroreceptor reflex causes stimulation of vagal cardioinhibitory neurons, which produces a decrease in heart rate, a decrease in cardiac contractility, and dilation of peripheral blood vessels. Overall, the net effect is to lower blood pressure.

      The second major class of afferents that trigger reflex responses are chemoreceptors found in the major arteries near the heart in groups close to the high-pressure mechanoreceptors. Functioning as oxygen sensors, these receptors are innervated by separate sets of fibres that travel parallel with the baroreceptor nerves, and they also project to the nucleus of the solitary tract. Overall, the chemoreceptor reflex regulates respiration, cardiac output, and regional blood flow, ensuring that proper amounts of oxygen are delivered to the brain and heart.

Vasopressin and cardiovascular regulation
      Vasopressin is a peptide hormone that is synthesized in magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus. These neurons send their axons into the posterior lobe of the pituitary gland, from which vasopressin is released into nearby capillaries and distributed throughout the body.

      Vasopressin has two main functions: volume regulation and vasomotor tone. It acts to increase water retention by increasing the permeability of kidney tubules to water as the kidney filters blood plasma. As more water is reabsorbed, extracellular fluid volume is increased, and this in turn increases venous volume and, ultimately, blood pressure. Under emergency conditions, vasopressin also selectively constricts certain vascular beds that are nonessential for life (e.g., gastrointestinal, muscle); this shunts blood to critical tissues such as the heart and brain.

      Two major stimuli trigger the release of vasopressin: increases in extracellular fluid osmolality and decreases in blood volume (as in hemorrhage). Osmotic stimuli cause vasopressin to be released by acting on specialized brain centres called circumventricular organs surrounding the third and fourth ventricles of the brain. These “osmosensitive” areas contain neurons with central projections that alter autonomic and neuroendocrine functions and possess a unique vascular system that permits diffusion of large molecules such as peptides and ions to cross readily from the plasma to the brain. Normally, such chemical agents do not have free passage, because the capillaries form a blood-brain barrier, but at these special sites they have direct access to central neurons. One of the areas, called the organum vasculosum of the lamina terminalis, lies in the third ventricle and is involved in osmo- and sodium regulation. Another circumventricular organ, called the subfornical organ, lies in the dorsal part of the third ventricle; it is particularly sensitive to hormones such as angiotensin II and signals that changes are needed for the regulation of salt and water balance. Both regions project directly to vasopressin-producing hypothalamic neurons. The area postrema, which lies on the floor of the fourth ventricle in the medulla oblongata, is also involved as a special chemical sensor of the plasma.

      When blood is lost through hemorrhage, atrial receptors and baroreceptors relay volume and pressure information, via the vagus nerve, into the nucleus of the solitary tract. Neurons in this nucleus send commands to other relay neurons that project directly to the magnocellular hypothalamic neurons and cause the release of vasopressin.

Arthur D. Loewy

Theories of pain
      There have always been two theories of the sensation of pain, a quantitative, or intensity, theory and a stimulus-specific theory. According to the former, pain results from excessive stimulation (e.g., excessive heat or cold, excessive damage to the tissues). This theory in its simplest form entails the belief that the same afferent nerve fibres are activated by all of these various stimuli; pain is felt merely when they are conducting far more impulses than usual. But knowledge acquired in the 20th century has shown that the quantitative theory—at least in its classic form—is wrong. Peripheral nerve fibres are stimulus-specific; each one is excited by certain forms of energy. The stimulus-specific theory of pain proposes that pain results from interactions between various impulses arriving at the spinal cord and brain, that these impulses travel to the spinal cord in certain nonmyelinated and small myelinated fibres, and that the specific stimuli that excite these nerve fibres are noxious, or harmful.

      Certain kinds of nerve fibres in the somatic tissues do not give rise to pain, no matter how many there are or how frequently they are stimulated. Included in this category are mechanoreceptors that report only deformation of the skin and larger afferent nerve fibres of muscles and tendons that form part of the organization of posture and movement. No matter how they are excited, these receptors never give rise to pain. But the smaller fibres from these tissues do cause pain when they are excited mechanically or chemically.

      Thermoreceptors of the skin are also stimulus-specific. Warmth fibres are excited by rising temperature and inhibited by falling temperature, and cold fibres respond similarly with cold stimuli. Although pain arises from very hot and very cold stimulation and with intense forms of mechanical stimulation, this occurs only with the activation of afferent nerve fibres that specifically report noxious events. When no noxious events are occurring, these nerve fibres are silent.

      In contrast, the quantitative theory of pain seems to apply to the viscera, where afferent nerve fibres used in reflex organization also report events that cause pain. In the heart, rectum, and bladder, pain appears to be due to a summation of impulses in sensory nerve fibres and may not be mediated by a special group of fibres reserved for reporting noxious events. In the heart, for example, the same nerve fibres are excited by mechanical stimulation as are excited by chemical substances formed in the body that cause pain. In the bladder, rectum, and colon, nerve fibres activated by substances that cause pain are the same as those activated by distension and contraction of the viscera. This means that the same nerve fibres are reporting the state that underlies the desire to urinate or defecate and the sensation underlying the pain felt when these organs are strongly contracting in an attempt to evacuate their contents.

Lower-level pain pathways

Tissues (tissue)
      Not all tissues give rise to pain; furthermore, each tissue must be stimulated in an appropriate way to invoke its particular sensation of pain. The skin, being the outer covering of the body, easily raises the warning of pain, but other tissues that do not come in direct contact with the outer environment are just the opposite. The brain, for example, can be pierced, cut, and burned in neurosurgery, while the patient would require only local anesthesia of the pain-sensitive scalp. The lung, liver, and spleen also do not give rise to pain, no matter how they are stimulated. Pain arises from hollow viscera when the passage of their contents is obstructed and the musculature must undergo strong contraction and stretching. Pain cannot be induced by cutting or burning the wall of the intestines, but pulling on the mesenteric tissue that attaches the intestines to the posterior wall of the abdomen causes pain. The reason for these differences is clear. Tissues are sensitive to the kinds of damage that are likely to occur and not to those that probably will never occur.

      Although the warning function of pain is obvious, it is not equivalent to nociception, the perception of forces likely to damage the tissues of the body. Nociception can occur without pain and vice versa; also, the sensation of pain is only a part of the total act of nociception. There are reflex effects as well, such as a local reflex withdrawal from a sudden noxious stimulation of the skin. Autonomic effects, such as a rise in blood pressure, quickening of the heart rate and respiration, and other excitatory sympathetic nervous effects, also occur. There may even be shrieking or howling, warning other animals that something dangerous and painful is occurring.

      Acute and chronic pain differ in many ways. Acute pain occurs with sudden damage, such as stepping on a nail or biting the tongue. Chronic pain is the pain of pathological (pathology) conditions—the pain that accompanies gout, arthritis, or cancer.

