Suhail AR Doi PhD FRCP

• Consultant in endocrinology
• Mubarak Al-Kabeer Teaching Hospital and
• Faculty of Medicine, Kuwait University,
• Kuwait

Although amygdalectomies are still occasionally performed to treat aggressive behavior treatment centers in mn purchase cheap paroxetine line, medication is the usual treatment treatment goals generic 10 mg paroxetine mastercard. Today medications known to cause hair loss discount paroxetine 10 mg visa, it is difficult for many people to imagine that destroying a large portion of the brain was once thought to be therapeutic medications adhd cheap paroxetine 10 mg without a prescription. Even stranger is the fact that Moniz was shot in the spine and partially paralyzed by a lobotomized patient medications j-tube purchase paroxetine without a prescription. In the 1930s medications 7 rights buy 10mg paroxetine with visa, John Fulton and Carlyle Jacobsen of Yale University reported that frontal lobe lesions had a calming effect in chimpanzees. It has been suggested that frontal lesions have this effect because of the destruction of limbic structures and, in particular, connections with frontal and cingulate cortex. Moniz proposed that ablations of the frontal cortex might be effective in treating psychiatric diseases. A frightening variety of techniques were used to produce lesions in the frontal lobes. The handle was then swung medially and laterally to destroy cells and interconnecting pathways. Note that although this surgery left no outward scars, the physician could not see what was being destroyed. Frontal lobotomy reportedly had beneficial effects on people with a number of disorders, including psychosis, depression, and various neuroses. The effect of the surgery was described as a relief from anxiety and escape from E thoughts that were unendurable. The changes that appear to be related to the limbic system are a blunting of emotional responses and a loss of the emotional component of thoughts. In addition, lobotomized patients often developed "inappropriate behavior" or an apparent lowering of moral standards. Like Phineas Gage, patients had considerable difficulty planning and working toward goals. With our modest understanding of the neural circuitry underlying emotion and other brain functions, it is hard to justify destroying a large portion of the brain. Fortunately, treatment with lobotomy decreased fairly rapidly, and today, instead, drug therapy is primarily used for serious emotional disorders. For example, human brain imaging studies have found that there is greater activity in orbitofrontal cortex and anterior cingulate cortex when subjects recall past experiences that made them angry. Interpreting these patterns of brain activation involves the same challenges we have discussed for other emotions. Historically, studies of anger and aggression have been important for their implications for the involvement of subcortical structures in emotion. One of the earliest structures linked to anger and aggressive behavior is the hypothalamus. Experiments performed in the 1920s showed that a remarkable behavioral transformation took place in cats or dogs whose cerebral hemispheres had been removed. Animals that were not easy to provoke prior to the surgery would go into a state of violent rage with the least provocation after the surgery. This state was called sham rage because the animal demonstrated all the behavioral manifestations of rage but in a situation that normally would not cause anger. It was also a sham in the sense that the animals would not actually attack as they normally might. While the extreme behavioral condition called sham rage resulted from removing all of both cerebral hemispheres (the telencephalon), remarkably, the behavioral effect can be reversed by making the lesion just a little bit larger to include portions of the diencephalon, particularly the hypothalamus. The implication is that the posterior hypothalamus may be particularly important for the expression of anger and aggression and that normally it is inhibited by the telencephalon. But we must bear in mind that these lesions were large, and something other than the posterior hypothalamus may have been destroyed with the larger lesion. Hess at the University of Zurich investigated the behavioral effects of electrically stimulating the diencephalon. Hess made small holes in the skulls of anesthetized cats and implanted electrodes in the brain. After the animal awoke, a small electrical current was passed through the electrodes, and behavioral effects were noted. Various structures were stimulated, but here we will focus on the effects of stimulating different regions of the hypothalamus. If the cerebral hemispheres are removed and the