NEUROBIOLOGICAL PERSPECTIVE OF BEHAVIOUR

1 INTRODUCTION It sets humans apart from all other species by allowing us to achieve the wonders of walking on the moon and composing masterpieces of literature, art, and music. The human brain — a spongy, three-pound mass of fatty tissue — has been compared to a telephone switchboard and a super computer. But the brain is much more complicated than either of these devices, a fact scientists confirm almost daily, with each new discovery. The extent of the brain’s capabilities is unknown, but it is the most complex living structure known in the universe. This single organ controls all body activities, ranging from heart rate and sexual function to emotion, learning, and mem- ory. The brain is even thought to influence the immune system’s response to disease and to determine, in part, how well people respond to medical treatments. Ultimately, it shapes our thoughts, hopes, dreams, and imaginations. In short, the brain is what makes us human. Neuroscientists have the daunting task of deciphering the mystery of this most complex of all machines: how as many as a trillion nerve cells are produced, grow, and organize themselves into effective, functionally active systems that ordinarily remain in working order throughout a person’s lifetime. The motivation of researchers is twofold: to understand

2 human behavior better—from how we learn to why people have trouble getting along together—and to discover ways to prevent or cure many devastating brain disorders and behavioral problems. However, during the congressionally designated Decade of the Brain, which ended in 2000, neuroscience made significant discoveries in these areas: ∫ Genetics. Disease genes were identified that are key to several neurodegenerative disorders—including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lat- eral sclerosis. This has provided new insights into underlying disease mechanisms and is beginning to suggest new treatments. With the mapping of the human genome, neuroscientists will be able to make more rapid progress in identifying genes that either contribute to human neurological disease or that directly cause disease. Mapping animal genomes will aid the search for genes that regulate and control many complex behaviors. ∫ Brain Plasticity. Scientists began to uncover the molecular basis of neural plasticity, revealing how learning and memory occur and how declines might be reversed. These discoveries are leading to new approaches to the treatment of chronic pain. ∫ New Drugs. Researchers gained new insights into the mech- anisms of molecular neuropharmacology, which provides a new understanding of the mechanisms of addiction. These advances also have led to new treatments for depression and obsessive compulsive disorder.

3 ∫ Imaging. Revolutionary imaging techniques, including mag- netic resonance imaging and positron emission tomography, now reveal brain systems underlying attention, memory, and emotions and indicate dynamic changes that occur in schizophrenia. ∫ Cell Death. The discovery of how and why neurons die, as well as the discovery of stem cells, which divide and form new neurons, has many clinical applications. This has dramatically improved the outlook for reversing the effects of injury in both the brain and the spinal cord. The first effective treatments for stroke and spinal cord injury based on these advances have been brought to clinical practice. ∫ Brain Development. New principles and newly discovered molecules responsible for guiding nervous system development now give scientists a better understanding of certain disorders of childhood. Together with the discovery of stem cells, these advances are pointing to novel strategies for helping the brain or spinal cord regain functions lost as a result of injury or develop- mental dysfunction. This book only provides a glimpse of what is known about the nervous system, the disorders of the brain, and some of the exciting avenues of research that promise new therapies for many neurological diseases and behavioral problems

4 Chapter – 1 Nerve impulses involve the opening and closing of ion channels water-filled molecular The neuron tunnels that pass through the cell membrane and allow ions—electrically A specialized cell designed to transmit charged atoms—or small molecules to enter information to other nerve cells, muscle, or or leave the cell. The flow of these ions gland cells, the neuron is the basic working creates an electrical current that produces unit of the brain. The brain is what it is tiny voltage changes across the membrane. because of the structural and functional properties of interconnected neurons. It The ability of a neuron to fire—that is, to contains between one billion and one trillion become sufficiently activated by incoming neurons, depending on the species. The synapses to discharge and communicate to neuron consists of a cell body containing the its own synaptic target neurons—depends nucleus, cytoplasm, and an electrically on a small difference in electrical charge excitable output fiber, the axon. Most axons between the inside and outside of the cell. also give rise to many smaller branches When a nerve impulse begins, a dramatic before ending at nerve terminals. Synapses, reversal occurs at one point on the cell’s from the Greek word meaning “to clasp membrane. The change, called an action together,” are the contact points where one potential, then passes along the membrane neuron communicates with another. Other structures, dendrites, Greek for “tree of the axon at speeds up to several hundred branches,” extend from the neuron cell body and receive messages from other neurons. miles per hour. In this way, a neuron may be The dendrites and cell body are covered with able to fire impulses scores of times every synapses formed by the ends of axons of second. other neurons. Upon reaching the end of an axon, these Neurons signal by transmitting electrical voltage changes trigger the release of neurotransmitters, the brain’s chemical impulses along their axons, which can range messengers. Neurotransmitters are released at nerve ending terminals, diffuse across the in length from a tiny fraction of an inch to intra synaptic space, and bind to receptors on the surface of the target neuron. three or more feet. Many axons are covered with a layered insulating myelin sheath, made of specialized cells called oligodendrocytes in the brain and Schwann cells in the peripheral nervous system, which speeds the transmission of electrical signals a long the axon.

5 These receptors act as on and off ACh is formed at the axon terminals. switches for the next cell. Each receptor has When an action potential arrives at the a distinctly shaped part that selectively terminal the electrically charged calcium ion recognizes a particular chemical messenger. rushes in and Ach is released in to the A neurotransmitter fits into this region in synapse and attaches to Ach receptors. In much the same way as a key fits into a lock. voluntary muscles this opens sodium And when the transmitter is in place, this channels and causes the muscles to alters the neuron’s outer membrane potential contract. .Ach is then broken down and re- (or excitability) and triggers a change, such synthesized in the nerve terminal. Antibodies as the contraction of a muscle or increased that block the receptor for Ach causes activity of an enzyme in the cell. Myesthenia gravis, a disease characterized by fatigue and muscle weakness. Knowledge of neurotransmitters in the brain and the action of drugs on these Much less is known about Ach in the chemicals—gained largely through the study brain. Recent discoveries suggest, however, of animals—is one of the largest fields in that it may be critical for normal attention, neuroscience. Armed with this information, memory, and sleep. Since ACh-releasing scientists hope to understand the circuits neurons die in Alzheimer’s patients, finding responsible for disorders such as ways to restore this neurotransmitter is one Alzheimer’s disease and Parkinson’s goal of current research. disease. Sorting out the various chemical circuits is vital to understanding how the brain stores memories, why sex is such a powerful motivation, and what the biological basis of mental illness is. Neurotransmitters Acetylcholine The first neurotransmitter, identified about 75 years ago, was acetylcholine (ACh). This chemical is released by neurons connected to voluntary muscles (causing them to contract) and by neurons that control the heartbeat. ACh also serves as a transmitter in many regions of the brain.

6 Aminoacids Amino acids, widely Glutamate or aspartate activates N- distributed throughout the body and the methyl-d-aspartate (NMDA) receptors, one brain, serve as the building blocks of of three major classes of glutamate proteins. Certain amino acids can also serve receptors, which have been implicated in as neurotransmitters in the brain. activities ranging from learning and memory to development and specification of nerve The neurotransmitters glutamate and contacts in a developing animal. The aspartate act as excitatory signals. Glycine stimulation of NMDA receptors may promote and gamma-aminobutyric acid (GABA) beneficial changes in the brain, whereas inhibit the firing of neurons. The activity of overstimulation can cause nerve cell GABA is increased by benzodiazepine damage or cell death in trauma and stroke. (Valium) and by anticonvulsant drugs. In Huntington’s disease, a hereditary disorder Key questions remain about this that begins during midlife, the GABA- receptor’s precise structure, regulation, producing neurons in the brain centers location, and function. For example, coordinating movement degenerate, thereby developing drugs to block or stimulate causing uncontrollable movements. activity at NMDA receptors holds promise NEURON. A neuron fires by transmitting electrical signals along its axon. When signals reach the end of the axon, they trigger the release of neurotransmitters that are stored in pouches called vesicles. Neurotransmitters bind to receptor molecules that are present on the surfaces of adjacent neurons. The point of virtual contact is knownas the synapse. Nerve endings on a Cyton

7 For improving brain function and treating Nerve fibers containing norepinephrine neurological disorders. But this work is still are present throughout the brain. in the early stage. Deficiencies in this transmitter occur in Catecholamines Dopamine and norepinephrine are widely present in the patients with Alzheimer’s disease, brain and peripheral nervous system. Dopamine, which is present in three circuits Parkinson’s disease, and Korsakoff’s in the brain, controls movement, causes psychiatric symptoms such as psychosis, syndrome, a cognitive disorder associated and regulates hormonal responses. with chronic alcoholism. Thus, researchers The dopamine circuit that regulates movement has been directly linked to believe norepinephrine may play a role in disease. The brains of people with Parkinson’s disease—with symptoms of both learning and memory. Norepinephrine muscle tremors, rigidity, and difficulty in moving—have practically no dopamine. is also secreted by the sympathetic nervous Thus, medical scientists found that the administration of levodopa, a substance system in the periphery to regulate heart from which dopamine is synthesized, is an effective treatment for Parkinson’s, allowing rate and blood pressure. Acute stress patients to walk and perform skilled movements successfully. increases the release of norepinephrine. Another dopamine circuit is thought to be Serotonin This neurotransmitter is important for cognition and emotion; abnormalities in this system have been present in many tissues, particularly blood platelets, the lining of the digestive tract, and the brain. Serotonin was first thought to be involved in high blood pressure because it is present in blood and induces a very powerful contraction of smooth muscles. In the brain, serotonin has been implicated in sleep, mood, depression, and anxiety. Because serotonin controls the different switches affecting various emotional states, implicated in schizophrenia. Because drugs scientists believe these switches can be that block dopamine receptors in the brain manipulated by analogs, chemicals with are helpful in diminishing psychotic molecular structures similar to that of symptoms, learning more about dopamine is serotonin. Drugs that alter serotonin’s important to understanding mental illness. action, such as fluoxetine (Prozac), have In a third circuit, dopamine regulates the relieved symptoms of depression and obsessive-compulsive disorder. endocrine system. It directs the Peptides These are chains of amino hypothalamus to manufacture hormones acids linked together. Brain peptides called endorphins act like opium to kill pain or and hold them in the pituitary gland for cause sleepiness. (Peptides differ from proteins, which are much larger and more release in to the blood stream or to trigger the release of hormones held within cells in the pituitary.