      The effect of acute inflammation of the joints on nerves reporting the state of the joint and on the central nervous system has been studied by inducing arthritis in animals. In this condition, locally formed chemical substances excite the small myelinated and nonmyelinated afferent fibres that report noxious events. Most of these nerves, sensitized by the inflammatory exudate, begin to fire impulses continuously. This flow of impulses to the dorsal-horn neurons of the spinal cord increases their excitability so that many of them also begin to fire continuously. Neurons that are normally excited only by noxious stimulation now respond to light touch as well. Meanwhile, motor neurons in related areas also fire spontaneously, and stimuli that would not normally cause withdrawal reflexes now cause a prolonged reflex response. There is no change in the motor neurons themselves; the change is in the firing threshold of peripheral neurons coming from the inflamed area and in the interneurons between the afferent nerve fibres and the motor neurons. These interneurons are ultimately connected to the brain, so that the state of increased sensitivity is passed on to related cerebral neurons. Eventually, neurons in the cerebral hemispheres continuously and spontaneously generate impulses. Other neurons of the brain start responding to movements of the affected joints that normally would not do so.

      In some people with chronic painful conditions, the constant pain impulses change the character of neurons of the thalamus and cerebral cortex. For example, an individual who had a toothache 10 days before he had surgery on the thalamus for parkinsonism suddenly got a toothache again when the thalamus was stimulated electrically. Normally, no pain can be induced by stimulating that part of the thalamus.

Peripheral nerves
      Most of the afferent nerves making up the dorsal roots are nonmyelinated fibres. These fibres are activated by warmth within a physiological range (and by higher temperatures likely to damage the body), by chemical substances (including those produced by the body), and by strong mechanical stimulation such as pricking and crushing. The smaller myelinated fibres report mechanical stimulation of the skin, noxious stimulation, and cold temperatures.

      As stated above, pain is not the inevitable result of the firing of nonmyelinated fibres reporting noxious events. These fibres may fire at a slow rate without causing pain; they may even continue to fire for an hour or so without pain. Furthermore, the pain threshold does not correspond with the onset of activity in the nonmyelinated fibres, for pain can increase while the discharge of nerve impulses decreases.

      The stimulus-specific organization of the peripheral nerve fibres is not continued within the spinal cord, as the various afferent nerve fibres do not transmit their impulses exclusively to neurons of only one kind of sensibility. In the dorsal horns (the spinal region that receives afferent impulses) a few neurons are purely nociceptive, but most neurons reporting noxious events receive both noxious and mechanoreceptive input. The latter are called convergent neurons. The size of the peripheral field (the area of the body from which it receives stimuli) of a dorsal-horn neuron continually varies, depending on the state of excitability of the neuron. Furthermore, events in the peripheral field affect future responses. For example, repeated input along a group of afferent nerve fibres produces a gradually decreasing response in the central nervous system, called habituation. Also, the region of decreased response spreads from local neurons that initially received the input to neighbouring neurons.

      The state of excitability of a dorsal-horn neuron depends on many variables. If it is very excitable, it will respond to impulses from many afferent peripheral nerve fibres; if it is relatively inexcitable, it will be affected only by those peripheral fibres that are connected to it and located near it. A neuron excited by many afferent fibres receives input from a larger area than a neuron receiving only from the fibres most nearly related to it. For this reason the area of skin or deep tissue connected to neurons of the dorsal horn varies and changes. In experiments using damaged skin, it has been found that a barrage of nerve impulses from the damaged region increases the excitability of the dorsal-horn neurons. Once this hyperexcitable state has been set up, it continues for some time without further input from the peripheral nerves. In this state of local excitability, some dorsal-horn neurons receive input from the area of damaged skin that they would not receive were the skin in a normal state.

      The activity of the convergent neurons mentioned above can be inhibited by tactile stimulation of a region near their peripheral fields or of a homologous region on the opposite side of the body. Also, their responsiveness to stimuli can be increased by damage to the skin in their peripheral fields. Tracts of long fibres arise from these convergent neurons and from other neurons of the dorsal horns that cross the midline and lead to the thalamus and other nuclei of the brain. These fibres constitute the spinothalamic tracts. The other main pathway of pain impulses ends in the reticular formation of the medulla oblongata and pons and is known as the spinoreticular tract. It is believed that spinoreticular input to the brain serves the autonomic responses and emotional components associated with pain, whereas the spinothalamic tract serves conscious sensation, with its exact temporal and spatial aspects. Neurons around the central spinal canal that receive input from the bladder and colon and their overlying somatic tissues may be connected to an ascending tract that stays within the gray matter in the neighbourhood of the central canal.

Higher-level pain pathways

      Many regions of the brain can influence the input arriving at lower levels of the nervous system. This descending inhibition can be selective, with different regions of the brain inhibiting certain inputs to the spinal cord. Some regions reduce mechanoreceptive input, and others reduce noxious and warmth inputs. Descending inhibition can also reduce input from the skin while increasing input related to movement.

      Prominent regions of influence are those that themselves receive noxious input. For instance, the lateral reticular nuclei of the medulla oblongata cause a constant inhibition of input brought to the spinal cord by the nonmyelinated fibres. In the rat (in which the discovery was first made) descending inhibition can be so effective that a noxious input does not enter the spinal cord. In other words, normally painful stimuli cause no reaction or concern, and there is no change in blood pressure, respiration, or other reflex activities. In these circumstances it seems that pain simply is not felt.

      Electrical stimulation of the nucleus ceruleus, a small nucleus with widely ranging axons, and the nucleus raphe magnus, a nucleus in the central reticular formation of the medulla oblongata, inhibits input from noxious stimulation of the skin, and it also inhibits activities of dorsal-horn neurons receiving mechanoreceptive input. Since it was discovered that pain could be obliterated in this manner, attempts have been made to stop the chronic pain of cancer and other conditions by implanting electrodes in relevant parts of the brain so that constant stimulation can inhibit the input coming from the region of the pain.

      This system for obliterating or reducing pain can normally be activated by stress. Furthermore, it has always been known that one pain can mask another. A barrage of nerve impulses reaching the brain via the spinothalamic and spinoreticular tracts and causing a moderate degree of pain is stopped when the cells of origin of this tract are inhibited. Experiments have shown that this suppression can be brought about by a more severe pain or by a pain in a larger area of the body, which causes descending inhibition of neurons of the spinal tract. This descending inhibition is the main mechanism of acupuncture.

      The reticular formation consists of a vast number of small interconnected neurons occupying the central area of the brainstem. Parts of the reticular formation, hypothalamus, and thalamus excite the cerebral hemispheres and keep the cerebral cortex active and alert—partly in response to noxious input. In fact, it may be said that pain reaches consciousness in the thalamus. The thalamus receives noxious input from the spinal cord in two regions, a lateral part called the ventrobasal complex and a medial part consisting of several nuclei. The ventrobasal complex is involved with the accurate temporal and spatial localization of conscious sensation, while the medial nuclei are concerned with the emotional, affective, and autonomic components of pain and other sensations. The ventrobasal nuclei relay impulses to the sensory areas of the postcentral gyrus. Noxious stimuli also cause responses in many areas of the cerebral cortex and the deeper islands of gray matter. This is to be expected, for pain is the least-pure sensation; it startles, it excites, and it has unpleasant qualities. All these aspects of pain are added by different parts of the brain.

Central pain
      Pain arising within the central nervous system when there is no damage to the body is known as central pain. The most common central pain is due to lesions in or near the thalamus and is called the thalamic syndrome. This condition is characterized by diminution in sensibility as well as severe pain when any stimulus exceeds a certain threshold.

