In the central \Tnervous system\t of animals, the brain is a segregated group of nerve cells, or neurons, within the cranium, or skull, in vertebrates, and within the head segment in lower forms of animals. The brain varies in size and complexity from rudimentary ganglia (a group of nerve-cell bodies) in the central nervous systems of primitive worms to the large and complex human brain. As the central control organ of the body, the brain governs the functioning of the body's other organs. Sensory nerve cells feed external and internal information from all parts of the body to the brain. At least four medical subspecialties have a primary concern with the human brain: neurology, psychobiology, neurosurgery, and psychiatry. The average human brain at birth weighs 390 g (14 oz); its average maximum weight, reached at age 15, is 1,315 g (46 oz). The total number of neurons in the human brain is approximately 10 billion. In contrast, the brain of a whale may weigh more than 5 kg (11 lb), four times as much as a human brain, and the brain of a grasshopper contains no more than a few thousand neurons. A theory has been proposed which states that behavioral capacity, a broad term indicating intelligence, is related not to the size of brain but to the index of cephalization--the amount of brain tissue in excess of that required for transmitting impulses to and from the brain. Studies have shown that a progressive evolutionary encephalization relative to body size occurs in vertebrates and culminates in humans. Of equal importance to encephalization has been the evolutionary development of the human forebrain, a greatly expanded and convoluted mantle containing neuronal centers necessary for understanding and producing language, for conceptualization and abstraction, for judgment, and for the capacity of humans to contemplate and influence their lives. EVOLUTION During the first few weeks of embryonic life the bodies and central nervous systems of different vertebrates are remarkably similar. It is difficult to differentiate between the human embryo at the gestational age of 1 month and the embryo of a fish, reptile, amphibian, or rodent at a comparable stage. All have tails, primordial (primitive) gill clefts, and similar nervous systems, including primordial brains in the form of small bulges in the neural tube. The early embryos of these vertebrates most closely resemble, on a miniature scale, the adult fish, which is the oldest true vertebrate on the phylogenetic, or evolutionary, ladder. The developing human embryo, including the brain, passes through stages that, on a small scale, resemble the evolution of its ancestors. The embryological development of the human brain thus parallels the evolution of the brain. The small bulges in the primitive neural tube gradually enlarge and form the anatomical divisions of the future adult brain, or encephalon. These divisions are known as the hindbrain (rhombencephalon), the midbrain (mesencephalon), and the forebrain (prosencephalon). The prefixes describe either the shape (rhomb, derived from "rhombus") or the position (meso, meaning "middle"; and pros, meaning "before" or "in front of") of the structure along the longitudinal axis of the brain. In the mammalian brain the olfactory cortex is part of a larger neuronal system called the limbic system. The ancient olfactory system has been modified to serve not only smell but also the behavioral responses known as emotion and sexual behavior. Embryologically--and according to evolutionary development--the brain of the mammal gradually enlarges because of the expansion of the neocortex (composed of the frontal, parietal, occipital, and temporal lobes). The neocortex reaches its fullest development in the primates, specifically in humans. The neocortex constitutes the most highly evolved cerebral tissue. In primitive animals, the forebrain lags in development, but certain parts of the brain that are essential to survival of the species develop much more than others. In fish and amphibians, the olfactory (smell) system, including the olfactory cortex, the cortex being the outer layer of the brain, is particularly well developed. The olfactory cortex and the adjacent structures are old in terms of evolution, and the microscopic structure of this cortex consists of simple layers of neurons arranged fairly uniformly. This structure contrasts with the highly complex neocortex (most highly evolved cerebral tissue) in phylogenetically newer areas of the brain, such as the frontal lobes. In reptiles and birds, both evolutionary descendants of the amphibians, the corpus striatum (a mass of gray matter close to the thalamus) is well developed and serves as a coordination center for reflexes involving the eye and ear. In addition, the cerebellum (part of the hindbrain) of birds is extremely large compared to the rest of the brain, because it controls the motor coordination and balance necessary for flight. The visual systems of reptiles and birds are also well developed. Reptiles and birds have a small cerebral cortex. Thus the brain of most submammalian vertebrates is characterized by a well-developed brain stem that may weigh more than the rest of the brain, as well as by the selective development of the