hypothalamus is left intact, sham rage results. Depending on where the electrode is placed, stimulation may cause the animal to sniff, pant, eat, or express behaviors characteristic of fear or anger. These reactions illustrate the two primary functions of the hypothalamus discussed in Chapters 15 and 16: homeostasis and the organization of coordinated visceral and somatic motor responses. Responses related to emotional expression can include changes in heart rate, pupillary dilation, and gastrointestinal motility, to name a few. Because stimulation of some parts of the hypothalamus also elicits behavior characteristic of fear and anger, we hypothesize that the hypothalamus is an important component of the system normally involved in expressing these emotions. The expression of rage Hess evoked by hypothalamic stimulation was similar to the sham rage seen in animals whose cerebral hemispheres had been removed. With a small application of electrical current, a cat would spit, growl, and fold its ears back, and its hair would stand on end. This complex and highly coordinated set of behaviors would normally occur when the cat feels threatened by an enemy. If the intensity of the stimulation was increased, the animal might make an actual attack, swatting with a paw or leaping onto an imaginary adversary. When the stimulation was stopped, the rage disappeared as quickly as it started, and the cat might even curl up and go to sleep. Affective aggression, also known as a threat attack, was observed after stimulating specific sites in the medial hypothalamus. Similar to the rage response reported by Hess, the cat would arch its back, hiss, and spit but would usually not actually attack a victim, such as a nearby rat. Predatory aggression, which Flynn called a silent-biting attack, was evoked by stimulating parts of the lateral hypothalamus. While the back might be somewhat arched and the hair slightly on end, predatory aggression was not accompanied by the dramatic threatening gestures of affective aggression. Nonetheless, in this "quiet attack," the cat would move swiftly toward a rat and viciously bite its neck. There are two major pathways by which the hypothalamus sends signals involving autonomic function to the brain stem: the medial forebrain bundle and the dorsal longitudinal fasciculus. Axons from the lateral hypothalamus make up part of the medial forebrain bundle, and these project to the ventral tegmental area in the midbrain. Stimulation of sites within the ventral tegmental area can elicit behaviors characteristic of predatory aggression, just as stimulation of the lateral hypothalamus does. Conversely, lesions in the ventral tegmental area can disrupt offensive aggressive behaviors. One finding suggesting that the hypothalamus influences aggressive behavior via its effect on the ventral tegmental area is that hypothalamic stimulation will not evoke aggression if the medial forebrain bundle is cut. Interestingly, aggressive behavior is not entirely eliminated by this surgery, suggesting that this route is important when the hypothalamus is involved, but that the hypothalamus need not always be involved. Interestingly, the hypothalamus and the midbrain periaqueductal gray matter appear to influence behavior partially based on input from the amygdala. Serotonergic Regulation of Anger and Aggression A variety of studies suggest that the neurotransmitter serotonin plays an important role regulating anger and aggression. For the most part, experimental evidence supports the serotonin deficiency hypothesis, which states that aggression is inversely related to serotonergic activity. One link between serotonin and aggression comes from studies of induced aggression in rodents. If male mice are isolated in a small cage for several weeks, about half of them will become hyperactive and unusually aggressive when they subsequently encounter other mice. Although the isolation has no effect on the level of serotonin in the brain, there is a decrease in the turnover rate (the rate of synthesis, release, and resynthesis) of this neurotransmitter. Moreover, this decrease is found only in the mice that later become unusually aggressive and not in those relatively unaffected by the isolation. Also, female mice typically do not become aggressive following isolation, and they show no decrease in serotonin turnover. Evidence indicates that drugs that block the synthesis or release of serotonin increase aggressive behavior. Other experiments paint a somewhat different picture, however, suggesting that rather than simply being more aggressive, the knockout mice are more impulsive. The relationship between serotonin and aggression is similar in primates that have been studied. For example, researchers