8 complex combinations of amino acids.) Trophic factors Researchers have In 1973, scientists discovered receptors discovered several small proteins in the for opiates on neurons in several regions of brain that are necessary for the the brain, suggesting that the brain must development, function, and survival of make substances very similar to opium. specific groups of neurons. These small Shortly thereafter, scientists made their first proteins are made in brain cells, released discovery of an opiate produced by the brain locally in the brain, and bind to receptors that resembles morphine, an opium expressed by specific neurons. Researchers derivative used medically to kill pain. They have also identified genes that code for named it enkephalin, literally meaning “in receptors and are involved in the signaling the head.” Soon after, the endorphins— mechanisms of trophic factors. These another type of opioid peptide, whose name findings are expected to result in a greater comes from endogenous morphine—were understanding of how trophic factors work in discovered. The precise role of the opioid peptides in the brain. This information should also prove the body is unclear. A plausible guess is useful for the design of new therapies for that they are released by brain neurons in brain disorders of development and for times of stress to minimize pain and degenerative diseases, including enhance adaptive behavior. The presence of opioid peptides may explain, for example, Alzheimer’s disease and Parkinson’s why injuries received during the stress of combat are often not noticed until hours disease. later. Hormones After the nervous system, the Opioids and their receptors are closely associated with pathways in the brain that endocrine system is the second great are activated by painful or tissue-damaging stimuli. These signals are transmitted to the communication system of the body. The central nervous system—the brain and spinal cord—by special sensory nerves, pancreas, kidneys, heart, adrenal glands, small myelinated fibers, and tiny unmyelinated C fibers. gonads, thyroid, thymus, and pituitary gland Scientists have discovered that some C are sources of hormones. The endocrine fibers contain a peptide called substance P that causes the sensation of burning pain. system works in large part through the The active component of chili peppers, pituitary gland, which secretes hormones into the blood. Because endorphins are released from the pituitary gland into the blood stream, they might also function as endocrine hormones. Hormones activate specific receptors in target organs that release other hormones in to the blood, capsaicin, causes the release of substance which the n act on other tissues, the P.

9 pituitary itself, and the brain. This system response to a changing environment. is very important for the activation and Hormones are important agents of control of basic behavioral activities such as protection and adaptation, but stress and sex, emotion, responses to stress, and the stress hormones can also alter brain regulation of body functions such as function, including learning. Severe and prolonged stress can cause permanent growth, energy use, and metabolism. brain damage. Actions of hormones show the brain to be Reproduction is a good example of a regular, cyclic process driven by circulating very malleable and capable of responding to hormones: The hypothalamus produces gonadotropin releasing hormone (GnRH), a environmental signals. peptide that acts on cells in the pituitary. In both males and females, this causes two The brain contains receptors for both the hormones—the follicle-stimulating hormone thyroid hormone and the six classes of steroid hormones estrogens, androgens, progestins, glucocorticoids, mineralocorticoids, and vitaminD. The receptors are found in selected (FSH) and the luteinizing hormone (LH)—to populations of neurons in the brain and be released into the bloodstream. In males, relevant organs in the body. Thyroid and these hormones are carried to receptors on steroid hormones bind to receptor proteins cells in the testes, where they release the that in turn bind to the DNA genetic material male hormone testosterone in to the blood and regulate the action of genes. This can stream. In females, FSH and LH act on the result in long-lasting changes in cellular ovaries and cause the release of the female structure and function. In response to stress hormones estrogen and progesterone. In and changes in our biological clocks, such turn, the increased levels of testosterone in as day and night cycles and jetlag, males and estrogen in females act back on hormones enter the blood and travel to the the hypothalamus and pituitary to decrease brain and other organs. In the brain, the release of FSH and LH. The increased hormones alter the production of gene levels also induce changes in cell structure products that participate in synaptic and chemistry that lead to an increased neurotransmission as well as the structure capacity to engage in sexual behavior. of brain cells. As a result, the circuitry of the brain and its capacity for neurotransmission Scientists have found statistically and are changed over a course of hours to days. biologically significant differences between In this way, the brain adjusts its the brains of men and women that are performance and control of behavior in similar to sex differences found in experimental animals. These include differences in the size and shape of brain

10 structures in the hypothalamus and the enzymes. arrangement of neurons in the cortex and Though only recently characterized, nitric hippocampus. Some functions can be attributed to these sex differences, but much oxide has already been shown to play more must be learned in terms of important roles. For example, nitric oxide perception, memory, and cognitive ability. neurotransmission governs erection in Although differences exist, the brains of neurons of the penis. In nerves of the men and women are more similar than they intestine, it governs the relaxation that are different. contributes to the normal movements of Recently, several teams of researchers digestion. In the brain, nitric oxide is the have found anatomical differences between major regulator of the intracellular the brains of heterosexual and homosexual messenger molecule — cyclic GMP. In men. Research suggests that hormones and conditions of excess glutamate release, as genes act early in life to shape the brain in occurs in stroke, neuronal damage following terms of sex-related differences in structure the stroke may be attributable in part to and function, but scientists are still putting nitric oxide. Exact functions for together all the pieces of this puzzle. carbonmonoxide have not yet been shown. Sex differences go well beyond sexual Second messengers behavior and reproduction and affect many brain regions and functions, ranging from Substances that trigger biochemical mechanisms for perceiving pain and dealing communication within cells, after the action with stress to strategies for solving cognitive of neurotransmitters at their receptors, are problems. called second messengers; these intracellular effects maybe responsible for Gases Very recently, scientists identified long-term changes in the nervous system. a new class of neurotransmitters that are They convey the chemical message of a gases. These molecules—nitricoxide and neurotransmitter (the first messenger) from carbon monoxide—do not obey the “laws” the cell membrane to the cell’s internal governing neurotransmitter behavior. Being biochemical machinery. Second messenger gases, they cannot be stored in any effects may endure for a few milliseconds to structure, certainly not in synaptic storage as long as many minutes. structures. Instead, they are made by An example of the initial step in the enzymes as they are needed. They are activation of a second messenger system released from neurons by diffusion. And involves adenosine triphosphate (ATP), the rather than acting at receptor sites, they chemical source of energy in cells. ATP is simply diffuse into adjacent neurons and act present throughout the cell. For example, upon chemical targets, which may be when norepinephrine binds to its receptors

11 on the surface of the neuron, the activated receptor binds Gproteins on the inside of the membrane. The activated G protein causes the enzyme adenylyl cyclase to convert ATP to cyclic adenosine monophosphate (cAMP). The second messenger, cAMP, exerts a variety of influences on the cell, ranging from changes in the function of ion channels in the membrane to changes in the expression of genes in the nucleus, rather than acting as a messenger between one neuron and another. cAMP is called a second messenger because it acts after the first messenger, the transmitter chemical, has crossed the synaptic space and attached Itself to a receptor Second messengers also are thought to play a role in the manufacture and release of neurotransmitters, intracellular movements, carbohydrate metabolism in the cerebrum—the largest part of the brain, consisting of two hemispheres—and the processes of growth and development. Direct effects of these substances on the genetic material of cells may lead to long- term alterations of behavior.

12 Chapter – 2Brain development Three to four weeks after conception, structures and acquire specific ways o f trans one of the two cell layers of the gelatinlike mitting nerve messages. Their axons grow human embryo, now about one-tenth of an long distances to find and connect with inch long, starts to thicken and build up appropriate partners, forming elaborate and along the middle. As this flat neural plate specific circuits. Finally, sculpting action grows, parallel ridges, similar to face. Within eliminates redundant or improper a few days, the ridges fold in toward each connections, honing the specific purposes of other and fuse to form the hollow neural the circuits that remain. The result is a tube.The top of the tube thickens into three precisely elaborated adult net work of 100 bulges that form the hindbrain, midbrain, and billion neurons capable of body movement, forebrain.The first signs of the eyes and then perception, emotion, and thought. the hemispheres of the brain appear later. Knowing how the brain is put together is How does all this happen? Although many essential for understanding its ability to of the mechanisms of human brain reorganize in response to external influences development remain secrets, neuroscien- or injury. Such studies also shed light on tists are beginning to uncover some of these brain functions such as learning and complex steps through studies of the memory. Brain diseases such as roundworm, fruit fly, frog, zebrafish, mouse, schizophrenia and mental retardation are rat, chicken, cat, and monkey. thought to result from a failure to construct proper connections during development. Many initial steps in brain development Neuroscientists are beginning to discover some general principles to understand the are similar across species, although later processes of development, many of which overlap in time. steps are different . By studying these sim- Birth of neurons and brain wiring ilarities and differences, scientists can learn The embryo has three layers that undergo how the human brain develops and how many interactions in order to grow into organ, bone, muscle, skin, or neural tissue. brain abnormalities, such as mental retarda- tion and other brain disorders, can be prevented or treated. Neurons are initially produced along the central canal in the neural tube. These neurons then migrate from their birth place to a final destination in the brain. They collect together to form each of the various brain

13 BRAIN DEVELOPMENT. The human brain and nervous system begin to develop at about three weeks’ gestation with the closing of the neural tube (left). By four weeks, major regions of the human brain can be recognized in primitive form, including the forebrain, midbrain, hindbrain, and optic vesicle (from which the eye develops). Irregular ridges, or convolutions, are clearly seen by six months. NEURON MIGRATION. A cross-sectional view of the occipital lobe (which processes vision) of a three-month-old monkey fetus brain (center) shows immature neurons migrat- ing along glial fibers. These neurons make transient connections with other neurons before reaching their destination. A single migrating neuron, shown about 2,500 times its actual size (right), uses a glial fiber as a guiding scaffold. To move, it needs adhesion molecules, which recognize the pathway, and contractile proteins to propel it along.

14 Skin and neural tissue arise from one layer, glial cells. Cells farther away are exposed to the ectoderm, in response to signals lower concentrations of sonic hedgehog, and provided by the next layer, the mesoderm. they become the motor neurons that control muscles. An even lower concentration A number of molecules interact to promotes the formation of interneurons that determine whether the ectoderm becomes relay messages to other neurons, not neural tissue or develops in another way to muscles. become skin. Studies of spinal cord development in frogs show that one major A combination of signals also determines mechanism depends on specific molecules the type of chemical messages, or that inhibit the activity of various proteins. If neurotransmitters, that a neuron will use to nothing interrupts the activity of such communicate with other cells. For some, proteins, the tissue becomes skin. If other such as motor neurons, the type of molecules, which are secreted from the neurotransmitter is fixed, but for others it is a mesoderm, block protein signaling, then the matter of choice. Scientists found that when tissue becomes neural. certain neurons are maintained in a dish with no other cell type, they produce the neuro- Once the ectodermal tissue has acquired transmitter norepinephrine. In contrast, if the its neural fate, more signaling interactions same neurons are maintained with other determine the type of neural cell to which it cells, such as cardiac or heart tissue cells, gives rise. The mature nervous system they produce the neurotransmitter contains a vast array of cell types, which acetylcholine. Since all neurons have genes can be divided into two main categories: the containing the information for the production neurons, responsible primarily for signaling, of these molecules, it is the turning on of a and supporting cells called glial cells. particular set of genes that begins the production of specific neurotransmitters. Researchers are finding that the destiny Many researchers believe that the signal to of neural tissue depends on a number of engage the gene and, therefore, the final factors, including position, that define the determination of the chemical messengers environmental signals to which the cells are that a neuron produces, is influenced by exposed. For example, a key factor in spinal factors coming from the targets themselves. cord development is a secreted protein called sonic hedge hog that is similar to a As neurons are produced, they move from signaling protein found in flies. The protein, the neural tube’s ventricular zone, or inner initially secreted from mesodermal tissue surface, to near the border of the marginal lying beneath the developing spinal cord, zone, or outer surface. After neurons stop marks young neural cells that are directly dividing, they form an intermediate zone adjacent to become a specialized class of where they gradually accumulate as the brain develops.