      With central pain, there is both spontaneous pain and excessive pain on stimulation of all kinds. Pain may occur in an entire half of the body, affecting even visual and auditory inputs, or it may occur in a restricted region, such as an upper limb and side of the face or a lower limb.

      The term referred pain is used to describe pain felt in a region where it does not originate but to which it is referred. It is usually used to describe pain arising in hollow viscera and felt in somatic tissues, such as the body wall. Referred pain is always referred in one direction—from deep to superficial tissues. It is pain referred from an unknown or unfamiliar part of the body to a known or familiar part.

      Certain regions of the dorsal horns of the spinal cord receive both nerve fibres from the viscera and nerve fibres reporting noxious events in the skin and musculature. For example, afferent nerve fibres from the heart travel to the same regions as those from the muscles and skin of the chest wall and upper limbs. ( angina pectoris, a spasm of pain in the chest that results from diseased heart tissue, is often referred to the chest and arm.) There is an intermingling of inputs in visceral and somatic tissues, and there is similar convergence in the thalamus. This anatomical arrangement is likely to form the basis of referred pain, although the mere convergence of impulses from viscera and soma onto the same neurons does not alone account for the false localization of visceral pain. It is probable that in sensory areas of the brain, the skin is served by a large number of neurons, the muscles with fewer, and the viscera with least, the visceral representation in the cortex being very small compared with that of the somatic tissues. It is supposed that, as the input to these sensory regions of the cortex usually comes from the skin and body wall, localization of the visceral input will be to these tissues and not to the viscera, the cortical region of which is small and relatively unused.

Changes in the cerebral cortex
      Normally, electrical stimulation of the sensory region of the postcentral gyrus does not cause pain. But in many patients who have a painful state on the opposite side of the body, such as an amputation stump or damage to the median nerve of the hand, stimulation of this region reproduces the pain. Pain also arises from stimulation of the white matter deep in the cerebral cortex.

      In these cases the character of the sensory region of the cortex changes so that neurons that normally never cause pain when stimulated now invariably produce the pain from which the individual is suffering. Also, the cortical area subserving the limb enlarges. For instance, the sensory area receiving impulses from the opposite lower limb is normally at the upper end of the postcentral gyrus. If there is a painful amputation of the limb, then the area of the cortex in which electrical stimulation induces the pain spreads downward from the normal area to include the trunk area and sometimes the upper limb area; this phenomenon is called phantom pain.

      To the biologist, the life of animals (including that of humans) consists of seeking stimulation and responding appropriately. A reflex occurs before an individual knows what has happened—for example, what made him lift a foot or drop an object. It is biologically correct to be alarmed before one knows the reason. It is only after the immediate and automatic response that the cerebral cortex is involved and conscious perception begins.

      Perception comes between simple sensation and complex cognitional behaviour. It is so automatic that people hardly realize that seeing what they see and hearing what they hear is only an interpretation. Each act of perception is a hypothesis based on prior experience; the world is made up of things people expect to see, hear, or smell, and any new sensory event is perceived in relation to what they already know. People perceive trees, not brown upright masses and blotches of green. Once one has learned to understand speech, it is all but impossible to hear words as sibilants and diphthongs, sounds of lower and higher frequencies. In other words, recognizing a thing entails knowing its total shape or pattern. This is usually called by its German name, gestalt (Gestalt psychology).

      As well as perception of the external environment, there is perception of oneself. Information about one's position in space, for example, comes from vision, from vestibular receptors, and from somatic receptors in the skin and deep tissues. This information is collected in the vestibular nuclei and passed on to the thalamus. From there it is relayed to the central gyri and the parietal region of the cerebral cortex, where it becomes conscious perception. (For detailed discussion of the perception of movement, see above The vestibular system (nervous system, human).)

General organization of perception
      Perception relies on the special senses—visual, auditory, gustatory, and olfactory. Each begins with receptors grouped together in sensory end organs, where sensory input is organized before it is sent to the brain. A reorganization of impulses occurs at every synapse on a sensory pathway, so that by the time an input arrives at the thalamus, it is far from being the original input that stimulated the receptors.

      The afferent parts of the thalamus fall into two divisions: a medial part, which is afferent but not sensory, and a ventral and lateral part, which is sensory. Nerve impulses reaching the medial part of the thalamus are derived from the reticular formation. This pathway is for emotional and other rapid reactions such as surprise, alarm, vigilance, and the readiness to react. The lateral part of the thalamus is a station on the way to areas of the cerebral cortex that are specific for each kind of sensation.

 The cerebral cortex has three somatosensory areas. The primary sensory area occupies the postcentral gyrus immediately behind the motor strip and receives input from the ventrolateral thalamus. The secondary area is above the Sylvian fissure, behind the secondary motor area, and receives somatosensory input from the lateral part of the thalamus and also auditory and visual input from the medial and lateral geniculate nuclei. The primary and secondary areas are reciprocally connected. The supplementary area is in the upper part of the parietal lobe on the medial surface of the hemisphere, just behind the primary area.

      The cerebral cortex (and the thalamus as well) is composed of nonspecific and specific sensory areas. Most neurons of the specific regions have small receptive fields in the periphery, respond to only one kind of stimulus, and follow the features of stimulation exactly. Most neurons of the nonspecific regions have large receptive fields and respond to many kinds of stimuli; many do not exactly reproduce the features of the stimulus.

      Although different regions of the body are normally represented by specific parts of the somatosensory regions of the cortex, the parts of the body where afferent impulses arrive are not fixed. For example, the leg area is at the top of the postcentral gyrus, but when there is a painful state in the periphery— sciatica, for example—the leg area of the cortex can enlarge and occupy some of the arm area. Furthermore, injury to the peripheral nerves or brain may alter the sensory map of the cortex. These changes in the cortex and similar changes in anatomical function are referred to as plasticity (neuroplasticity).

      From the somatosensory area, nerve fibres run to other regions of the cortex, traditionally called association areas. It is thought that these areas integrate sensory and motor information and that this integration allows objects to be recognized and located in space. With these regions acting upon all their inputs, the brain is carrying out those aspects of neural activity that are commonly labeled mental. It is not known how or where the brain collects messages from sensory receptors and then arranges them to produce a complete representation of the world and of the individual's place in the world.

      Most investigations of the visual pathways in the brain have been carried out in the cat.

 The area of the brain concerned with vision makes up the entire occipital lobe and the posterior parts of the temporal and parietal lobes. The primary visual area, also called the striate cortex, is on the medial side of the occipital lobe and is surrounded by the secondary visual area. The visual cortex is sensitive to the position and orientation of edges, the direction and speed of movement of objects in the visual field, and stereoscopic depth, brightness, and colour; these aspects combine to produce visual perception.

      The ganglion neurons of the retina are categorized into three functional types: X-, Y-, and W-cells. X-cells have small peripheral fields and are necessary for high-resolution vision. Y-cells are the largest of the three cells, have large peripheral fields, and respond to fast movement. W-cells are the smallest of the three cells, have large peripheral fields, and are sensitive to directional movement. In the retina, 50 to 55 percent of ganglion cells are W-type, 40 percent are X-type, and 5 to 10 percent are Y-type.