cerebellum (in birds) and the areas of the forebrain that are vital for survival. In the mammalian brain, the olfactory cortex is part of a larger neuronal system called the limbic system. The ancient olfactory system has been modified to serve not only smell but also the behavioral responses known as emotion and sexual behavior. Embryologically--and according to evolutionary development--the brain of the mammal gradually enlarges because of the expansion of the neocortex (composed of the frontal, parietal, occipital, and temporal lobes). The neocortex reaches its fullest development in the primates, specifically in humans. In the forebrain, the primitive neural tube expands into a system of fluid-filled cavities, or ventricles. The thalamus and other parts of the diencephalon (literally, "between brain") develop as bulges on the neural tube above the developing brain stem. The two cerebral hemispheres at first grow out and then back over the two halves of the thalamus, eventually burying them completely. The hemispheres grow in a manner that is singular to individual species. Simultaneous with the species-dependent development of the limbic lobe and neocortex is the development of the corpus striatum--three pairs of large nuclei, or ganglia--from the diencephalic part of the primitive forebrain. The main difference between the neocortex of humans and that of other primates is the more extensive development of the frontal, parietal, and temporal cortical areas in humans. An increase in weight and in the number and complexity of cortical gyri (elevated convolutions) occurs. The cortical areas essential for language function are located in the frontal and temporal lobes (see Cerebral Cortex below). The extensive infolding and overlapping of the human cerebral cortex makes possible the efficient connection by converging nerve fibers of a large area of gray matter in a small volume to much less voluminous areas of subcortical gray matter--the basal ganglia. Approximately 70 percent of the cerebral cortex of humans is not visible on the surface of the brain. If the human cerebral cortex were unfolded to its greatest extent, it would cover an area of several square feet. MICROSCOPIC STRUCTURE AND APPEARANCE The brain is composed of nerve cells (or neurons), glial cells, and nutrient blood vessels. Neurons transmit nerve impulses, and glial cells, which account for half of the brain's weight, form the supporting structure of the brain. Each multipolar neuron has a soma, or cell body, from which extends a single large process, or axon, along which impulses are transmitted to other neurons when the soma is sufficiently excited by incoming impulses. Axons of functionally similar neurons are frequently grouped as more or less discrete fiber tracts. The somas from which they arise are grouped as nuclei, or ganglia (a group of nerve cell bodies). The soma also has shorter processes, called dendrites, whose principal function is to receive incoming nerve impulses. The area at the dendrites where the terminal branch of an axoncomes into contact with another neuron is called a synapse. Nerve impulses are transmitted from one neuron to another across synapses. When the combined interplay of many incoming impulses reaches a certain threshold, the soma depolarizes and sends a nerve action potential down its axon to other nerve cells and their processes (see \Tbiopotential\t; \Tneurophysiology\t). The terms afferent and efferent describe nerve tracts as going toward or away from the cerebral cortex or other higher brain structures. The corticospinal nerve tract from cortex to spinal cord is efferent, with somas of the cells of origin in the cortex, their axons traveling downward to the cord, away from the highest center. The terms sensory and afferent are used synonymously, as are motor and efferent. The exposed living brain is a soft mass of glistening, grayish white tissue above which numerous small, bright red arteries and bluish veins are visible. The brain is protected by the skull and three membranes, called meninges. When the brain is "fixed" with chemicals, it becomes firm and can be sliced. A coronal section (that is, one that is vertical and cut from one side of the head to the other) shows an outer layer of gray matter 3 to 5 mm (0.12 to 0.20 in) thick, comprising the cerebral cortex, where the nerve-cell bodies lie. Beneath this is the white matter, nerve fibers sheathed in myelin. Below the white matter are globular areas of other gray matter; these are the thalamus and the subcortical nuclei, or basal ganglia, including the corpus striatum. ANATOMY AND FUNCTION Localization of function is defined by two investigative techniques: ablation and stimulation. Ablation, the removal of a small area of the brain, may result in a neurological deficit that is considered in terms of a lost function, one that is assigned to the area of the brain that was ablated. In humans, correlation of the indications of brain dysfunction during life with lesions of the brain found at autopsy has added greatly to the knowledge of localized functions. Movements and sensations can be produced in conscious humans by stimulating the brain electrically in appropriate areas. A portion of the skull may be removed (a