15 The migration of neurons occurs in most axon may travel from the spinal cord all the structures of the brain but is particularly way down to a foot muscle. prominent in the formation of a large cerebral cortex in primates, including Axon growth is directed by growth cones. humans. In this structure, neurons slither These enlargements of the axon’s tip from the place of origin near the ventricular actively explore the environment as they surface, along non neuronal fibers that form seek out their precise destinations. a trail to their proper destination. Proper Researchers have discovered many special neuron migration requires multiple molecules that help guide growth cones. mechanisms, including the recognition of the Some molecules lie on the cells that growth proper path and the ability to move long cones contact, whereas others are released distances. One such mechanism for long- from sources found near the growth cone. distance migration is the movement of neurons along elongated fibers that form Once axons reach their targets, they form transient scaffolding in the fetal brain. Many synapses, which permit electric signals in external forces, such as alcohol, cocaine, or the axon to jump to the next cell, where they radiation, prevent proper neuronal migration can either provoke or prevent the generation and result in misplacement of cells, which of a new signal. The regulation of this may lead to mental retardation or epilepsy. transmission at synapses, and the inte- Furthermore, mutations in genes that gration of inputs from the thousands of regulate migration have recently been synapses each neuron receives, are shown to cause some rare genetic forms of responsible for the astounding information- retardation and epilepsy in humans. processing capacity of the brain. For processing to occur properly, the Once the neurons reach their final connections must be highly specific. Some location, they must make the proper specificity arises from the mechanisms that connections for a particular function, such as guide each axon to its proper target area. vision or hearing, to occur. They do this Additional molecules mediate “target through their axons. These wire like recognition,” where by the axon chooses appendages can stretch out a thousand the proper neuron, and often the proper part times longer than the cell body from which of the target, once it arrives at its destination. they arise. The journey of most axons ends Few of these molecules have been when they meet thicker appendages, called identified. There has been more success, dendrites, on other neurons. These target however, in identifying the ways in which the neurons can be located at a considerable synapse forms once contact has been made. distance, sometimes at opposite sides of the The tiny portion of the axon that contacts the brain. In the case of a motor neuron, the dendrite becomes specialized for the release of neurotransmitters, and the tiny portion of

16 the dendrite that receives the contact Communication between neurons with becomes specialized to receive and chemical and electrical signals is necessary to respond to the signal. Special molecules weed out the connections. The connections that pass between the sending and receiving are active and generating electrical currents cells to ensure that the contact is formed survive, whereas those with little or no activity properly and that the sending and receiving are lost. Thus, the circuits of the adult brain are specializations are precisely opposed to each formed, at least in part, by sculpting away other so that transmission can be fast and incorrect connections to leave only the correct efficient. ones. Paring back Critical periods After growth, the network is pared back to create The brain’s refining and building of the network in a more sturdy system. Only about half the mammals, including humans, continues after neurons generated during development survive birth. An organism’s interact system must obtain to function in the adult .Entire populations of neu certain critical experiences, such as sensory, rons are removed through internal suicide movement, or emotional input, to develop programs initiated in the cells. The programs are properly. activated if a neuron loses its battle with other neurons to receive life-sustaining nutrients called After a critical period, connections diminish in trophic factors. These factors are produced in number and are less subject to change, but the limited quantities by target tissues. Each type of ones that remain are stronger, more reliable, trophic factor supports the survival of a distinct and more precise. Injury or sensory or social group of neurons. For example, nerve growth deprivation occurring at a certain stage of factor is important for sensory neuron survival. It postnatal life may affect one aspect of has recently become clear that the internal development, whereas the same injury at a suicide program is maintained into adulthood and different period may affect another aspect. constantly held in check. On the basis of this idea, researchers have found that injuries and In one example, a monkey is raised from some neuro degenerative diseases kill neurons birth to 6 months of age with one eyelid closed. not directly by the damage they inflict but rather The animal permanently loses useful vision in by activating the cells’ own death programs. that eye because of diminished use. This gives cellular meaning to the saying “use it or lose Brain cells also form too many connections at it.”Loss of vision is caused by the actual loss of first. For example, in primates, the projections functional connections between that eye and from the two eyes to the brain initially overlap neurons in the visual cortex. This finding has led and then sort out to separate territories devoted to earlier and better treatment for the eye only to one eye or the other. Furthermore, in the disorders of congenital cataracts and “crossed young primate cerebral cortex, the connections eyes” in children. between neurons are greater in number than and twice as dense as those in an adult primate.

17 SPINAL CORD AND NERVES. The mature central nervous system (CNS) consists of the brain and spinal cord. The brain sends nerve signals to specific parts of the body through peripheral nerves, known as the peripheral nervous system (PNS). Peripheral nerves in the cervical region serve the neck and arms; those in the thoracic region serve the trunk; those in the lumbar region serve the legs; and those in the sacral region serve the bowels and bladder. The PNS consists of the somatic nervous system that connects voluntary skeletal muscles with cells specialized to respond to sensations, such as touch and pain. The autonomic nervous system is made of neurons connecting the CNS with internal organs. It is divided into the sym- pathetic nervous system, which mobilizes energy and resources during times of stress and arousal, and the parasympathetic nervous system, which conserves energy and resources during relaxed state

18 Research also shows that enriched environments can bolster brain development during postnatal life. For example, studies show that animals brought up in toy-filled surroundings have more branches on their neurons and more connections than isolated animals. In one recent study, scientists found that enriched environments resulted in more neurons in a brain area involved in memory. Scientists hope that new insights into brain development will lead to treatments for those with learning disabilities, brain damage, and neuro degenerative disorders, as well as helping us understand aging.

19 Chapter – 3 Sensation and perception Vision. This wonderful sense allows us to types of cones that are sensitive to red, image the world around us, from the genius green, and blue, but working together they of Michelangelo’s Sistine Chapel ceiling to convey information about all visible colours. mist filled vistas of a mountain range. Vision is one of the most delicate and complicated Primates, including humans, have well- senses of the brain is involved in visual developed vision using two eyes. Visual processing, more than for any other sense. signals pass from each eye along the mil- More is known about vision than any other lion or so fibers of the optic nerve to the optic vertebrate sensory system, with most of the chiasm, where some nerve fibers cross information derived from studies of monkeys over, so both sides of the brain receive and cats. signals from both eyes. Consequently, the left halves of both retinas project to the left Vision begins with the cornea, which does visual cortex and the right halves project to about three-quarters of the focusing, and the right visual cortex. then the lens, which varies the focus. Both help produce a clear image of the visual The effect is that the left half of the scene world on the retina — the sheet of you are watching registers in your right photoreceptors that process vision, and hemisphere. Conversely, the right half of the neurons lining the back of the eye. scene registers in your left hemisphere. A similar arrangement applies to movement As in a camera, the image on the retina is and touch: Each half of the cerebrum is reversed: Objects to the right of center responsible for the opposite half of the body. project images to the left part of the retina and vice versa, and objects above the center Scientists know much about the way cells project to the lower part and vice versa. The encode visual information in the retina, the shape of the lens is altered by the muscles lateral geniculate nucleus—an intermediate of the iris so that near or far objects can be point between the retina and visual cortex. brought into focus on the retina. These studies give us the best knowledge so far about how the brain analyzes and Visual receptors, about 125 million in processes information. each eye, are neurons specialized to turn The visual process begins with a comparison of the amount of light striking light into electrical signals. They occur in two any small region of the retina and the amount of light around it. Located in the forms. Rods are most sensitive to dim light occipital lobe, the primary visual cortex—two millimeters thick (a bit larger than a half- and donot convey color. Cones work in dollar) and densely packed with cells in many layers— receives messages from the bright light and are responsible for acute detail, black-and-white vision, and colorvision. The human eye contains three

20 lateral geniculate. In the middle layer, which edges moving in a particular direction. also receives input from the lateral Although the process is not yet completely geniculate, scientists found patterns of responsiveness similar to those observed in understood, recent findings suggest that the retina and lateral geniculate cells. Cells visual signals are fed into at least three above and below this layer responded separate processing systems. One system differently. They preferred stimuli in the appears to process information about shape of bars or edges. Further studies shape; a second, color; and a third, showed that different cells preferred edges movement, at particular angles, edges that moved, or VISION. The cornea and lens help produce a clear image of the visual world on the retina, the sheet of photoreceptors and neurons lining the back of the eye. As in a camera, the image on the retina is reversed: Objects to the right of the center project images to the left part of the retina and vice versa. The eye’s 125 million visual receptors — composed of rods and cones — turn light into electrical signals. Rods are most sensitive to dim light and do not convey the sense of color; cones work in bright light and are responsible for acute detail, black and white vision, and color vision. The human eye contains three types of cones that are sensitive to red, green, and blue, but, in combination, convey information about all visible colors. Rods and cones connect with a middle cell layer and third cell layer (see inset, above). Light passes through these two layers before reaching the rods and cones. The two layers then receive signals from rods and cones before transmitting the signals onto the optic nerve, optic chiasm, lateral geniculate nucleus, and, finally, the visual cortex.