      As constituent fibres of the optic nerves and optic tracts, X- and Y-cells connect to the lateral geniculate nucleus of the thalamus, while W-cells connect primarily to the superior colliculus of the midbrain. From these regions, input from the X-cells travels mainly to the primary visual area, that from the Y-cells to the secondary visual area, and that from the W-cells to the area surrounding the secondary area. The collicular pathway serves movement detection and direction of gaze. The tract from the lateral geniculate nucleus is the pathway for visual acuity.

      The primary area sends fibres back to the lateral geniculate nucleus, the superior colliculus, and the pupillary reflex centre for feedback control of input to the visual areas. It also sends fibres to the secondary area and to the visual area of the temporal lobe. The secondary area sends fibres to the temporal and parietal lobes. Also, fibres cross from visual areas of one cerebral hemisphere to the other in the corpus callosum. This link allows neurons of the two hemispheres with similar visual fields to have direct contact with each other.

      Neurons of the striate cortex may form the first step in appreciation of orientation of objects in the visual field. It is thought, however, that excitation of cortical neurons is insufficient to account for orientation and that inhibition of other neurons in the visual cortex is also necessary. Whatever the mechanism, experiments on cats and monkeys have shown that individual neurons are activated by lines at different angles—for example, at 90° to the horizontal or at an angle of 45°.

      Most neurons of the deeper layers of striate cortex are movement analyzers. Some are direction analyzers, activated by a line or an edge moving in one direction and silenced when it changes direction (the changed direction then activating other neurons). Some neurons may be excited by a dark line on a bright background and others by a light line on a dark background. Form analyzers are located in other regions of the striate cortex; for example, some are activated by rectangles and others by stars. Position neurons respond strongly to a spot located in a certain position and poorly to stimulation of a larger area; others respond only to simultaneous binocular stimulation. Colour-specific neurons are sensitive to red, green, or blue. Each of these neurons is excited by one colour and inhibited by another.

      In the secondary visual area, many neurons respond particularly to the direction of moving objects. Neurons activated by colour are not activated by white light. In the part of this area where there are many neurons responding to colour, the periphery of the visual field is not mapped; this is because the periphery of the retina does not contain colour receptors, called cones (cone). The peripheral field is mapped in an area with neurons that respond to movement—notably in the region of the superior temporal gyrus.

      It seems that one function of the pathway from the superior colliculus to the temporal and parietal cortices is as a tracking system, enabling the eyes and head to follow moving objects and keep them in the visual field. The pathway from the geniculate nucleus to the primary visual area may be said to perceive what the object is and also how and in what direction it moves.

      Some neurons in the parietal cortex become active when a visual stimulus comes in from the edge of the visual field toward the centre, while others are excited by particular movements of the eyes. Other neurons react with remarkable specificity—for example, only when the visual stimulus approaches from the same direction as a stimulus moving on the skin, or during the act of reaching for an object and tracking it with the hand. These parietal neurons greatly depend on the state of vigilance. In monkeys that are apparently merely waiting for something to happen or that have nothing to which to pay attention, the neurons are inactive or minimally active. But when the animal is looking at a visual target whose change it has to detect in order to obtain a reward, the parietal neurons become active.

      A great number of neurons of the middle temporal area are sensitive to the direction of movement of a visual stimulus and to the size of an object. Neurons involved in perceiving shape and colour are located in the inferior temporal area. The neurons of the superior temporal polysensory area respond best to moving stimuli—in particular to movements away from the centre of the visual field. Both these areas are involved with the incorporation of visual stimuli and movement.

      Much of the knowledge of the neurological organization of hearing has been acquired from studies on the bat, an animal that relies on acoustic information for its livelihood.

      In the cochlea (the specialized auditory end organ of the inner ear), the frequency of a pure tone is reported by the location of the reacting neurons in the basilar membrane, and the loudness of the sound is reported by the rate of discharge of nerve impulses. From the cochlea, the auditory input is sent to many auditory nuclei. From there, the auditory input is sent to the medial geniculate nucleus and the inferior colliculus, as with the relay stations of the retina. The auditory input finally goes to the primary and secondary auditory areas of the temporal lobes.

 The auditory cortex provides the temporal and spatial frames of reference for the auditory data that it receives. In other words, it is sensitive to aspects of sound more complex than frequency. For instance, there are neurons that react only when a sound starts or stops. Other neurons are sensitive only to particular durations of sound. When a sound is repeated many times, some neurons respond, while others stop responding. Some neurons are sensitive to differences in the intensity and timing of sounds reaching the ears. Certain neurons that never respond to a note of constant frequency respond when the frequency falls or rises. Others respond to the rate of change of frequency, providing information on whether distance from the source of a sound is increasing or decreasing. Some neurons respond to the ipsilateral ear, others to the contralateral, and yet others to both ears.

emotion and behaviour (human behaviour)
      In order to carry out correct behaviour—that is to say, correct in relation to the survival of the individual—humans have developed innate drives, desires, and emotions and the ability to remember and learn. These fundamental features of living depend on the entire brain, yet there is one part of the brain that organizes metabolism, growth, sexual differentiation, and the desires and drives necessary to achieve these aspects of life. This is the hypothalamus and a region in front of it comprising the septal and preoptic areas. That such basic aspects of life might depend on a small region of the brain was conceived in the 1920s by the Swiss physiologist Walter Rudolph Hess (Hess, Walter Rudolf) and later amplified by German physiologist Erich von Holst. Hess implanted electrodes in the hypothalamus and in septal and preoptic nuclei of cats, stimulated them, and observed the animals' behaviour. Finally, he made minute lesions by means of these electrodes and again observed the effects on behaviour. With this technique he showed that certain kinds of behaviour were organized essentially by just a few neurons in these regions of the brain. Later, von Holst stimulated electrodes by remote control after placing the animals in various biologically meaningful conditions.

      When such acts result from artificial stimulation of the neurons, the accompanying emotion also occurs, as do the movements expressing that emotion.

      The hypothalamus, in company with the pituitary gland, controls the emission of hormones, body temperature, blood pressure and the rate and force of the heartbeat, and water and electrolyte levels. The maintenance of these and other changing events within normal limits is called homeostasis; this includes behaviour aimed at keeping the body in a correct and thus comfortable environment.

      The hypothalamus is also the centre for organizing the activity of the two parts of the autonomic system, the parasympathetic and the sympathetic (see above The autonomic system (nervous system, human)). Above the hypothalamus, regions of the cerebral hemispheres most closely connected to the parasympathetic regions are the orbital surface of the frontal lobes, the insula, and the anterior part of the temporal lobe. The regions most closely connected to the sympathetic regions are the anterior nucleus of the thalamus, the hippocampus, and the nuclei connected to these structures.

      In general, the regions of the cerebral hemispheres that are closely related to the hypothalamus are those parts that together constitute the limbic lobe, first considered as a unit and given its name in 1878 by the French anatomist Paul Broca (Broca, Paul). Together with related nuclei, it is usually called the limbic system, consisting of the cingulate and parahippocampal gyri, the hippocampus, the amygdala, the septal and preoptic nuclei, and their various connections.

      The autonomic system also involves the hypothalamus in controlling movement. Emotional expression, which depends greatly on the sympathetic nervous system, is controlled by regions of the cerebral hemispheres above the hypothalamus and by the midbrain below it.