found that the dominance hierarchy in a colony of vervet monkeys could be manipulated by injecting animals with drugs that either increased or decreased serotonergic activity. The behavior of these animals was consistent: More aggression was associated with less serotonergic activity. However, there was one interesting sociological twist; aggression did not correlate with dominance in the group. If the dominant male was removed, the top position was taken by an animal with artificially enhanced serotonergic activity. Conversely, the injection of drugs that reduced serotonin function (serotonin antagonists) was correlated with animals becoming subordinate. The subordinate animals were actually significantly more likely to initiate aggression. Interestingly, the less aggressive dominant male garnered his status by his skills in recruiting females to support his position. In humans, there are a large number of reports of a negative correlation between serotonin activity and aggression. Questions have been raised, however, about the generality of the correlation between serotonin and aggression when people of different ages and people without personality disorders are examined. As with the animal studies, a correlation is often reported, but the reality is probably more complex. Many scientists would agree that serotonin is involved in the modulation of anger and aggressive behavior. However, some scientists in the field consider this relationship overly simplistic. Animals exhibit aggressive behaviors for a variety of reasons, and serotonin is not involved equally in all forms. Some autoreceptors are presynaptic on the raphe neurons that send serotonin widely to the brain. With this negative feedback, serotonin release affects the raphe neurons in such a way as to decrease further release. Because of the diversity of receptor locations and functions, interpretation of pharmacological and knockout experiments is challenging; new approaches are needed to tease out the details of the relationships among serotonin, anger, and aggressive behavior. We do know from brain imaging studies that emotions are associated with widespread brain activation. Some of the structures involved are part of the limbic system, and other structures are not. But even with images of brain activity in various emotional states, understanding the neural basis of emotional experience is challenging. What should we make of the observation that some brain structures are activated in multiple emotional states while others are more specific to particular emotions For that matter, is it even correct to think of brain activity as reflecting feelings, or might feelings be emergent sensations based on combinations of active neurons, none of which independently signals an emotion In this chapter, we have focused on a handful of brain structures for which there is particularly strong evidence for involvement in emotion. A way to look at our current state of understanding is that the combined lesion, stimulation, and brain imaging studies have done a good job identifying structures that are candidates for emotional processing. It will take a good deal more work to figure out what various cortical and subcortical areas contribute. Emotional experiences are the result of complex interactions among sensory stimuli, brain circuitry, past experiences, and the activity of neurotransmitter systems. In light of this complexity, we probably should not be surprised that humans exhibit a broad spectrum of emotional and mood disorders, as we will see in Chapter 22. When thinking about the neural basis of emotion, keep in mind that the structures apparently involved in emotion also have other functions. For a considerable time after Broca defined the limbic lobe, it was thought to be primarily an olfactory system. We will see in Chapter 24 that some of the limbic structures are also important for learning and memory. Emotions are nebulous experiences that influence our brains and behavior in many ways, so it seems logical that emotional processing should be intertwined with other brain functions. How have the definition of the limbic system and thoughts about its function changed since the time of Broca Of the numerous anatomical structures they removed, which is thought to be closely related to changes in temperament Why might performing bilateral amygdalectomy on a dominant monkey in a colony result in that monkey becoming a subordinate What assumptions about limbic structures underlie the surgical treatment of emotional disorders What distinguishes basic emotion, dimensional, and psychological constructionist theories of emotion Mapping discrete and dimensional emotions onto the brain: controversies and consensus.