craniotomy) under local anesthesia, giving access to the brain in a conscious patient. Gray and white matter may be cut, stimulated, or cauterized without the patient experiencing pain. Apparently no nerve endings sensitive to pain exist within the brain substance. Large blood vessels supplying the brain and certain sensory nerves attached to the brain stem are pain sensitive. Brain Stem The most notable structures of the adult human brain are the brain stem, the cerebellum, and the cerebrum (cerebral hemispheres). The lowest, or most caudal, portion of the brain stem, the medulla oblongata, is continuous with the spinal cord. Above it, the pons bulges prominently and is continuous with the midbrain, into which the cerebral peduncles (stemlike connections) extend. The cerebral peduncles carry upper motor neuron fibers that originate in the cerebral cortex to the cell bodies of cranial nerves in the brain stem and to cells in the spinal cord, called lower motor neurons, which cause certain muscles to move. The brain stem contains all afferent and efferent nerve fibers between the spinal cord and the higher brain centers. Some upper motor neuron fibers cross in the brain stem, whereas others do not. Most cranial nerves to each side of the head connect evenly with both cerebral hemispheres. In contrast, 80 percent of the fibers in the corticospinal tract from each side cross over in the medulla oblongata, so that the affected muscles are primarily controlled by one hemisphere. Thus a unilateral (single-sided) lesion in the cerebrum or brain stem above this crossover causes weakness or paralysis on the opposite side of the body. Cranial Nerves The human brain has 12 paired cranial nerves. The first 2, the olfactory and optic nerves, enter the brain above the brain stem and are actually extensions of the brain rather than peripheral nerves. Afferent impulses originating in peripheral sensory organs form ascending fiber tracts that cross either in the spinal cord or in the brain stem on their way to synapsing in nuclei above. The largest of these nuclei is the thalamus, whose many subdivisions act as relay stations to the cerebral cortex. Some thalamic nuclei project to specific receiving areas of the cerebral cortex, the primary cortical areas. Different afferent tracts and thalamic areas subserve sensations of pain; sensations of heat and cold; proprioception (the sensation of movement at joints); and special senses of sight, taste, and hearing. A knowledge of the level of crossing of the various afferent and efferent tracts, when correlated with symptoms and signs, enables physicians to localize with considerable accuracy the level and extent of lesions in the nervous system. The other 10 cranial nerves, in descending order of location, are the oculomotor, trochlear, trigeminal, abducens, facial, acoustic, glossopharyngeal, vagus, spinal accessory, and hypoglossal nerves. Cerebellum The cerebellum accounts for about 10 percent of the brain's weight and is a center for coordinating automatic (reflex) and voluntary movements of the body. It receives afferent impulses from the spinal cord as well as from various brain-stem nuclei. The cerebellum is connected by fibers, both going and coming, to parts of the basal ganglia and the extrapyramidal system (various nuclei and tracts governing motor function that are not part of the corticospinal, or pyramidal, tract). Fibers also go to the cerebral cortex by way of thalamic nuclear relays. The cerebral cortex (principally the frontal lobe) is connected to the cerebellum by numerous fibers. Lesions of the cerebellum and basal ganglia cause incoordination and other disorders of movement, such as tremor or choreiform movements (sudden involuntary movements or muscle contractions). Reticular Formation Deep within the brain stem is a large group of cells known as the reticular formation. Ascending fibers from this area project via thalamic nuclei to large association areas in the cortex. The reticular formation is a regulator of the state of alertness; its destruction at the midbrain level results in a state of coma. In contrast, large areas of the cerebrum may be destroyed without a loss of consciousness. The mechanism of cerebral concussion is thought to be a temporary derangement in the reticular formation. Hypothalamus The hypothalamus, located below the thalamus and including the pituitary gland, is an important part of the diencephalon. It contains centers for regulating body temperature, blood pressure, pulse rate, perspiration, and other functions controlled by the autonomic nervous system. The hypothalamus is the neural regulatory center for the production and release of hormones. Lesions of it that occur early in life may affect an individual's growth and sexual development. In adults, a sudden, destructive lesion such as an intraventricular hemorrhage may result in diabetes insipidus, hyperthermia (high body temperature), and frequently death. Emerging from the rear of the diencephalon is a small organ, the \Tpineal gland\t, which plays a role in controlling certain biorhythms such as the onset of puberty. Cerebral Cortex In terms of evolution, the cerebral cortex of humans has become increasingly complex. In present-day humans, it has a highly