      A great deal of human behaviour involves social interaction. Although the whole brain contributes to social activities, certain parts of the cerebral hemispheres are particularly involved. The surgical procedure of leucotomy, cutting through the white matter that connects parts of the frontal lobes with the thalamus, upsets this aspect of behaviour. This procedure, proposed by the Spanish neurologist Egas Moniz, used to be performed for severe depression or obsessional neuroses. After the procedure, patients lacked the usual inhibitions that were socially demanded, appearing to obey the first impulse that occurred to them. They told people what they thought of them without regard for the necessary conventions of civilization.

      Which parts of the cerebral hemispheres produce emotion has been learned from patients with epilepsy and from surgical procedures under local anesthesia in which the brain is electrically stimulated. The limbic lobe, including the hippocampus, is particularly important in producing emotion. Stimulating certain regions of the temporal lobes produces an intense feeling of fear or dread; stimulating nearby regions produces a feeling of isolation and loneliness, other regions a feeling of disgust, and yet others intense sorrow, depression, anxiety, ecstasy, and, occasionally, guilt.

      In addition to these regions of the cerebral cortex and the hypothalamus, regions of the thalamus also contribute to the genesis of emotion. The hypothalamus itself does not initiate behaviour; that is done by the cerebral hemispheres.

The defense reaction
      When certain neurons of the hypothalamus are excited, an individual either becomes aggressive or flees. These two opposite behaviours are together called the defense reaction, or the fight-or-flight response; both are in the repertoire of all vertebrates. The defense reaction is accompanied by strong sympathetic activity. Aggression is also influenced by the production of androgen hormones.

Mating
      The total act of copulation is organized in the anterior part of the hypothalamus and the neighbouring septal region. In the male, erection of the penis and the ejaculation of semen are organized in this area, which is adjacent to the area that controls urination. Under normal circumstances, the neurons that organize mating behaviour do so only when they receive relevant hormones in their blood supply. But when the septal region is electrically stimulated in conscious patients, sexual emotions and thoughts are produced.

      There are visible differences between the male and female sexes in nuclei of the central nervous system related to reproduction. These differences are a form of sexual dimorphism.

      Electrical stimulation in cats of regions in and related to the anterior part of the hypothalamus can induce the behaviour of expelling or retaining urine and feces. When electrodes planted in these regions are stimulated by radio waves, the cat stops whatever it is doing and behaves as though it is going to urinate or defecate. It goes through its usual behaviour of digging a hole, squatting, and assuming the correct posture, and then it passes urine or feces. At the end, it even goes through its customary ritual of hiding its excreta.

Eating and drinking
      The eating and drinking centres are in the lateral and ventromedial regions of the hypothalamus, although such basic aspects of living concern most of the brain. If the lateral region is experimentally destroyed, the animal consumes less food or stops eating altogether; if the ventromedial region is destroyed, it eats enormously. When neurons of the lateral region are electrically stimulated, a monkey eats, and when those of the ventromedial area are stimulated, the monkey stops eating. There is an increase in the activity of these neurons when the monkey looks at food, but only when it is hungry. Receptors in the lateral region monitor blood glucose and are stimulated only when blood glucose is low; satiety stops their response.

      Hunger does not depend only on these glucose receptors. Severe hunger is associated with contractions of the stomach, which are felt almost as a sensation of pain. Yet neither is this an essential mechanism for feeling hungry, as patients who have had total removal of the stomach still feel hunger. In experiments in rats, it is found that stress may make the animal either increase or reduce the amount it eats. This is probably the same in humans.

      When certain neurons in the same regions of the hypothalamus are experimentally destroyed, animals lose the urge to drink, although they continue to eat normally. Stimulation of these neurons causes them to drink excessively. Control of drinking depends on osmoreceptors located throughout the hypothalamus. When receptors detect a minimal increase in the concentration of dissolved substances in the extracellular fluid, which indicates cellular dehydration, the sensation of thirst occurs. A less-important contributor to the sensation of thirst is a reduction in blood volume. Dryness of the mouth can also be a component of thirst, noted by receptors in the mucous membrane. The feeling of having drunk enough depends not only on the hypothalamic neurons but also on receptors in the wall of the stomach, which report when the stomach is full.

      Both glucose receptors and osmoreceptors are sensitive to the temperature of the passing blood. When the temperature starts to rise, one feels thirsty but not hungry; cooling the blood makes one feel hungry.

Temperature regulation (thermoregulation)
      To maintain homeostasis, heat production and heat loss must be balanced. This is achieved by both the somatomotor and sympathetic systems. The obvious behavioral way of keeping warm or cool is by moving into a correct environment. The posture of the body is also used to balance heat production and heat loss. When one is hot, the body stretches out—in physiological terms, extends—thus presenting a large surface to the ambient air and losing heat. When one is cold, the body curls itself up—in physiological terms, flexes—thus presenting the smallest area to the ambient temperature.

      The sympathetic system is the most important part of the nervous system for controlling body temperature. On a long-term basis, when the climate is cold, the sympathetic system produces heat by its control of certain fat cells called brown adipose tissue. From these cells, fatty acids are released, and heat is produced by their chemical breakdown.

      Body temperature fluctuates regularly within 24 hours; this is a type of circadian rhythm (see below). It also fluctuates in rhythm according to the menstrual cycle (menstruation). During fever, the body temperature is set at a higher point than normal.

Reward and punishment
      In a fundamental discovery made in 1954, Canadian researchers James Olds and Peter Milner found that stimulation of certain regions of the brain of the rat acted as a reward in teaching the animals to run mazes and solve problems. The conclusion from such experiments is that stimulation gives the animals pleasure. The discovery has also been confirmed in humans. These regions are called pleasure, or reward, centres. One important centre is in the septal region, and there are reward centres in the hypothalamus and in the temporal lobes of the cerebral hemispheres as well. When the septal region is stimulated in conscious patients undergoing neurosurgery, they experience feelings of pleasure, optimism, euphoria, and happiness.

      Regions of the brain also clearly cause rats distress when electrically stimulated; these are called aversive centres. However, the existence of an aversive centre is less certain than that of a reward centre. Electrodes stimulating neurons or neural pathways may cause an animal to have pain, anxiety, fear, or any unpleasant feeling or emotion. These pathways are not necessarily centres that provide punishment in the sense that a reward centre provides pleasure. Therefore, it is not definitely known that connections to aversive centres punish the animal for biologically wrong behaviour, but it is thought that correct behaviour is rewarded by pleasure provided by neurons of the brain.

Circadian rhythms (circadian rhythm)
      Humans have inevitably adapted to the orderly rhythms of the universe. These biological cycles are called circadian rhythms, from the Latin circa (“about”) and dies (“day”). They are essentially endogenous, built into the central nervous system. Circadian activities include sleeping and waking, rest and activity, taking in of fluid, formation of urine, body temperature, cardiac output, oxygen consumption, cell division, and the secreting activity of endocrine glands. Rhythms are upset by shift work and by rapid travel into different time zones. After long journeys it takes several days for the endogenous rhythm generator to become synchronized to the local time.

      The alternation of night and day has been important in inducing rhythms affecting many physiological functions. Even in isolation, rhythms related to the time of day are maintained from clues giving information about light and dark. Curiously, the endogenous sleep-wake rhythm deviates slightly from the Earth's 24-hour cycle; a bird's endogenous cycle is 23 hours, and the human cycle is 25 hours. In both cases the cycle is corrected by features of the environment called zeitgebers (“time givers”). One zeitgeber is the Earth's magnetic field, which changes on a 24-hour cycle as the Earth turns on its axis. More obvious and important a zeitgeiber is the alternation of dark and light.