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22 location, and spatial organization. These blindness becomes permanent. But until a few decades ago, ophthalmologists waited findings of separate processing systems until children reached the age of 4 before operating to align the eyes, or prescribing come from monkey anatomical and exercises or an eye patch. Now strabismus is corrected very early in life—before age 4, physiological data. They are verified by when normal vision can still be restored. human psychological studies showing that Hearing the perception of movement, depth, Often considered the most important sense for humans, hearing allows us to perspective, the relative size of objects, the communicate with each other by receiving sounds and interpreting speech. It also gives relative movement of objects, shading, and us information vital to survival. For example, the sound of an oncoming train tells us to gradations in texture all depend primarily on stay clear of the rail road track. contrasts in light intensity rather than in Like the visual system, our hearing system distinguishes several qualities in the signal it color. detects. However, our hearing system does not blend different sounds, as the visual Why movement and depth perception system does when two different wavelengths of light are mixed to produce color. We can should be carried out by only one processing follow the separate melodic lines of several instruments as we listen to an orchestra or system may be explained by a school of rock band. thought called Gestalt psychology. From the chirping of crickets to the roar of a rocket engine, most of the sounds Perception requires various elements to be processed by the ear are heard by a mecha- nism known as air conduction. In this organized so that related ones are grouped together. This stems from the brain’s ability process, sound waves are first funneled through the externally visible part of the ear, to group the parts of an image together and the pinna (or external ear) and the external auditory canal, to the tympanic membrane also to separate images from one another (eardrum), which vibrates at different speeds. and from their individual backgrounds. The malleus (hammer), which is attached to How do all these systems combine to the tympanic membrane, transmits the produce the vivid images of solid objects vibrations to the incus (anvil). This structure that we perceive? This involves extracting passes them onto the stapes (stirrup), which biologically relevant information at each delivers them, through the oval window, to stage and associating firing patterns with past experience. Vision studies also have led to better treatment for visual disorders. Information from research in cats and monkeys has improved the therapy for strabismus, or squint, a term for “cross eye” or wall-eye. Children with strabismus initially have good vision in each eye. But because they cannot fuse the images in the two eyes, they tend to favor one eye and often lose useful vision in the other. Vision can be restored in such cases, but only during infancy or early childhood. Beyond the age of 6 or so, the

23 the inner ear. The fluid-filled spiral passages concerned with distinguishing among sweet, of each cochlea contain16,000 hair cells, salty, sour, bitter, and umami (Japanese for whose microscopic, hair like projections savory). The interaction between taste and smell respond to the vibrations produced by explains why loss of the sense of smell sound. The hair cells, in turn, excite the apparently causes a serious reduction in the 28,000 fibers of the auditory nerve, which overall taste experience, which we call flavor. terminate in the medulla of the brain. Auditory information flows via the thalamus Tastes are detected within taste buds, special to the temporalgyrus, the part of the cerebral structures of which every human has some 5,000 cortex involved in receiving and perceiving to 10,000. Taste buds are embedded within sound. papillae, or protuberances, located mainly on the tongue, with others found in the back of the The brain’s analysis of auditory mouth and on the palate. Taste substances information follows a pattern similar to that stimulate specialized sensory cells. Each taste of the visual system. Adjacent neurons bud consists of 50 to 100 of these cells, which respond to tones of similar frequency. Some respond to salts, acidity, sweet substances, bitter neurons respond to only a small range of compounds, and monosodium glutamate and frequencies, others react to awide range; related amino acids. some react only to the beginning of a sound, others only respond to the end. Taste signals in the sensory cells are transferred by synapses to the ends of nerve Speech sounds, however, may be fibers, which send impulses along cranial nerves processed differently than others. Our to taste regions in the brain. From here, the auditory system processes all the signals impulses are relayed to other brainstem centers that it receives in the same way until they responsible for the basic responses of reach the primary auditory cortex in the acceptance or rejection of the tastes, and to the temporal lobe of the brain. When speech thalamus and on to the cerebral cortex for sound is perceived, the neural signal is conscious perception of taste. funneled to the left hemisphere for processing in language centers. Specialized smell receptor cells are located in a small patch of mucus membrane lining the roof Taste and smell of the nose. Axons of these sensory cells pass through perforations in the overlying bone and Although different, the two sensory enter two elongated olfactory bulbs lying on top of experiences of taste and smell are intimately the bone. The portion of the sensory cell that is entwined. They are separate senses with exposed to odors possesses hair like cilia. These their own receptor organs. However, these cilia contain the receptor sites that are stimulated two senses act together to allow us to by odorants carried by airborne molecules. distinguish thousands of different flavors. Alone, taste is a relatively focused sense These dissolve in the mucus lining in order to stimulate receptor proteins in the cilia to start the smell response. An odorant acts on many receptors to different degrees. Similarly, a receptor interacts with many

24 different odorants to varying degrees. several hundred times more sensitive to painful stimuli than are the soles of the feet. The v pattern of activity setup in the The fingertips are good at touch discrimi- receptor cells is projected to the olfactory nation, but the chest and back are less bulb, where it forms a spatial image of the sensitive. odor. Impulses created by this stimulation pass to other smell regions, giving rise to HEARING. From the chirping of crickets to conscious perceptions of odor in the frontal the roar of a rocket engine, almost all of the lobe and emotional responses in the limbic thousands of single tones processed by the system of the brain. human ear are heard by a mechanism known as air conduction. In this process, sound Touch and pain waves are first funneled through the external ear — the pinna and the external auditory Touch is the sense by which we determine canal — to the middle ear — the tympanic the characteristics of objects: size, shape, membrane (eardrum) — that vibrates at and texture. We do this through touch different speeds. The malleus (hammer), receptors in the skin. In hairy skin areas, which is attached to the tympanic mem- some receptors consist of webs of sensory brane, transmits the vibrations to the incus nerve cell endings wrapped around the base (anvil). The vibrations are then passed onto of hairs. The nerve endings are remarkably the stapes (stirrup) and oval window that, in sensitive, being triggered by slight turn, pass them onto the inner ear. In the movement of the hairs. Other receptors are inner ear, the fluid-filled spiral passage of the more common in nonhairy areas, such as cochlea contains cells with microscopic, the lips and fingertips, and consist of nerve hairlike projections that respond to the cell endings that may be free or surrounded vibrations produced by sound. The hair cells, by bulblike structures. in turn, excite the 28,000 fibers of the auditory nerve that end in the medulla in the Signals from touch receptors pass via brain. Auditory information flows via the sensory nerves to the spinal cord, where thalamus to the temporal gyrus, the part of they synapse (make contact) and then travel the cerebral cortex involved in receiving and to the thalamus and sensory cortex.The perceiving sound. transmission of this information is highly topographic, meaning that the body is represented in an orderly fashion at differentlevels of the nervous system. Larger areas of the cortex are devoted to sensations from the hands and lips; much smaller cortical regions represent less sensitive parts of the body. Different parts of the body vary in their sensitivity to touch discrimination and painful stimuli according to the number and distribution of receptors. The cornea is

25 Not surprisingly, acuity is greatest in the painful stimulus is not experienced as most densely nerve-packed areas of the body. This feature, in fact, is used to test unpleasant, activity in only some areas of the clinically for the integrity of these somatosensory pathways. For example, brain is suppressed. As such techniques for neurologists can run tests by using a two- point threshold . This method involve s brain study improve, it should be possible to touching the skin with calipers at two points. The two-point threshold is the distance better monitor the changes in the brain that between the two points that is necessary for the individual to distinguish two distinct occur in people with persistent pain and to stimuli from one. better evaluate the different analgesic drugs Until recently, pain was thought to be a simple message by which neurons sent being developed. electrical impulses from the site of injury directly to the brain. We now know that the TASTE AND SMELL . Specialized process is far more complicated. Nerve receptors for smell are located in a impulses from sites of injury that persist for patch of mucus membrane lining the hours, days, or longer lead to changes in the roof of the nose. Each cell has nervous system that result in an amplification several fine hair like cilia containing and increased duration of the pain. These receptor proteins, which are changes involve dozens of chemical stimulated by odor molecules in the messengers and receptors. Persistent pain air, and a long fiber (axon), which is in many respects a disease of the ner- passes through perforations in the vous system, not merely a symptom of some overlying bone to enter the olfactory other disease process. bulb. Stimulated cells give rise to impulses in the fibers, which set up Many new insights in to the pain patterns in the olfactory bulb that are experience are coming from studies in relayed to the brain’s frontal lobe to which modern imaging tools are used to give rise to smell perception, and to monitor brain activity when pain is the limbic system to elicit emotional experienced. One finding is that there is no responses. Tastes are detected by single area in the brain where pain is special structures, taste buds, of generated; rather, there are both emotional which every human has some 5,000 and sensory components. Interestingly, to 10,000. Taste buds are embedded when people are hypnotized so that a within papillae (protuberances) mainly on the tongue, with a few located in the back of the mouth and on the palate. Each taste bud consists of about 100 receptors that respond to the four types of stimuli — sweet, salty, sour, and bitter — from which all tastes are formed. A substance is tasted when chemicals in foods dissolve in saliva, enter the pores on the tongue, and come in contact with taste buds. Here they stimulate hairs projecting from the receptor cells and cause signals to be sent from the cells, via synapses, to cranial nerves and taste centers in the brain.

26 PAIN. Messages about tissue damage are picked up by receptors and transmitted to the spinal cord via small myelinated fibers and very small unmyelinated fibers. From the spinal cord, the impulses are carried to the brainstem, thalamus, and cerebral cortex and ultimately centers. Some of these descending pathways use naturally occurring, opiate like chemicals called endorphins

27 Chapter – 4 temporal region are connected to widespread areas of the cerebral cortex, Learning, memory, and especially the vast regions responsible for language thinking and language. Whereas the medial temporal region is important for forming and The conscious memory of a patient known organizing memory, cortical areas are as H.M. is limited almost entirely to events important for the long-term storage of that occurred years before his surgery, in knowledge about facts and events and for which part of the medial temporal lobe of his how this knowledge is used in everyday brain was removed to relieve epilepsy. situations. H.M.can remember recent events for only afew minutes talk with him a while and then Working memory, a type of leave the room. When you return, he has no transient,“online” memory that enables us to recollection of ever having seen you. retain what someone has said just long enough to reply, depends in part on the The medial temporal lobe, which includes prefrontal cortex. Researchers discovered the hippocampus and adjacent brain areas, that certain neurons in this area are seems to play a role in converting memory influenced by neurons releasing dopamine from a short-term to a long-term, permanent and other neurons releasing glutamate. form. The fact that H.M. retains memories for events that are remote to his surgery is Although much remains to be discovered evidence that the medial temporal region is about learning and memory, scientists have not the site of permanent storage but that it already put together important pieces of the plays a role in the formation of new puzzle. For example, the brain appears to memories. Other patients like H.M.have also process different kinds of information in been described. separate ways and then store it differently. Declarative knowledge requires processing Additional evidence comes from patients in the medial temporal region and parts of undergoing electroconvulsive therapy (ECT) the thalamus and can be grouped into for depression. ECT is thought to working memory, episodic memory, and temporarily disrupt the function of the semantic memory. Working memory allows hippocampus and related structures. These us to keep and use information in our minds patients typically have difficulty with new and is mediated by a network of areas in the learning and have amnesia for events that cerebral cortex. Episodic memory lets us occurred during the several years before store and replay events in our minds and treatment. Memory of earlier events is depends on the hippocampus. Semantic unimpaired. As time passes after treatment, memory includes raw facts and data and is much of the lost part of memory becomes stored throughout the cerebral cortex. The available once again. hippocampus may play a role in integrating The hippocampus and the medial