convoluted surface, greatly increasing the total area of the cortex. It comprises about 85 percent of the nerve cells in the brain. Because it is easily accessible, the cerebral cortex has been studied extensively, and some parts have been mapped in great detail. In primates, the deep horizontal Sylvian fissure (groove) separates in each hemisphere the temporal lobe, below, from the frontal, parietal, and occipital lobes, above. Running vertically, the less constant Rolandic fissure separates the frontal from the parietal lobe. Other landmarks separate the parietal from the occipital lobe on each side. The motor cortex in the frontal lobe and the sensory cortex in the parietal lobe are involved in the integration of muscular action and sensations. An important area of the frontal lobe is Broca's area, which lies in the left hemisphere of the brain of right-handed people, just forward of the lips-teeth-tongue areas of the sensorimotor strip. A lesion here causes a motor aphasia, the inability to produce meaningful spoken language (in the absence of any weakness of the muscles used in speech and with understanding preserved, including the ability to read and follow commands). In right-handed people, language dominance is located in the left hemisphere. About 50 percent of left-handed persons have right cerebral dominance. A lesion in Wernicke's area (the posterior, upper part of the temporal lobe on the dominant side) causes a receptive aphasia. The individual may verbalize extensively, talking in gibberish with occasional mispronounced words. The person is also unable to understand spoken or written language and may show a lack of concern over his or her plight. Olfactory impulses enter the brain through the olfactory bulbs, and synapse occurs in the olfactory cortex of the limbic system. Visual impulses travel through the optic nerves to the optic chiasma, where half of the fibers from each eye cross to the opposite side. They then synapse in a part of the thalamus that projects to the primary visual cortex in the occipital lobe. A complete lesion in one optic tract behind the chiasma causes an inability to see objects on one side of the midline opposite the lesion. Auditory impulses travel up the brain stem in a series of complex crossings and uncrossings with several synapses, ending in the auditory primary cortex deep in the temporal lobe. The temporal lobe cortex and certain portions of the limbic system have important functions involving recall and memory. This was first observed by Wilder Graves Penfield (1891-1976) during surgical operations on people having an unusual type of temporal lobe seizure during which they had vivid auditory and visual hallucinations of previously experienced events. Their experiential hallucinations could be reproduced by stimulating the surface of the temporal lobe--an activation of a specific complex memory, or engram. Bilateral removal of the hippocampal gyri causes a loss of recent memory or an inability to retain new information or experiences longer than a few minutes. Memory of information acquired before the lesions occurred is preserved, however, as is abstract thinking and general intelligence. BRAIN WAVES In an electroencephalogram, or EEG, brain waves (oscillating electric currents) from the scalp are recorded. In 1874, brain waves were first recorded by the Englishman Richard Caton, who connected primitive equipment directly to the cerebral cortex of a rabbit. In 1929 the German psychiatrist Hans Berger published the first information about scalp-recorded brain waves of humans. The invention of the differential input amplifier by B. H. C. Matthews in 1934 revolutionized the highgain amplification of biologic electrical signals, including brain waves. Frederic Gibbs, Hallowell Davis, and William Lennox, of the Harvard Medical School, published (1935) the first paper in English on the EEG in epilepsy in humans, thus initiating the era of clinical electroencephalography. The EEG is extensively used in diagnosing epilepsy and in the study of how the brain functions in animals and humans. An EEG is painless and harmless. The data gained from it is interpreted and correlated with other medical data by physicians as an aid to diagnosis. The different types and causes of epileptic seizures are correlated with certain recognizable focal or diffuse brain wave abnormalities, such as spikes. Treatment with anticonvulsant drugs or, in rare instances, neurosurgical removal of brain scars often depends on the data furnished by an EEG. Minute brain wave currents in the scalp, measured in microvolts, are amplified as changes in potential, which are then written out in a series of wavy lines or channels, one above the other, each channel corresponding to recording electrodes over different brain areas. Scalp-recorded activity originates primarily in the underlying cerebral cortex. During brain operations, designed to ameliorate some forms of epilepsy, brain waves are recorded directly from the cerebral cortex and from depth electrodes in subcortical nuclei. Brain waves are classified according to frequency bands in cycles per second (Hz), the most common of which are alpha activity (8 to 14 Hz), beta activity (above 14 Hz), delta activity (below 4 Hz), and