      The suprachiasmatic nucleus of the hypothalamus is essential for the rhythms of sleeping, waking, rest, and activity. It is not surprising that this nucleus is adjacent to the incoming fibres from the eye; for this reason, the light-dark cycle appears to be the most important zeitgeber for circadian rhythms. The suprachiasmatic nucleus is most active in light. In experiments on the hamster, when the nucleus is destroyed, the rhythms of general activity, drinking, sleeping, waking, body temperature, and some endocrine secretion are disrupted.

Peter W. Nathan

Higher cerebral functions
      The neurons of the cerebral cortex constitute the highest level of control in the hierarchy of the nervous system. Consequently, the terms higher cerebral functions and higher cortical functions are used by neurologists and neuroscientists to refer to all conscious mental activity, such as thinking, remembering, and reasoning, and to complex volitional behaviour such as speaking and carrying out purposive movement. The terms also refer to the processing of information in the cerebral cortex, most of which takes place unconsciously.

Analytical approaches
      Neuroscientists investigate the structure and functions of the cerebral cortex, but the processes involved in thinking are also studied by cognitive psychologists, who group the mental activities known to the neuroscientist as higher cortical functions under the headings cognitive function or human information processing. From this perspective, complex information processing is the hallmark of cognitive function. Cognitive science attempts to identify and define the processes involved in thinking without regard to their physiological basis. The resulting models of cognitive function resemble flowcharts for a computer program more than neural networks—and, indeed, they frequently make use of computer terminology and analogies.

      The discipline of neuropsychology, by studying the relationship between behaviour and brain function, bridges the gap between neural and cognitive science. Examples of this bridging role include studies in which cognitive models are used as conceptual frameworks to help explain the behaviour of patients who have suffered damage to different parts of the brain. Thus, damage to the frontal lobes can be conceptualized as a failure of the “central executive” component of working memory, and a failure of the “generate” function in another model of mental imagery would fit with some of the consequences of left parietal lobe damage.

      The analysis of changes in behaviour and ability following damage to the brain is by far the oldest and probably the most-informative method adopted for studying higher cortical functions. Usually these changes take the form of what is known as a deficit—that is, an impairment of the ability to act or think in some way. With certain stipulations, one can assume that the damaged part of the brain is involved in the function that has been lost. However, people vary considerably in their abilities, and most brain lesions occur in subjects whose behaviour was not formally studied before they became ill. Lesions are rarely precisely congruent with the brain area responsible for a given function, and their exact location and extent can be difficult to determine even with modern imaging techniques. Abnormal behaviour after brain injury, therefore, is often difficult to attribute to precisely defined damage or dysfunction.

      It would also be naive to suppose that a function is represented in a particular brain area just because it is disrupted after damage to that area. For example, a tennis champion does not play well with a broken ankle, but this would not lead one to conclude that the ankle is the centre in which athletic skill resides. Reasonably certain conclusions about brain-behaviour relationships, therefore, can be drawn only if similar well-defined changes occur reliably in a substantial number of patients suffering from similar lesions or disease states.

      The most prominent series of observations clearly belonging to modern neuropsychology were made by Paul Broca (Broca, Paul) in the 1860s. He reported the cases of several patients whose speech had been affected following damage to the left frontal lobe and provided autopsy evidence of the location of the lesion. Broca explicitly recognized the left hemisphere's control of language, one of the fundamental phenomena of higher cortical function.

      In 1874 the German neurologist Carl Wernicke (Wernicke, Carl) described a case in which a lesion in a different part of the left hemisphere, the posterior temporal region, affected language in a different way. In contrast to Broca's cases, language comprehension was more affected than language output. This meant that two different aspects of higher cortical function had been found to be localized in different parts of the brain. In the next few decades there was a rapid expansion in the number of cognitive processes studied and tentatively localized.

      Wernicke was one of the first to recognize the importance of the interaction between connected brain areas and to view higher cortical function as the buildup of complex mental processes through the coordinated activities of local regions dealing with relatively simple, predominantly sensory-motor functions. In doing so, he opposed the view of the brain as an equipotential organ acting en masse.

      Since Wernicke's time, scientific views have swung between the localization and mass-action theories. Major advances in the 20th century included vast increases in knowledge, the discovery of new ways of studying the anatomy and physiology of the brain, and the introduction of better quantitative methods in the study of behaviour.

Hemispheric asymmetry, handedness, and cerebral dominance
      Broca's declaration that the left hemisphere is predominantly responsible for language-related behaviour is the clearest and most dramatic example of an asymmetry of function in the human brain. This functional asymmetry is related to hand preference (handedness) and probably to anatomical differences, although neither relationship is simple.

      Evidence from a number of converging sources, notably the high incidence of the language disturbance aphasia after left- but not right-hemisphere damage, indicates that the left hemisphere (laterality) is dominant (laterality) for the comprehension and expression of language in close to 99 percent of right-handed people. At least 60 percent of left-handed and ambidextrous people also have left-hemisphere language, but up to 30 percent have predominantly right-hemisphere language. The remainder have language represented to some degree in both hemispheres.

      The posterior temporal region of the brain, which is one of the regions responsible for language in the dominant hemisphere, is physically asymmetrical; specifically, the area known as the planum temporale is larger in the left hemisphere in most people. This asymmetry is more common in right-handers, while left-handed individuals are likely to have more nearly symmetrical brains. Reduced anatomical asymmetry has also been found in people with right-hemisphere dominance for speech and in some people with the reading disorder dyslexia. These results point to some relationship between handedness, cerebral dominance for language, anatomical asymmetry in the temporal lobe, and some aspects of language competence. Certainly there is a tendency for right-handedness, left-hemisphere dominance for language, and a larger left planum temporale to occur together. However, there are exceptions; for example, a few right-handers are right-hemisphere dominant for speech, and some right-handers who have left-hemisphere speech do not have a larger left planum temporale. In people who are atypical in one of these respects—for example, by being left-handed—the relationship between handedness, cerebral dominance, and anatomical asymmetry is much less consistent. Therefore, language is not invariably located in the hemisphere opposite the dominant hand or in the hemisphere with the larger planum temporale.

      Studies of individuals being treated for epilepsy in whom the corpus callosum (the bundle of nerve fibres connecting the two halves of the brain) has been severed, allowing the two hemispheres to function largely independently, have revealed that the right hemisphere has more language competence than was thought. These individuals show evidence of comprehension of words presented to the isolated right hemisphere, although that hemisphere is not able to initiate speech. The speech of individuals with a lesion of the right hemisphere may lack normal melodic quality, and they may have difficulty expressing and understanding such things as emotional overtones. They may also have difficulty appreciating some of the more subtle, connotative aspects of language, such as puns, figures of speech, and jokes. Nevertheless, the dominance of the left hemisphere for language, particularly the syntactic aspects of language and language output, is the clearest example yet discovered of the lateralization of higher cortical function.

      The left hemisphere also appears to be more involved than the right in the programming of complex sequences of movement and in some aspects of awareness of one's own body. Thus, apraxia is more common after damage to the left hemisphere. In apraxia, the individual has difficulty performing actions involving several movements or the manipulation of objects in an appropriate and skillful way. The difficulty appears to be in programming the motor system to control the sequence of movements required to perform a complex action in the appropriate order and with the appropriate timing.