28 new episodic memories into the semantic memory is the phenomenon of long-term memory store house. potentiation (LTP), a long-lasting increase in In contrast, nondeclarative knowledge, the knowledge of how to do something, is the strength of a synaptic response following expressed in skilled behavior and learned habits and requires processing by the basal stimulation.LTP occurs prominently in the ganglia. hippocampus, as well as in other brain The amygdala appears to play an important role in the emotional aspects of areas. Studies of rats suggest that LTP memory. An important factor that influences what is stored and how strongly it is stored is occurs through changes in synaptic whether the action is followed by reward, punishment, or highly emotional conse- strength at contacts involving NMDA quences. These consequences help determine what behaviors an organism will receptors. It is now possible to study LTP learn and remember. and learning in genetically modified mice Memory of motor learning tasks in which precise timing is involved depends on the that have alterations in specific genes. cerebellum. Examples of these modified genes can be How exactly does memory occur? After years of study, there is much support for the limited both to particular brain areas and to idea that memory involves a persistent change in the connection between neurons. specific times, such as during learning. In animal studies, scientists found that this occurs in the short term through two bio- Much of what we have learned about chemical events that affect the strength of the relevant synapses. The stability of long- memory comes from studies of amnesia due term memory is conferred by turning on genes that may lead to modifications within to damage to the hippocampus and cor- neurons that change the strength and tical areas—called the parahippocampal number of synapses. For example, region—in the medial part of the temporal researchers can correlate specific chemical and structural changes in the relevent cells lobe. Patients with damage in these areas with several simple forms of memory exhibited by the sea slug Aplysia californica. can remember recent events only while actively engaged in the material—yet they Another important model for the study of often retain childhood memories quite well. This pattern suggests that the temporal lobe is critical in integrating early memories in to a permanent store house that can be accessed whenever needed. Several types of memory are spared in amnesia. Reports indicate that the sense of familiarity one has with a face or a scene is spared, even though the specific context of the experience may be lost. The emotional association one might develop with a given item is also commonly spared in amnesia. Scientists believe that no single brain

29 center stores memory. It most likely is along the same pathways in the opposite stored in distributed collections of cortical direction—from the auditory cortex to processing systems that are also involved in Wernicke’s area to the angular gyrus. This the perception, processing, and analysis of model accounts for much of the data from the material being learned. In short, each patients and is the most widely used for part of the brain most likely contributes clinical diagnosis and prognosis. Some differently to permanent memory storage. refinements to this model may be One of the most prominent intellectual necessary, however, because of both recent activities dependent on memory is language. studies with patients and functional neuro Although the neural basis of language is not imaging studies in healthy people. fully understood, scientists have learned a great deal about this function of the brain For example, using an imaging technique from studies of patients who have lost called positron emission tomography (PET), speech and language abilities due to stroke, scientists have demonstrated that some and from behavioral and functional reading tasks performed by normal people neuroimaging studies of normal people. do not activate Wernicke’s area or the angular gyrus. These results suggest that, A prominent and influential model, based atleast under some conditions, there is a on studies of these patients, proposes that direct reading route that does not involve the underlying structure of speech com- speech-sound recoding of the visual stimulus prehension arises in part of the left before the processing of either meaning or hemisphere of the brain, called Wernicke’s speaking. Other studies with patients also area. This temporal lobe region is connected have indicated that it is likely that familiar with another region, Broca’s area, in the words need not be recoded into sound frontal lobe, where a program for vocal before they can be understood. expression is created. This program is then transmitted to a nearby area of the motor Although the understanding of how cortex that activates the mouth, tongue, and language is implemented in the brain is far larynx. from complete, there are now several tech- niques that may be used to gain important This same model proposes that, when we insights in to this critical aspect of brain function. read a word, the information is transmitted from the primary visual cortex to the angular gyrus, where the message is somehow matched with the words when they are spoken. The auditory form of the word is then processed for comprehension in Wernicke’s area as if the word had been heard. Writing in response to an oral instruction requires information to be passed

30 LEARNING AND MEMORY. Different brain areas and systems mediate distinct forms of memory. The hippocampus, parahippocampal region, and areas of the cerebral cortex (including prefrontal cortex) compose a system that supports declarative, or cognitive, memory. Different forms of nondeclarative, or behavioral, memory are supported by the amygdala, striatum, and cerebellum. Brain Activity in Memory Positron emission tomography (PET) scans reveal brain regions involved in memory. Left, an encoding task (the initial processing of information into memory) activates the left prefrontal cortex. Right, an attempt to retrieve memories activates the right prefrontal cortex

31 Chapter –5 the eyes and the limbs during sleep. They Sleep found that over the course of the first hour or so of sleep each night, the brain pro- Sleep remains one of the great mysteries gresses through a series of stages during of modern neuroscience. We spend nearly one third of life asleep, but the function of which the brain waves progressively slow sleep is still not known. Fortunately over the down. This period of slow wave sleep is past few years researchers have made great accompanied by relaxation of the muscles headway in understanding some of the brain and the eyes. Heart rate, blood pressure, circuitary that controls wake-sleep states. and body temperature all fall. If awakened at this time, most people recall only Scientists now recognize that sleep fragmented thoughts, not an active dream. consists of several different stages; that the choreography of a night’s sleep involves the Over the next half hour or so, brain interplay of these stages, a process that activity alters drastically from the deep slow depends upon a complex switching wave sleep to generate neocortical EEG mechanism; and that the sleep stages are waves that are indistinguishable from those accompanied by daily rhythms in bodily observed during waking. Paradoxically,the hormones, body temperature, and other fast,waking-like EEG activity is accompanied functions. by atonia, or paralysis of the body’s muscles (only the muscles that allow breathing The stuff of sleep remain active). This state is often called rapid eye movement (REM) sleep. During Although sleep appears to be a passive and REM sleep, there is active dreaming. Heart restful time, it actually involves a highly rate, blood pressure, and body tempera- active and well-scripted interplay of brain ture become much more variable.Men often circuits to produce its various stages. have erections during this stage of sleep.The first REM period usually lasts 10 to 15 The stages of sleep were discovered in minutes. the 1950s in experiments using electro encephalography (EEG) that examined During the night, these cycles of slow human brain waves during sleep. wave and REM sleep alternate, with the Researchers also measured movements of slow wave sleep becoming less deep and the REM periods more prolonged until waking occurs. Over the course of a lifetime, the pattern of sleep cycles changes. Infants sleep up to 18 hours per day, and they spend much

32 more time in deep slow wave sleep. As deeper stages of slow wave sleep.This children mature, they spend less time condition can also cause high blood asleep and less time in deep slow wave pressure and may increase the risk of heart sleep. Older adults may sleep only six to attack.The increased daytime sleepiness seven hours per night, often complain of leads to an increased risk early waking that they cannot avoid, and of day time accidents, especially automobile spend very little time in slow wave sleep. accidents. Treatment may include a variety of attempts to reduce airway collapse dur- Sleep disorders ing sleep. Where as simple things like losing The most common sleep disorder, and the weight, avoiding alcohol and sedating drugs one most people are familiar with, is prior to sleep, and avoiding sleeping on insomnia. Some people have difficulty falling one’s back can sometimes help, most people asleep initially, but other people fall asleep with sleep apnea require devices that and then awaken partway through the night induce continuous positive airway pressure and cannot fall asleep again. Although there to keep the airway open. This can be are a variety of short-acting sedatives and provided by fitting a small mask over the sedating anti depressant drugs available to nose that provides an air stream under help, none of these produces a truly natural pressure during sleep. In some cases, and restful sleep state, because they tend to surgery is needed to correct the air way suppress the deeper stages of slow wave anatomy. sleep. Periodic limb movements of sleep are Excessive daytime sleepiness may have intermittent jerks of the legs or arms that many causes. The most common are occur as the individual enters slow wave disorders that disrupt sleep and result in sleep and can cause arousal from sleep. inadequate amounts of sleep, particularly of Other people have episodes in which their the deeper stages. These are usually muscles fail to be paralyzed during REM diagnosed in the sleep laboratory, where the sleep, and they act out their dreams.This EEG, eye movements, and muscle tone are REM behavior disorder can also be very monitored electrically as the individual disruptive to a normal night’s sleep. Both sleeps. In addition, the heart, breathing, and disorders are more common in people with oxygen content of the blood can be Parkinson’s disease and both can be monitored. treated with drugs that treat Parkinson’s or with a drug called clonazepam. Obstructive sleep apnea causes the airway muscles in the throat to collapse as Narcolepsy is a relatively uncommon sleep deepens. This prevents breathing, which causes arousal from sleep, and prevents the sufferer from entering the

33 condition—only one case per 2,500 people— cortex and produces awaking EEG pattern. in which the switching mechanism for REM sleep does not work properly. Narcoleptics Another important wakefulness center is in have sleep attacks during the day, in which they suddenly fall asleep. This is socially the basal forebrain, whose neurons project disruptive, as well as dangerous, for example, if they are driving. They tend to directly to the cerebral cortex. In addition to enter REM sleep very quickly as well and may even enter a dreaming state while still acetylcholine, other neurotransmitters partially awake, a condition known as hypnagogic hallucination. They also have promote wakefulness, including attacks during which they lose muscle tone, similar to what occurs during REM sleep, but norepinephrine, serotonin, histamine, and while they are awake. These attacks of paral ysis, known as cataplexy, can be triggered glutamate. by emotional experiences, even by hearing a funny joke. During REM sleep, the cholinergic nerve Recently, studies into the mechanism of cells and the thalamus and cortex are in a narcolepsy have given major insights into the processes that control these mysterious condition similar to wakefulness, but the transitions between waking, slow wave, and REM sleep states. brain is not very responsive to external How is sleep regulated? stimuli. The difference is in the activity of During wakefulness, the brain is kept in an three sets of monoamine nerve cells: the alert state by the interactions of two major systems of nerve cells. Nerve cells in the brainstem nerve cells in the locus coeruleus upper part of the pons and in the midbrain, which produce acetylcholine, send inputs to that use the neurotransmitter activate the thalamus. When the thalamus is activated, it in turn activates the cerebral norepinephrine; the dorsal and median raphe groups that contain serotonin; and, in the hypothalamus, the tuberomammillary cell group that uses histamine. These monoamine neurons fire most rapidly during wakefulness, but they slow down during slow wave sleep and stop during REM sleep. These monoamine neurons act to suppress the occurrence of REM sleep. The brain stem cell groups that control arousal from sleep are, in turn, influenced by two groups of nerve cells in the hypothal- amus, part of the brain that controls basic body cycles. One group SLEEP PATTERNS. During a night of sleep, the brain waves of a young adult recorded by the electroencephalogram (EEG) gradually slow down and become larger as the individual passes into deeper stages of slow wave sleep. After about an hour, the

34 brain re-emerges through the same series of stages, and there is usually a brief period of REM sleep (on dark areas of graph), during which the EEG is similar to wake- fulness. The body is completely relaxed; the person is deeply unresponsive and usually is dreaming. The cycle repeats over the course of the night, with more REM sleep, and less time spent in the deeper stages of slow wave sleep as the night progresses. SLEEPING BRAIN. Wakefulness is maintained by activity in two systems of neurons. Neurons that make the neurotransmitter acetylcholine are located in two main arousal centers, one in the brainstem and one in the forebrain . The brainstem arousal center supplies the acetylcholine for the thalamus and brainstem, and the forebrain arousal center supplies that for the cerebral cortex. Activation of these centers alone can create rapid eye movement sleep. Activation of other neurons that make monoamine neurotransmitters such as norepinephrine, sero- tonin, and histamine is needed for waking.