theta activity (4 to less than 8 Hz), activity defined as a series of waves. Characteristic EEG patterns correspond to the level and type of behavioral activity. For example, alpha activity is usually produced during periods of relaxation. In most people, alpha activity is abolished by attention. Beta activity occurs in bursts in the anterior part of the brain and is associated with mental activity. \Tsleep\t involves changes in EEG patterns as well as physiologic changes such as heart rate. In sleep, slow rhythmic activity occurs. This tends to alternate with periods of low-voltage faster frequencies associated with rapid eye movements (\Trem\t). CHEMICAL ACTIVITY The transmission of nerve impulses across a synaptic gap involves the release of chemicals. In the brain, the group of chemical transmitters that perform this function are biogenic amines, formed from amino acids. These \Lneurotransmitter\ls include \Tacetylcholine\t, norepinephrine, dopamine, and \Tserotonin\t. Because acetylcholine is a transmitter in the reticular activating formation, it is involved in arousal and alertness. Norepinephrine is found in high concentrations in the hypothalamus and in the limbic system. Dopamine is concentrated most heavily in the basal ganglia and is associated with muscular activity. Serotonin is found in many parts of the central nervous system but particularly in the brain stem. Many temporary changes that occur in body chemistry would have a drastic effect on brain function if the brain were not protected by physiological barriers. One of these, the blood-brain barrier, depends on the unusually tight junctions between the endothelial cells in brain capillaries, which are triggered by the brain's astrocyte cells to keep otherwise harmful water-soluble substances from passing into the brain from the blood. Another barrier, called the blood-cerebrospinal fluid barrier, lies deep within the brain. These same systems, however, also make it difficult to introduce various therapeutic drugs into the brain. Such substances as antibiotics, hormones, and tranquilizers are admitted, along with various small or fat-soluble molecules. Other drugs are blocked, however, including a number of cancer drugs and other large, water-soluble compounds. One technique is to use glucose injections that apparently shrink capillary cells long enough for drugs to get in through openings in the walls of the brain's blood vessels. Different techniques are being studied and developed, such as the linking of fat-soluble with water-soluble molecules. ADVANCED BRAIN RESEARCH TECHNIQUES From a technical viewpoint, the invention of the computerized axial tomograph (see \TCAT scan\t) in the early 1960s marked the opening of a new era in brain research. The machine uses a weak X-RAY beam rotated about a person's head to produce an image of a "slice" of the brain in terms of varying tissue densities. A computer then plots the results in an oscilloscope display or on photographic film. With considerable accuracy, the \Tcat\t scan differentiates and localizes the extent and site of brain tumors, blood clots and areas of cerebral damage. Various other \Tradiology\t techniques have since been developed for imaging the brain. These include magnetic resonance (MR) imaging (see \Tnuclear magnetic resonance\t \Limagin\lg), which involves placing the subject in an intense magnetic field that magnetizes hydrogen nuclei (protons) within the brain's tissues. By means of radio frequency pulses, the locations of the nuclei can then be transformed into diagnostic images that reveal different tissue characteristics. Another technique, called positron emission tomography (see \TPETT\t), obtains images through the injection of a glucose-related compound that has been tagged by a radioactive isotope. As the isotope decays, it emits positrons that collide with electrons in the brain to form photons, which are then recorded by a \TPET\t scanner. This technique yields information on the varying levels of glucose metabolism at different brain sites. Abnormal levels are observed, for example, at sites of tumors and stroke damage. A further imaging technique involves the use of \Tultrasonic\t waves. All of these techniques have their relative advantages and disadvantages, depending on physiological differences between the brain sites under study and on the kind of brain activity or pathology being investigated. What all these noninvasive methods for studying the living brain have done has been to enable researchers to probe the interplay of chemical activities within different brain tissues in ways that had never before been possible. Huntington Mavor Bibliography: Armstrong, Este, and Falk, Dean, eds., Primate Brain Evolution (1982); Bradbury, M.W., et al., eds., The Blood-Brain Barrier in Health and Disease (1986); Bradshaw, J.R., Brain Imaging (1988); Calvin, W. H., and Ojemann, G. A., Inside the Brain (1980); Coen, C.W., ed., Functions of the Brain (1985); Eccles, John, and Robinson, D.N., The Wonder of Being Human (1985); Hart, Leslie, Human Brain and Human Learning (1983); Nolte, John, The Human Brain (1981); Oakley, David, ed., Brain and Mind (1985); Shepherd, G.M., Neurobiology, 2d ed. (1988); Wise, S.P., Higher Brain Functions (1987).