By making neural recordings along the way and imaging the electrodes with X-rays treatment integrity checklist purchase paroxetine american express, it is possible to position the tip of the electrode in the amygdala medicine 2 times a day paroxetine 20 mg with amex. Electrical current is then passed through the electrode symptoms of buy paroxetine us, or a solution is injected treatment broken toe buy paroxetine 20 mg otc, to destroy all or part of the amygdala treatment kawasaki disease order generic paroxetine on line. The lesions that are produced have a "taming effect" in some patients treatment strep throat safe 20 mg paroxetine, reducing the incidence of aggressive outbursts. Brain surgery used as a method of treating psychiatric disorders is called psychosurgery. Early in the twentieth century, treating severe disorders involving anxiety, aggression, or neuroses with psychosurgical techniques, including the frontal lobotomy, was a common practice (Box 18. Temperature, precipitation, and daylight vary with the seasons; light and dark trade places each day; tides ebb and flow. The functions of some rhythms are obvious, while others are obscure, and some rhythms indicate pathology. In this chapter, we explore selected brain rhythms, beginning with the fast and proceeding to the slow. The forebrain, especially the cerebral cortex, produces a range of rapid electrical rhythms that are easily measured and that closely correlate with interesting behaviors, including sleep. Sleep is explored in detail because it is complex, ubiquitous, and so dear to our hearts. Finally, we summarize what is known about the timers that regulate the everyday ups and downs of our hormones, body temperature, alertness, and metabolism. Almost all physiological functions change according to daily cycles known as circadian rhythms. The clocks that time circadian rhythms are in the brain, calibrated by the sun via the visual system, and they profoundly influence our health and well-being. Similarly, we are often less concerned with the activities of single neurons than with understanding the activity of a large population of neurons. Caton made electrical recordings from the surface of dog and rabbit brains using a primitive device sensitive to voltage. The electrodes are wires taped to the scalp, along with conductive paste to ensure a low-resistance connection. Small voltage fluctuations, usually a few tens of microvolts (V) in amplitude, are measured between selected pairs of electrodes. Different regions of the brain-anterior and posterior, left and right-can be examined by selecting the appropriate electrode pairs. When a group of cells is excited simultaneously, the tiny signals sum to generate one larger surface signal. Notice that in this case, the number of activated cells and the total amount of excitation may not have changed, only the timing of the activity. A, auricle (or ear); C, central; Cz, vertex; F, frontal; Fp, frontal pole; O, occipital; P, parietal; T, temporal. Wires from pairs of electrodes are fed to amplifiers, and each recording measures voltage differences between two points on the scalp. When the afferent axon fires, the presynaptic terminal releases glutamate, which opens cation channels. Positive current flows into the dendrite, leaving a slight negativity in the extracellular fluid. Current spreads down the dendrite and escapes from its deeper parts, leaving the fluid slightly positive at those sites. Only if thousands of cells contribute their small voltage is the signal large enough to reach the scalp surface. Recall from physics that whenever electrical current flows, a magnetic field is generated according to the "right hand rule" (hold up your right hand loosely; if your thumb points in the direction of electrical current flow, the rest of your curling fingers indicate the direction of the magnetic field). Even the strongest brain activity, with many synchronously active neurons contributing, produces a field strength just one billionth that of the magnetic field generated by the Earth, nearby power lines, and the movement of distant metal objects such as elevators and cars. I intended to study the mathematics of chaos, but as with many careers my path diverged unexpectedly. A year into my graduate study, mathematician Nancy Kopell established the Center for BioDynamics, catalyzing growing interest in the applications of dynamical systems theory to the study of biological phenomena, including neuroscience. After attending a few neuroscience lectures, I knew this was a puzzle I wanted to help solve. I began using mathematics to study rhythmic activity in simplified representations of neural circuits, such as the central pattern-generating network that regulates crayfish swimming. The first is my now close colleague, neurophysiologist Chris Moore, who was himself a postdoctoral fellow at the time. I learned that the intracellular currents within the long, aligned dendrites of pyramidal neurons are the primary generators of the recorded magnetic field signals. Delta rhythms are slow, less than 4 Hz, are often large in amplitude, and are a hallmark of deep sleep. We discovered that when a subject directs her attention to her finger before it is tapped, the beta rhythms in the hand area of S1 decrease compared to when her attention is directed elsewhere. Our results were similar to previous findings in the visual cortex, suggesting that beta rhythms may signal inhibitory processes in sensory areas of cortex. What is it about these rhythms, if anything, that links them to decreased perception To address this piece of the puzzle, I turned to my mathematics roots and began