35 of nerve cells, in the ventrolateral preoptic nucleus, contains the inhibitory neurotransmitters galanin and GABA.When which is linked to brain energy depletion, accumulates in the brain during prolonged the ventrolateral preoptic neurons fire, they wakefulness and that it may drive sleep homeostasis. Interestingly, the drug caffeine, are thought to turn off the arousal systems, which is widely used to prevent sleepiness, acts as an adenosine blocker. causing sleep. Damage to the ventrolateral If an individual doesnot get enough sleep, preoptic nucleus produces irreversible the sleep debt progressively accumulates and leads to a degradation of mental func- insomnia. tion. When the opportunity to sleep again comes, the individual will sleep much more, A second group of nerve cells in the to “repay” the debt. The slow wave sleep debt is usually “paid off first. lateral hypothalamus influences and The other major influence on sleep cycles suppresses REM sleep. They contain the is the body’s circadian clock, the suprachiasmatic nucleus. This small group of neurotransmitter orexin, which provides an nerve cells in the hypothalamus contains clock genes, which go through a excitatory signal to the arousal system, biochemical cycle of about 24 hours, setting the pace for daily cycles of activity, sleep, particularly to the monoamine neurons.In hormones, and other bodily functions. The suprachiasmatic nucleus also receives input experiments in which the gene for the directly from the retina, and the clock can be reset by light, so that it remains linked to the neurotransmitter orexin was experimentally outside world’s day-night cycle. The suprachiasmatic nucleus provides signals to removed in mice, the animals became the brain areas regulating sleep and arousal. narcoleptic. Similarly, in two dog species with naturally occurring narcolepsy, an abnormality was discovered in the gene for the type 2 orexin receptor. Recent studies show that in humans with narcolepsy, the orexin levels in the brain and spinal fluid are abnormally low. Thus, orexin appears to play a critical role in activating the monoamine system and in preventing abnormal transitions, particularly into REM sleep. Two main signals control our need for sleep and its circuitry. First, there is homeostasis, or the body’s need to seek a natural equilibrium of rest and sleep followed by wakefulness. Several mechanisms for the signal of accumulating sleep have been suggested. There is evidence that a chemical called adenosine,

36 Chapter-6 Stress controlled stress responses can provide the extra strength and energy needed to The ability to react in response to threatening cope. Moreover, the acute physiological events has been with us since the time of our response to stress protects the body and ancient ancestors. In response to impending brain and helps to reestablish or maintain danger, muscles are primed, attention is homeostasis. But stress that continues for focused, and nerves are readied for action— prolonged periods can repeatedly elevate “fight or flight.” response to stress is not the physiological stress responses or fail to enough, and the continued stimulation of the shut them off when not needed. When this systems that respond to threat or danger occurs, these same physiological mecha- may contribute to heart disease, obesity, nisms can badly upset the body’s arthritis, and depression, as well as biochemical balance and accelerate disease. accelerating the aging process. Nearly two- thirds of ailments seen in doctors’ offices are Scientists also believe that the individual commonly thought to be stress induced; variation in responding to stress is some indeed, stress can both cause diseases and what dependent on a person’s perception of exacerbate existing ones. external events. This perception ultimately shapes his or her internal physiological Stress is difficult to define because its response. Thus, by controlling your effects vary with each individual. Specialists perception of events, you can do much to now define stress as any external stimulus avoid the harmful consequences of the sorts that threatens homeostasis—the normal of mild to moderate stressors that typically equilibrium of body function. Stress also can afflict Westernized humans. be induced by the belief that homeostasis might soon be disrupted. Among the most The immediate response powerful stressors are psychological and psychosocial stressors that exist between A stressful situation activates three major members of the same species. Lack or loss communication systems in the brain that of control is a particularly important feature regulate bodily functions. Scientists have of severe psychological stress that can have come to understand these complex systems physiological consequences. Most harmful through experiments primarily with rats, are the chronic aspects of stress. mice, and nonhuman primates, such as monkeys. Scientists then verified the action During the last six decades, researchers of these systems in humans. using animals found that stress both helps The first of these systems is the voluntary and harms the body. When confronted with a crucial physical challenge, properly

37 STRESS REACTION. When stress occurs, the sympathetic nervous system is triggered. Norepinephrine is released by nerves, and epinephrine is secreted by the adrenal glands. By activating receptors in blood vessels and structures, these sub- stances ready the heart and working muscles for action. Acetylcholine is released in the parasympathetic nervous system producing calming effects. Digestive tract is stimulated digest a meal, the heart rate and the pupils of the become smaller. The neuroendocrine system also maintains the body’s normal internal functioning. Corticotrophin releasing hormone (CRH), a peptide formed by chains of amino is released from the hypothalamus, a collection of at the base of the brain acts as a control center for neuroendocrine system. travels to the pituitary where it triggers the release of adrenoco- rticotropic hormone (ACTH). ACTH travels the blood to the adrenal glands, where it stimulates the release of cortisol.

38 nervous system, which sends messages processes such as metabolic rate and to muscles so that we may respond to sexual functions. Major stress hormones are sensory information. For example, the sight epinephrine (also known as adrenaline) and of a growling bear on a trail prompts you to cortisol. When the body is exposed to run as quickly as possible. stressors, epinephrine, which combines elements of hormones and the nervous The second communication system is the system, is quickly released into the blood autonomic nervous system. It combines the stream to put the body into a general sympatheticor emergency branch, which state of arousal and enable it to cope with a challenge. gets us going in emergencies, and the parasympathetic or calming branch, which The adrenal glands secrete keeps the body’s maintenance systems, such as digestion, in order and calms the glucocorticoids, which are hormones affect body’s responses to the emergency branch. ing glucose metabolism. In primates, the Each of these systems has a specific task. The emergency branch causes main glucocorticoid is cortisol arteries supplying blood to the muscles to relax in order to deliver more blood, allowing (hydrocortisone). Some of the actions of greater capacity to act. At the same time, the emergency system reduces blood flow to glucocorticoids help to mediate the stress the skin, kidneys, and digestive tract and increases blood flow to the muscles. In response, while some of the other, slower contrast, the calming branch helps to regulate bodily functions and soothe the actions counteract the primary response to body once the stressor has passed, pre- venting the body from remaining too long in stress and help re establish homeostasis. a state of mobilization. Left mobilized and unchecked, these body functions could lead Over the short run, adrenaline mobilizes to disease. Some actions of the calming branch appear to reduce the harmful effects energy and delivers it to muscles for the of the emergency branch’s response to body’s response. With prolonged exposure, stress. cortisol enhances feeding and helps the The brain’s third major communication process is the neuroendocrine system, which body recover from energy mobilization. also maintains the body’s internal functioning. Various “stress hormones” travel Cortisol also raises blood pressure and through the blood and stimulate the release of other hormones, which affect bodily increases the risk of adult onset diabetes, immune suppression, reproductive impairments, and depression, among other difficulties. Acute stress enhances memory of threatening situations and events, increases activity of the immune system, and helps protect the body from pathogens. The two major stress hormones, cortisol and adrenaline, facilitate the movement of

39 immune cells from the blood stream and fleeing, but standing frustrated in a storage organs such as the spleen into supermarket checkout line or sitting in a tissue where they are needed to defend traffic jam, you are not engaging in muscular against infection. exercise. Yet these systems continue to be stimulated, and when they are stimulated Glucocorticoids also affect food intake chronically, there are different during the sleep wake cycle. Cortisol levels consequences: Memory is impaired, peak in the body in the early morning hours immune function is suppressed, and energy just before waking. This hormone acts as a is stored as fat. wake up signal and helps to turn on appetite and physical activity. This effect of Overexposure to cortisol also can lead to glucorticoids may help to explain disorders such as jet lag, which results when the light weakened muscles and the suppression of dark cycle is altered by travel over long distances, causing the body’s biological major bodily systems. Elevated epinephrine clock to reset itself more slowly. Until that clock is reset, cortisol secretion and hunger, production increases blood pressure. as well as sleepiness and wakefulness, occur at inappropriate times of day in the Together, elevated cortisol and epinephrine new location. can contribute to chronic hypertension (high Glucocorticoids do more than help the body respond to stress. In fact, they are an blood pressure), abdominal obesity, and integral part of daily life and the adaptation to environmental change. The adrenal glands atherosclerosis (hardening of the arteries). help protect us from stress and are essential for survival. Adrenaline also increases the activity of Chronic stress body chemicals that contribute to When glucocorticoids or adrenaline are inflammation, and these chemicals add to secreted in response to the prolonged psychological stress commonly encountered the burden of chronic stress, potentially by humans, the results are not ideal. Normally, bodily systems gear up under leading to atherosclerosis, arthritis, and stress and release hormones to improve memory, increase immune function, possibly also aging of the brain. enhance muscular activity, and restore homeostasis. If you are not fighting or Scientists have identified a variety of stress-related disorders, including colitis, high blood pressure, clogged arteries, impotency and loss of sex drive in males, irregular menstrual cycles in females, adult- onset diabetes, and possibly cancer. Aging rats show impairment of neuronal function in the hippocampus— an area of the brain important for learning, memory, and emotion—as a result of cortisol secretion throughout their lifetimes. Overexposure to glucocorticoids also increases the number of neurons damaged by stroke. Moreover, prolonged exposure before or immediately after birth can cause a decrease in the nor-