      Confusion of right and left is also found after left-hemisphere damage, making it appear that the left hemisphere is largely responsible for collating somatosensory information into a special awareness of the body called the body image. Finger agnosia is a condition in which the individual does not appear to “know” which finger is which and is unable to indicate which one the examiner touches without the aid of vision. The phenomenon of the phantom limb (phantom limb syndrome), whereby patients “feel” sensations in amputated limbs, indicates that the brain's internal representation of the body may persist intact for some time after the loss of a body part. This internal representation appears to be maintained chiefly by the left hemisphere.

      The special functions of the right hemisphere were recognized later than those of the left hemisphere, although a case of “imperception” reported by the English neurologist John Hughlings Jackson (Jackson, John Hughlings) in 1876 foreshadowed later findings. Jackson's patient, who had a lesion in the posterior part of the right hemisphere, lost her way in familiar surroundings, failed to recognize familiar places and people, and had difficulty in dressing herself—all of which became well-recognized consequences of right-hemisphere damage. The right hemisphere appears to be specialized for some aspects of higher-level visual perception, spatial orientation, and sense of direction, and it probably plays a dominant role in the recognition of objects and faces. The specialization of the right hemisphere, however, is less absolute than that of the left hemisphere in that these skills are less lateralized than language.

      There has been considerable speculation as to why the human brain is functionally asymmetrical. Initially, both functional and anatomical asymmetry were thought, like language, to be a uniquely human trait, but less-pronounced asymmetries have now been found in lower animals. One theory is that it is necessary to have language represented in a single hemisphere to avoid competition between the hemispheres for control of the muscles involved in speech. Another theory is that it is efficient to have the language system represented in a restricted area on one side of the brain because information needs to be transferred over short distances and fewer connections. A third theory is that the dominance of the left hemisphere over the right hand and skilled movement preceded its dominance over language. According to this view, language subsequently developed in the same hemisphere because language implies speech, which requires precise programming of sequences of movement in the articulatory musculature. None of these theories has been conclusively proved correct or has been generally accepted. Also, there remain some facts that are difficult to explain by any theory. For example, all of the above theories would predict that bilateral and, in some cases, right-hemisphere language representation would be disadvantageous, but this does not seem to be generally true.

 The language area of the brain surrounds the Sylvian fissure in the dominant hemisphere and is divided into two major components named after Paul Broca and Carl Wernicke. The Broca area lies in the third frontal convolution, just anterior to the face area of the motor cortex and just above the Sylvian fissure. This is often described as the motor, or expressive, speech area; damage to it results in Broca aphasia, a language disorder characterized by deliberate, telegraphic speech (speech disorder) with very simple grammatical structure, though the speaker may be quite clear as to what he wishes to say and may communicate successfully. The Wernicke area is in the superior part of the posterior temporal lobe; it is close to the auditory cortex and is considered to be the receptive language, or language-comprehension, centre. An individual with Wernicke aphasia has difficulty understanding language; speech is typically fluent but is empty of content and characterized by circumlocutions, a high incidence of vague words like “thing,” and sometimes neologisms and senseless “word salad.” The entire posterior language area extends into the parietal lobe and is connected to the Broca area by a fibre tract called the arcuate fasciculus. Damage to this tract may result in conduction aphasia, a disorder in which the individual can understand and speak but has difficulty in repeating what is said to him. The suggestion is that, in this condition, language can be comprehended by the posterior zone and spoken by the anterior zone, but is not easily shuttled from one to the other.

      Aphasia is a disorder of language and not of speech (although an apraxia of speech, in which the programming of motor speech output is affected, may accompany aphasia). The writing and reading of aphasic individuals, therefore, usually commit the same type of error as their speech, while the reverse is not the case. Isolated disorders of writing (dysgraphia) or, more commonly, reading ( dyslexia) may occur as well, but these reflect a disruption of additional processing required for these activities over and above that required for language.

      One particular form of dyslexia, dyslexia without dysgraphia, is an example of a disconnection syndrome—a disorder resulting from the disconnection of two areas of the brain rather than from damage to a centre. This type of dyslexia, also called letter-by-letter reading, is not associated with a writing disturbance; individuals tend to attempt to read by spelling words out loud, letter by letter. It usually results from a lesion in the posterior part of the left hemisphere that disconnects the visual areas of the brain from the language areas. This renders the language areas effectively blind, so that they cannot interpret visible language such as the written word. Writing is unaffected because the right hand is still connected to the left hemisphere, and, if letters can be spoken out loud correctly (which is not always the case), the individual will be able to hear himself say them and reintegrate them into words. Disconnection syndromes are an important concept in understanding behavioral disorders associated with brain damage. The possibility that deficits are caused by disconnection must always be borne in mind.

      Memory refers to the storage of information that is necessary for the performance of many cognitive tasks. Working, or short-term, memory is the memory one uses, for example, to remember a telephone number after looking it up in a directory and while dialing. In order to understand this sentence, for example, a reader must maintain the first half of the sentence in working memory while reading the second half. The capacity of working memory is limited, and it decreases if not exercised. Long-term memory, also called secondary or reference memory, stores information for longer periods. The capacity of long-term memory is unlimited, and it can endure indefinitely. In addition, psychologists distinguish episodic memory, a memory of specific events or episodes normally described by the verb remember, from semantic memory, a knowledge of facts normally said to be known rather than remembered.

      Memory is probably stored over wide areas of the brain rather than in any single location. However, amnesia, a memory disorder, can occur because of localized bilateral lesions in the limbic system—notably the hippocampus on the medial side of the temporal lobe, some parts of the thalamus, and their connections. This probably implies that these structures, rather than actually constituting a memory store, are important in the development of memories and in their recall. Memory impairment resulting from damage in these areas is a disorder of long-term episodic memory and is predominantly an anterograde amnesia—that is, it typically affects the memory of events occurring after the illness or accident causing the amnesia more than it does memories of the past. Substantial retrograde amnesia (loss of the memory of events occurring before the onset of the injury) rarely, if ever, occurs without significant anterograde amnesia as a result of brain damage, although it may occur alone in psychiatric disorders.

      Although amnesia is a disorder of long-term episodic memory and leaves short-term and semantic memory intact, both of the latter can be affected by brain damage. Some parietal lobe lesions may affect short-term memory without affecting long-term memory. Short-term memory impairment—at least for verbal material—may be further subdivided into auditory and visual domains; however, these disorders result in difficulty in understanding spoken and written language rather than in memory impairment (i.e., they appear more like aphasia and dyslexia). Impairment of semantic memory also results in an impairment that resembles a loss of concepts or a language deficit more than it resembles a memory impairment. Some forms of visual agnosia have been interpreted as semantic memory impairment, since patients are unable to recognize objects such as chairs because they no longer “know” what chairs are or what they look like (or can no longer access that knowledge).

Executive functions of the frontal lobes
      The frontal lobes are the part of the brain most remote from sensory input and whose functions are the most difficult to capture. They can be thought of as the executive that controls and directs the operation of brain systems dealing with cognitive function. The deficits seen after frontal lobe damage are described as a “dysexecutive syndrome.”