constructing a computational neural model to study the origins of these rhythms. My prior research had given me solid intuitions about how stable rhythms can emerge from neural circuits. However, after much exploration using simplified mathematical representations of neural circuits. This endeavor spanned several years that also included the birth of the first of my three children. To my delight, the detailed model yielded novel and nonintuitive predictions about rhythms. Specifically, it predicted that beta rhythms emerge from the integration of two sets of synaptic inputs that are roughly synchronous and that excite different parts of pyramidal cell dendrites. These inputs drive alternating electrical currents up and down within the dendrites to reproduce rhythms remarkably consistent with recordings. This discovery was thrilling since the mathematical model was now predicting what the data from new experiments would look like. Through continued collaboration with Chris Moore and other neurophysiologists and neurosurgeons, we are currently testing model-derived predictions with electrode recordings. However, through collaboration and the interplay of interdisciplinary methods, I am convinced we can build interpretive bridges between neural activity and human brain functions. Solving the puzzle of brain rhythms will be an important and exciting step along the way. About halfway through the recording, the subject opened his eyes, signaled by the large blink artifacts on the top traces (arrows), and alpha rhythms were suppressed. Each colored line represents the frequencies of a single type of rhythm recorded from several species (the absence of data about a particular rhythm for a species does not necessarily mean that species lacks that rhythm). In general, high-frequency, low-amplitude rhythms are associated with alertness and waking, or the dreaming stages of sleep. Low-frequency, high-amplitude rhythms are associated with nondreaming sleep states, certain drugged states, or the pathological condition of coma. This is logical because when the cortex is most actively engaged in processing information, whether generated by sensory input or by internal processes, the activity level of cortical neurons is relatively high but also relatively unsynchronized. In other words, each neuron, or a very small group of neurons, is vigorously involved in a slightly different aspect of a complex cognitive task; it fires rapidly but not quite simultaneously with most of its neighbors. In contrast, during deep sleep, cortical neurons are not engaged in information processing, and large numbers of them are phasically excited by a common, slow, rhythmic input. The activity of a large set of neurons will produce synchronized oscillations in one of two fundamental ways: (1) They may all take their cues from a central clock, or pacemaker, or (2) they may share or distribute the timing function among themselves by mutually exciting or inhibiting one another. The second mechanism is more subtle because the timing arises from the collective behavior of the cortical neurons themselves. The concept of shared synchronous rhythm can be easily demonstrated by a group of people, even nonmusical ones. Simply tell them to begin clapping, but give them no instructions about how fast to clap or whose beat to follow. By listening and watching each other, they will adjust their clapping rates to match. A key factor is person-to-person interaction; in a network of neurons, these interactions occur via synaptic connections. This kind of collective, organized behavior can generate rhythms of impressive dimensions, which can move in space and time. Have you ever been part of a human wave in the stands of a sold-out football stadium Most real neural oscillators include far more neurons but similar basic features: a source of constant excitatory drive, feedback connections, and synaptic excitation and inhibition. Within the mammalian brain, rhythmic, synchronous activity is usually coordinated by a combination of the pacemaker and collective methods. Synchronous rhythms can (a) be led by a pacemaker or (b) arise from the collective behavior of all participants. Some thalamic cells have a particular set of voltage-gated ion channels that allow each cell to generate very rhythmic, self-sustaining discharge patterns even when there is no external input to the cell. The rhythmic activity of each thalamic pacemaker neuron then becomes synchronized with many other thalamic cells via a hand-clapping kind of collective interaction. Synaptic connections between excitatory and inhibitory thalamic neurons force each individual neuron to conform to the rhythm of the group. These coordinated rhythms are then passed to the cortex by the thalamocortical axons, which excite cortical neurons. Some rhythms of the cerebral cortex do not depend on a thalamic pacemaker but rely instead on the collective, cooperative interactions of cortical neurons themselves. In this case, the excitatory and inhibitory interconnections of the neurons result in a coordinated, synchronous pattern of activity that may remain localized or spread to encompass larger regions of cortex. One excitatory cell (E cell) and one inhibitory cell (I cell) synapse upon each another. As long as there is a constant excitatory drive (which does not have to be rhythmic) onto the E cell, activity will tend to trade back and forth between the two neurons. One activity cycle through the network will generate the pattern of firing shown in the dashed box. At times during sleep states, thalamic neurons fire in rhythmic patterns that do not reflect their input. When you are