40 mal number of brain neurons and smaller blood pressure. In the short run, these brain size. The immune system, which changes help in response to stressors. But receives messages from the nervous when stressors are chronic and system, also is sensitive to many of the psychological, the effect can be harmful and circulating hormones of the body, including result in accelerated atherosclerosis and stress hormones. Moderate to high levels of increased risk for heart attack. Research glucocorticoids act to suppress immune supports the idea that people holding jobs function, although acute elevations of stress that carry high demands and low control, hormones actually facilitate immune such as telephone operators, waiters, and function. cashiers, have higher rates of heart disease than people who can dictate the pace and Although acute stress induced immune style of their working lives. enhancement can be protective against disease pathogens, the glucocorticoid Behavioral type affects a person’s induced immune suppression can also be susceptibility to heart attack. People at beneficial. It reduces inflammation and greatest risk are hostile, irritated by trivial counteracts allergic reactions and things, and exhibit signs of struggle against autoimmune responses, which occur when time and other challenges. the body’s defenses turn against body tissue. Synthetic glucocorticoids like Researchers found that two groups of hydrocortisone and prednisone are used men—one with high hostility scores and the often to decrease inflammation and other with low hostility scores—exhibited autoimmunity. But glucocorticoids may be similar increases in blood pressure and harmful in the case of increased tumor muscle blood flow when performing a lab growth associated with stress in experiments test. This finding confirmed that hostility on animals—an area of intense research yet scores do not predict the biological response to yield any final conclusions. to simple mental tasks. One important determinant of the immune Then the researchers added harassment system’s resistance or susceptibility to to the test by leading the subjects to believe disease may be a person’s sense of control that their performances were being unfairly as opposed to a feeling of helplessness. This criticized. Men with high hostility scores phenomenon may help explain large showed much larger increases in muscle individual variations in response to disease. blood flow and blood pressure and showed Scientists are trying to identify how the slower recovery than those with low hostility perception of control or helplessness scores. Scientists found that harassed men influences physiological processes that with high hostility scores had larger regulate immune function. increases in levels of stress hormones. Thus, if you have personality traits of The cardiovascular system receives many hostility, learning to reduce or avoid anger messages from the autonomic nervous could be important to avoid cardiovascular system, and stressful experiences have an damage. immediate and direct effect on heart rate and

41 Chapter 7 Aging Neuroscientists believe that the brain can studies measure trends and reflect what remain relatively healthy and fully happens to the norm—they don’t tell what functioning as it ages and that diseases happens to everybody. Some people in their cause the most severe decline in memory, 70s and 80s function as well as those in intelligence, verbal fluency, and other tasks. their 30s and 40s. The wisdom and Researchers are investigating the normal experience of older people often make up for changes that occur over time and their deficits in performance. effecton reasoning and other intellectual activities. The belief that pronounced and progressive mental decline is inevitable was It appears that the effects of age on brain and still is popular for several reasons. For function vary widely. Almost everyone gets one, until the 20th century, few people lived a bit forgetful in old age, particularly in past 65. In 1900, when average life forming memories of recent events. For expectancy was about 47 years,3 million example, once you reach your 70s, you may people, or 4 percent of the population, were start to forget names or phone numbers or older than age 65 and were typycally ill. In respond more slowly to conflicting 2003, when life expectancy was more than information. This is not disease. However, 77 years, nearly 36 million people, or more other individuals develop senile dementia, than 12 percent of the population, were older the progressive and severe impairment in than age 65. A generation ago, frailty was mental function that interferes with daily seen among people in their 60s; today it is living. The senile dementias include more typical among those in their 80s. Alzheimer’s and cerebro-vascular diseases Moreover, few people challenged the notion and affect about 1 percent of people younger that aging meant inevitable brain decline than age 65, with the incidence increasing to because scientists knew little about the brain nearly 50 percent in those older than 85. In a or the aging process. Today’s understanding small, third group, mental functioning seems of how the normal brain ages comes from unaffected by age. Many people do well studies of the nervous system that began throughout life and continue to do well even decades ago and are just now bearing when old. The oldest human, Jeanne results. Modern technologies now make it Calment, kept her wits throughout her 122- possible to explore the structure and function year lifespan. of the brain in more depth than ever before It’s important to understand that scientific

42 and to ask questions about what actually brain neuron can readjust to damage only if happens in its aging cells. its cell body remains intact. If it does, regrowth can occur in dendrites and axons. Thus, neuroscientists are increasingly When neurons are destroyed, near by able to distinguish between the processes of surviving neurons can compensate, in part, normal aging and disease. Although some by growing new dendrites and connections. changes do occur in normal aging, they are not as severe as scientists once thought. Intellectual capacity All human behavior is determined by how From the first large studies to monitor the well the brain’s communication systems same group of healthy humans for many work. Often a failure in the cascade of one years, scientists have uncovered unexpected of these systems results in a disturbance of results. They report declines in some mental normal function. Such a failure may be functions and improvements in others. In caused by an abnormal biochemical process several studies, the speed of carrying out or a loss of neurons. certain tasks became slower, but vocabulary improved. Several studies found less severe The cause of brain aging still remains a declines in the type of intelligence relying on mystery. Dozens of theories abound. One learned or stored information compared with says that specific “aging genes” are switched the type that uses the ability to deal with on at a certain time of life. Another points to new information. genetic mutations or deletions. Other theories implicate hormonal influences, an This research is supported by animal immune system gone awry, and the studies in which scientists found that accumulation of damage caused by free changes in mental function are subtle. For radicals, cell byproducts that destroy fats example, in rodents and primates in which and proteins vital to normal cell function. only minor brain abnormalities can be detected, certain spatial tasks, such as Aging neurons navigating to find food, tend to become more difficult with age. The brain reaches its maximum weight near age 20 and slowly loses about 10 percent of The aging brain is only as resilient as its its weight over a lifetime. Subtle changes in circuitry. Scientists debate whether this the chemistry and structure of the brain circuitry is changed only by neuron atrophy begin at midlife for most people. During a life time, the brain is at risk for losing some or whether some neuron loss over time of its neurons, but widespread neuron loss is also is inevitable. In any event, when the not a normal process of aging. Brain tissue circuitry begins to break down, remaining can respond to damage or loss of neurons neurons can adapt by expanding their roles. in Alzheimer’s disease or after stroke by expanding dendrites and fine tuning connections between neurons. A damaged

43 THE AGING BRAIN. Studies of people who have died contradict the popular belief that adults lose an enormous number of neurons every day. In fact, many areas of the brain, primarily in the cortex, maintain most of their neurons. Examples include the parietal cortex, which plays a role in sensory processes and language, and the striate cortex, which processes visual information. The connectivity between neurons changes with aging, so that the brain is constantly capable of being modified or improved. Learning conditions may dictate what a stimulating environment made happens to brain cells. Studies of rats significantly shed light on some of the changes that occur in brain cells when the animals live fewer errors in a maze test than did in challenging and stimulating similar rats kept in an isolated environment. environments. In tests of middle aged rats Moreover, the stimulated rats showed an exposed to such environments, increase in brain weight and cortical researchers found that dendrites in the thickness compared with animals in the cerebral cortex developed more and longer control group. branches than did rats housed in isolated conditions. Another study showed that In response to enriched environments, brain cells in rats given acrobatic training older rats tend to form new dendrites and had more synapses per cell than rats synapses, just as younger animals do. But given only physical exercise or rats that the response is more sluggish and not as were inactive. The scientists concluded that large. Compared with younger rats, older motor learning generates new synapses. rats have less growth of the new blood Physical exercise, however, improved vessels that nourish neurons. blood circulation in the brain. Neuroscientists speculate that certain Aerobic exercise can also improve genes may be linked to events leading to human cognitive performance. death in the nervous system. By understanding the biology of the proteins Other scientists report that rats reared in produced by genes, scientists hope to be able to influence the survival and function of neurons

44 Chapter – 8 given to manic patients, lithium calmed them and enabled them to return to work Advances in the field of neurobiology and live relatively normal lives. Regarded Bipolar disorder. Patients with bipolar as both safe and effective, lithium is often disorder, previously known as manic- used to prevent recurrent episodes. depressive illness, usually experience episodes of deep depression and manic Other useful medications include certain highs, with a return to relatively normal functioning in between. They also have an anticonvulsants, such as valproate or increased risk of suicide. carbamazepine, which can have mood- Brain Activity in Bipolar Disorder These positron emission tomography scans stabilizing effects, like lithium, and may be of the brain of a person with bipolar disorder show the individual shifting from especially useful for difficult to treat bipolar depression, top row, to mania, middle row, and back to depression, bottom row, over episodes. Newer anticonvulsant the course of 10 days. medications are being studied to Bipolar disorder tends to be chronic, and episodes can become more frequent determine how well they work in stabilizing without treatment. Because bipolar disorder runs in families, efforts are mood cycles. underway to identify the responsible gene or genes. Epilepsy Bipolar patients can benefit from a Epilepsy, a chronic neurological disorder broad array of treatments. One of these characterized by sudden, disorderly is lithium. During the 1940s, researchers discharge of brain cells, is marked by showed that lithium injections into recurrent, unprovoked seizures that guinea pigs made them placid, which temporarily alter one or more brain functions. implied mood stabilizing effects. When The disorder affects approximately 1 percent of the population. Many different types of epilepsy have been recognized. Epilepsy can start at any age and can be idiopathic (having an uncertain cause) or symptomatic. Most idiopathic epilepsies are likely due to inheriting a mutant gene, more than a dozen of which have been identified during the last decade. Symptomatic epilepsies result from a wide variety of brain diseases or injuries, including birth trauma, brain infection such as abscess or meningitis, brain tumors, and stroke. Seizures are of two types, generalized and partial. Generalized seizures, which typically result in loss of consciousness, can cause several behavioral changes, including