      Frontal lobe damage can affect people in any of several ways. On the one hand, they may have difficulty initiating a task or a behaviour, in extreme cases being virtually unable to move or speak, but more often they will simply have difficulty in initiating a task. On the other hand, individuals with frontal lobe damage may perservate, being apparently unable to stop a behaviour once it is started. Rather than appearing apathetic and hypoactive, patients may be uninhibited and may appear rude. Such people may also have difficulty in planning and problem solving and may be incapable of creative thinking. Mild cases of this deficit may be determined by a difficulty in solving mental arithmetic problems that are filled with words, even though the patient is capable of remembering the question and performing the required calculation. In such cases it appears that the patient simply cannot select the appropriate cognitive strategy to solve the problem.

      A unifying theme in these disorders is the notion of inadequate control of organization of pieces of behaviour that may in themselves be well formed. Patients with frontal lobe damage are easily distracted. Although their deficits may be superficially less dramatic than those associated with posterior lesions, they can have a drastic effect on everyday function. Irritability and personality change are also frequently seen after frontal lobe damage.

Graham Ratcliff

Additional Reading

Anatomy of the human nervous system
General overviews are provided by Malcolm B. Carpenter, Core Text of Neuroanatomy, 4th ed. (1991), a popular medical-student text with excellent drawings, photographs, and teaching diagrams; André Parent and Malcolm B. Carpenter, Carpenter's Human Neuroanatomy, 9th ed. (1996), a complete, well-documented sourcebook with a coloured atlas; Frank H. Netter (comp.), Nervous System, rev. and up-to-date ed., edited by Regina V. Dingle, Alister Brass, and H. Royden Jones, 2 vol. in 1 (1983–86), a work that contributes greatly to three-dimensional concepts; vol. 1 of The Ciba Collection of Medical Illustrations, a superb collection of instructive, authoritative colour drawings of the central, peripheral, and autonomic nervous systems as well as diseases of the brain and spinal cord; Stephen G. Waxman, Correlative Neuroanatomy, 24th ed. (2000); and Christopher M. Filley, Neurobehavioral Anatomy (1995), a discussion of the anatomy of the brain and its functions.The development of the human nervous system is discussed by Keith L. Moore and T.V.N. Persaud, The Developing Human: Clinically Oriented Embryology, 6th ed. (1998), a popular standard book presenting a synopsis of the embryonic development of the nervous system along with relevant clinical information and congenital malformations; Charles R. Noback, Norman L. Strominger, and Robert J. Demarest, The Human Nervous System: Introduction and Review, 4th ed. (1991), a general account of the development of the nervous system from its inception through old age, augmented with clinically significant information and appropriate illustrations; and T.W. Sadler and Jan Langman, Langman's Medical Embryology, 8th ed. (2000), a well-known work on human embryology with concise text, excellent illustrations and charts, and numerous points of clinical significance.Explorations of the central nervous system include Stephen J. DeArmond, Madeline M. Fusco, and Maynard M. Dewey, Structure of the Human Brain, 3rd ed. (1989), a photographic atlas of brain sections; Duane E. Haines, Neuroanatomy: An Atlas of Structures, Sections, and Systems, 5th ed. (2000), an atlas of brain photographs and vascular supply, with teaching diagrams; and R. Nieuwenhuys, J. Voogd, and Chr. van Huijzen, The Human Central Nervous System: A Synopsis and Atlas, 3rd rev. ed. (1988), a well-illustrated, readable text.Descriptions of the peripheral nervous system—the spinal and cranial nerves—are included in the work by Haines and in the general overviews cited above and in a standard anatomy reference work available in two editions: Henry Gray, Anatomy of the Human Body, 30th American ed., edited by Carmine D. Clemente (1985); and Gray's Anatomy, 38th (British) ed., edited by Peter L. Williams et al. (1995).The anatomy of the autonomic nervous system is dealt with in Louis Sanford Goodman and Alfred Gilman, Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., edited by Joel G. Hardman, Lee E. Limbird, and Alfred Goodman Gilman (2005), a text that also provides extensive information on drugs that affect neurotransmission.Charles R. Noback Duane E. Haines Arthur D. Loewy Ed.

Functions of the human nervous system
General summaries of the functions of the human nervous system are provided by Peter Nathan, The Nervous System, 4th ed. (1997), a complete account of the anatomy, physiology, and psychology of the nervous system of humans and other animals, written for readers without an extensive background in biology; and Eric R. Kandel, James H. Schwartz, and Thomas M. Jessel (eds.), Principles of Neural Science, 4th ed. (2000), an authoritative introduction. Information on sensory receptors can be found in George Howard Parker, The Elementary Nervous System (1919), a classic book on the origin of the basic receptor-adjustor-effector system of neural function; and Charles S. Sherrington, The Integrative Action of the Nervous System, 2nd ed. (1947, reprinted 1973), a classic on the physiology of reflex mechanisms, by one of the important workers on the subject.Thomas L. Lentz Charles R. Noback Peter W. Nathan The vestibular system and its functions are the subject of Robert W. Baloh and Vincente Honrubia, Clinical Neurophysiology of the Vestibular System, 2nd ed. (1990), a review of the vestibular system in relation to disease states.Peter Rudge Discussions of various aspects of the autonomic nervous system include Arthur D. Loewy and K. Michael Spyer (eds.), Central Regulation of Autonomic Functions (1990), a review of the brain mechanisms involved in regulating the autonomic nervous system; and Leonard R. Johnson (ed.), Physiology of the Gastrointestinal Tract, 3rd ed., 2 vol. (1994), a series of comprehensive reviews on the tract's anatomy, physiology, and pathophysiology.Arthur D. Loewy The following works deal with other functions of the human nervous system: on pain, Ronald Melzack and Patrick D. Wall, The Challenge of Pain, updated 2nd ed. (1996); and on vision, Richard L. Gregory, Eye and Brain: The Psychology of Seeing, 5th ed. (1997). Also useful is Richard L. Gregory and O.L. Zangwill (eds.), The Oxford Companion to the Mind (1987, reissued 1998).Peter W. Nathan Cerebral functions are described in Alan Baddeley, Your Memory: A User's Guide, 2nd ed. (1993); Muriel Deutsch Lezak, Neuropsychological Assessment, 3rd ed. (1995); Kenneth M. Heilman and Edward Valenstein, Clinical Neuropsychology, 3rd ed. (1993); Bryan Kolb and Ian Q. Whishaw, Fundamentals of Human Neuropsychology, 4th ed. (1996); Sally P. Springer and Georg Deutsch, Left Brain, Right Brain: Perspectives from Cognitive Neuroscience, 5th ed. (1998); Susan Allport, Explorers of the Black Box: The Search for the Cellular Basis of Memory (1986); D. Frank Benson, The Neurology of Thinking (1994); Taketoshi Ono et al. (eds.), Brain Mechanisms of Perception and Memory: From Neuron to Behavior (1993); and Kevin Walsh and David Darby, Neuropsychology: A Clinical Approach, 4th ed. (1999). I.P. Pavlov, Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex, trans. and ed. by G.V. Anrep (1927, reissued 1960; originally published in Russian, 1923), describes the classic experiments and studies of cerebral function in response to signals and reflex behaviour as carried out in dogs and their application to humans.Graham Ratcliff

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