45 convulsions or sudden changes in muscle requires precise location and removal of the tone, and arise when there is simultaneous area of the brain where the seizures excessive electrical activity over a wide originate. After surgery, about 90 percent of area of the brain. Partial seizures may properly selected patients experience occur with maintained consciousness or striking improvement or complete remission with altered awareness and behavioral of seizures. changes. Partial seizures can produce localized visual, auditory, and skin sensory A new form of epilepsy treatment, disturbances; repetitive uncontrolled electrical stimulation therapy, was introduced movements; or confused, automatic during the mid-1990s as another option for behaviors. Such seizures arise from hard to control seizures. The implantable excessive electrical activity in a limited area pacemaker like device delivers small bursts of the brain. of electrical energy to the brain via the vagus nerve on the side of the neck. There are more than a dozen antiseizure medications, approximately half of which Major depression have been introduced in the last several years, available to prevent seizures. The This condition, with its harrowing feelings of principal targets of antiseizure drugs are voltage gated ion channels permeable to sadness, hopelessness, pessimism, loss of sodium or calcium and synapses using the transmitter GABA, a naturally occurring interest in life, and reduced emotional well- substance in the brain that acts to inhibit electrical discharge. Identification of the being, is one of the most common and mutant genes underlying human epilepsy may provide new targets for the next debilitating mental disorders and one of the generation of antiseizure drugs. In many instances, epilepsy can be controlled with leading causes of morbidity worldwide. a single anti seizure drug that lessens the frequency of seizures, but sometimes a Depression is as disabling as heart disease combination of drugs is necessary. Complete control of seizures can be or arthritis. Depressed individuals are 18 achieved in more than 50 percent of patients, and another 25 percent can be times more likely to attempt suicide than improved significantly. It is hoped that the newly available antiseizure drugs will people with no mental illness. provide complete control in additional patients. Annually, major depression affects 5 Surgery, considered for patients who percent of the population, or 9.8 million donot respond to antiseizure drugs, should Americans, aged 18 years and older. be performed only at specialized medical Fortunately, 80 percent of patients respond centers qualified to evaluate patients and to drugs, psychotherapy, or a combination perform epilepsy surgery. Epilepsy surgery of the two. Some severely depressed patients can be helped with electroconvulsive therapy. Depression arises from many causes: biological (including genetic), psychological, environmental, or a combination of these. Stroke, hormonal disorders,

46 antihypertensives, and birth control pills tricyclic antidepressants, such as imipramine, primarily block the reabsorption also can play a part. and inactivation of serotonin and norepinephrine to varying degrees. Another Physical symptoms—disturbances of class of antidepressant medications is the monoamine oxidase inhibitors (MAOIs). sleep, sex drive, energy level, appetite, These agents inhibit monoamine oxidase, and digestion—are common. Some of an enzyme that breaks down serotonin and norepinephrine, allowing these chemicals to these symptoms may reflect the fact that remain active. MAO Is available for use include isocarboxazid, phenelzine, and the disorder affects the delicate hormonal tranylcypromine. feedback system linking the hypothalamus, The popular medication fluoxetine (Prozac) is the first of a class of drugs called the pituitary gland, and the adrenal glands. selective serotonin reuptake inhibitors, or SSRIs. SSRIs block the reabsorption and For example, many depressed patients inactivation of serotonin and keep it active in certain brain circuits. Hence, they are secrete excess cortisol, a stress hormone, functionally similar to the tricyclic antidepressants, but act selectively on the and do not respond appropriately to a hormone that should counter cortisol secretion. When tested in sleep laboratories, depressed patients’ electroencephalograms (EEGs) often exhibit abnormalities in their sleep patterns. The modern era of drug treatment for depression began in the late 1950s. Most antidepressants affect norepinephrine or serotonin in the brain, apparently by correcting the abnormal signals that control mood, thoughts, and other sensations. The HOW PAIN KILLERS WORK. At the site of injury, the body produces prostaglandins that increase pain sensitivity. Aspirin, which acts primarily in the periphery, prevents the production of prostaglandins. Acetaminophen is believed to block pain impulses in the brain itself. Local anesthetics intercept pain signals traveling up the nerve. Opiate drugs, which act primarily in the central nervous system, block the transfer of pain signals from the spinal cord to the brain.

47 serotonin system. There are also several operations. The most famous of these newer antidepressants available, such as agents, which temporarily interrupt the action bupropion, that are also very effective but of pain-carrying nerve fibers, is Novocain, seem to have a different and as yet which dentists used as a local anesthetic for unknown mechanism of action. many years; lidocaine is more popular today. Pain Analgesia refers to loss of pain sensation without loss of sensitivity to touch. The two If there is a universal experience, pain is it. main types of analgesics are non opioids (aspirin and related nonsteroidal anti- Each year, more than 97 million inflammatory drugs [NSAIDs] such as ibuprofen, naproxen, and acetaminophen) Americans suffer chronic, debilitating and opioids (morphine, codeine). Nonopioid analgesics are useful for treating mild or headaches or a bout with a bad back or moderate pain, such as headache or the pain of arthritis—all at a total cost of toothache. Because NSAIDs are anti- inflammatory, they are effective for treating some $100 billion. But it need not be that such inflammatory conditions as arthritis. Moderate pain also can be treated by way. New discoveries about how chemicals combining a mild opioid, such as codeine, with aspirin. Opioids are the most potent in the body transmit and regulate pain pain killers and are used for severe pain, such as that occurring after major chest or messages have paved the way for new abdominal surgery. treatments for both chronic and acute pain. Studies of the body’s own pain-control system not only demonstrated the existence Until the mid-19th century, pain relief of naturally occurring opioids (the endorphins) but also identified the receptors during surgery relied on natural (targets) through which opioids exert their effects. These findings led to the use of substances, such as opium, alcohol, and injections of morphine and endorphins, and other opioids, into the cerebrospinal fluid ( in cannabis. All were inadequate and short- which the spinal cord is bathed) with- out causing paralysis, numbness, or other lived. Not until 1846 did doctors discover severe side effects. This technique came about through experiments with animals that the anesthetic properties of ether, first in first showed that injecting opioids into the animals and then in humans .Soon, the usefulness of chloroform and nitrous oxide became known and heralded a new era in surgery. The dozens of drugs used today during surgery abolish pain, relax muscles, and induce unconsciousness. Other agents reverse these effects. Local anesthesia is used in a limited area of a person’s body to prevent pain during examinations, diagnostic procedures, treat- ments, and surgical

48 spinal cord could produce profound pain proven effective in animal studies, control. This technique is now commonly suggesting that the development of drugs used in humans to treat pain after surgery that target these molecules in humans may and is a mainstay for pain relief after have great value for the treatment of caesarean section. persistent pain. Although NSAIDs and opioids are quite Parkinson’s disease effective for pain produced by tissue injury, they are much less effective when the pain This neurologic disorder afflicts 1 million results from injury to the nervous system. individuals in the United States, most of These so-called neuropathic pains include whom are older than 50. Parkinson’s dis- the pain of diabetic neuropathy, post- ease is characterized by symptoms of therapeutic neuralgia, phantom limb pain, slowness of movement, muscular rigidity, and post-stroke pain. For these pains, tremor, and postural instability. anticonvulsants are more effective, and some patients can be helped with low The discovery in the late 1950 s that the doses of antidepressants. level of dopamine was decreased in the brains of Parkinson’s patients was followed New targets, however, are on the in the 1960s by the successful treatment of horizon. Molecular biology has identified this disorder by administration of the drug many molecules (ion channels and levodopa, which is converted to dopamine in receptors) that are predominantly, if not the brain. The successful treatment of exclusively, expressed by the nociceptor, Parkinson’s by replacement therapy is one of which is the first order nerve fiber in the the greatest success stories in neurology. pain pathway. Because adverse side Levodopa is now combined with another effects of drugs arise from the widespread drug, carbidopa, that reduces the peripheral location of the molecules targeted by breakdown of levodopa, thus allowing analgesics (e.g., constipation results from greater levels to reach the brain and morphine’s action on opioid receptors in reducing side effects. Also playing an the gut), new analgesics that target only important role are newer drugs, such as the nociceptor may have a better side inhibitors of dopamine breakdown and effect profile. Among the many new targets dopamine agonists that act directly on are glutamate receptors, vanilloid receptors dopamine receptors. (which are targeted by capsaicin, the active ingredient in hot peppers), and a variety of Genetic studies have demonstrated acid-sensing ion channels. Blocking the several heritable gene abnormalities in activity of many of these molecules has certain families, but almost all cases of Parkinson’s occur sporadically. It is believed that hereditary factors may render some individuals more vulnerable to environmental

49 factors such as pesticides. The discovery in that surgical destruction of these overactive the late 1970s that a chemical substance, nuclei—the pallidum and sub thalamic MPTP, can cause parkinsonism in drug nucleus— can greatly reduce symptoms of addicts stimulated intensive research on Parkinson’s disease. The past decade has the causes of the disorder. MPTP was witnessed a resurgence in this surgical accidentally synthesized by illicit drug procedure, pallidotomy, and more recently designers seeking to produce a heroin-like chronic deep-brain stimulation. These compound. MPTP was found to be techniques are highly successful for treating converted in the brain to a substance that patients who have experienced significant destroys dopamine neurons. Parkinson’s is worsening of symptoms and are troubled by now being intensively studied in primate the development of drug-related involuntary MPTP models. movements. The past decade has also seen further attempts to treat such patients with In the past several decades, scientists surgical implantation of cells, such as fetal have shown in primate models of cells, capable of producing dopamine. Parkinson’s that specific regions in the Replacement therapy with stem cells also is basal ganglia, collections of cell bodies being explored. deep in the brain, are abnormally overactive. Most importantly, they found

50 Chapter- 9 Challenges drugs alter the ways neurotransmitters carry their messages from neuron to neuron. Addiction. Drug abuse is one of the nation’s Some drugs mimic neurotransmitters, where most serious health problems. If continued as others block them. Still others alter the long enough, drug abuse—often defined as way that the neurotransmitters are released harmful drug use— can eventually alter the or inactivated. The brain reward system is very structure and chemical makeup of the inappropriately activated because drugs alter brain, producing a true brain disorder. This the chemical messages sent among neurons disorder is called drug addiction or drug in this circuit. Finally, neuroscientists also dependence. Drug addiction is defined as have learned that addiction requires more having lost control over drug taking, even in than the activation of the brain reward the face of adverse physical, personal, or system. The process of becoming addicted social consequences. appears to be influenced by many factors. Motivation for drug use is an important one. People abuse drugs for a simple reason: For example, people who take drugs to get Drugs produce feelings of pleasure or high may get addicted, but people who use remove feelings of stress and emotional them properly as medicine rarely do. Genetic pain. Neuroscientists have found that almost susceptibility or environmental factors, such all abused drugs produce pleasure by as stress, may also alter the way that people activating a specific network of neurons respond to drugs. In addition, the called the brain reward system. The circuit is development of tolerance—the progressive normally involved in an important type of need that accompanies chronic use for a learning that helps us to stay alive. It is higher drug dose to achieve the same activated when we fulfill survival functions, effect— varies in different people, as does such as eating when we are hungry or drug dependence— the adaptive drinking when we are thirsty. In turn, our physiological state that results in withdrawal brain rewards us with pleasurable feelings symptoms when drug use stops. Tolerance that teach us to repeat the task. Because and dependence are standard responses of drugs inappropriately turn on this reward the brain and body to the presence of drugs. circuit, people want to repeat drug use. However, addiction requires that these occur while a motivational form of dependence— Neuroscientists also have learned the feeling that a person can’t live without a specifically how drugs affect neurons to exert their influence. Neurons release special chemicals, called neurotransmitters, to communicate with each other. Abused