awake, the thalamus allows sensory information to pass through it and be relayed up to the cortex. When you are asleep, thalamic neurons enter a self-generated rhythmic state that prevents organized sensory information from being relayed to the cortex. While this idea has intuitive appeal (most people do prefer to sleep in a dark, quiet environment), it does not explain why rhythms are necessary. One scheme for understanding visual perception takes advantage of the fact that cortical neurons responding to the same object are synchronously active. Walter Freeman, a neurobiologist at the University of California, Berkeley, pioneered the idea that neural rhythms are used to coordinate activity between regions of the nervous system. By momentarily synchronizing the fast oscillations generated by different regions of cortex, perhaps the brain binds together various neural components into a single perceptual construction. For example, when you are trying to catch a basketball, different groups of neurons that simultaneously respond to the specific shape, color, movement, distance, and even the significance of the basketball tend to oscillate synchronously. The fact that the oscillations of these scattered groups of cells (those that together encode "basketballness") are highly synchronous would somehow tag them as a meaningful group, distinct from other nearby neurons, thereby unifying the disjointed neural pieces of the "basketball puzzle. Instead, they may be intriguing but unimportant by-products of the tendency for brain circuits to be strongly interconnected, with various forms of excitatory feedback. When something excites itself, whether it is an audio amplifier or the human stadium wave, it often leads to instability or oscillation. Feedback circuits are essential for the cortex to do all the marvelous things it does for us. Oscillations may be the unavoidable consequence of so much feedback circuitry, unwanted but tolerated by necessity. The thalamus can generate rhythmic activity because of the intrinsic properties of its neurons and because of its synaptic interconnections. In the thalamus, green represents a population of excitatory neurons, and black represents a population of inhibitory neurons. The Seizures of Epilepsy Seizures, the most extreme form of synchronous brain activity, are always a sign of pathology. In both cases, the neurons within the affected areas fire with a synchrony that never occurs during normal behavior. The cerebral cortex, probably because of its extensive feedback circuitry, is never far from the runaway excitation we know as a seizure. Epilepsy is more common in developing countries, particularly in rural areas, presumably because of higher rates of untreated childhood epilepsy, infections, and poor pre- and postnatal care.

Neural activity in the awake brain increases adenosine levels medicine and manicures buy paroxetine 10 mg low price, thereby increasing the inhibition of neurons in the modulatory systems associated with wakefulness treatment neuropathy cheap 20 mg paroxetine amex. After sleep begins medications nursing purchase paroxetine with a mastercard, adenosine levels slowly fall internal medicine trusted paroxetine 20mg, and activity in the modulatory systems gradually increases until we wake up to start the cycle anew medicine emblem purchase cheap paroxetine line. Sleepiness is one of the most familiar consequences of infectious diseases medicine rock paroxetine 10 mg on line, such as the common cold and the flu. There are direct links between the immune response to infection and the regulation of sleep. Muramyl peptides are usually produced only by the cell walls of bacteria, not brain cells, and they also cause fever and stimulate immune cells of the blood. More recent research has implicated several cytokines, small signaling peptides involved in the immune system, in the regulation of sleep. One of them is interleukin-1, which is synthesized in the brain by glia, and by macrophages, cells throughout the body that scavenge foreign material. Another endogenous sleep-promoting substance is melatonin, a hormone secreted by the pea-sized pineal body (see the appendix to Chapter 7). It has been called the "Dracula of hormones" because it is released only when the environment darkens-normally at night-and its release is inhibited by light. In humans, melatonin levels tend to rise around the time we become sleepy in the evening, peak in the early morning hours, and then fall to baseline levels by the time we awaken. In recent years, melatonin has become popular as an over-the-counter sleep-promoting drug. Although it has shown some promise in treating the symptoms of jet lag and the insomnia that affects some older adults, the general effect of melatonin on improving sleep remains debatable. While the pieces do not all fit together quite yet, it is clear that the behavioral states of sleeping and waking are different even at the molecular level. For example, in the macaque monkey, most areas of cerebral cortex show higher rates of protein synthesis in deep sleep than in light sleep. Research has demonstrated that sleeping and waking are associated with differences in the expression of certain genes. Chiara Cirelli and Giulio Tononi, working at the Neurosciences Institute in San Diego and at the University of Wisconsin, have studied the expression of thousands of genes in rats that were awake or asleep. Most of the genes that were more highly expressed in the awake brain could be placed into one of three groups. One group includes what are called immediate early genes, genes that code for transcription factors that affect the expression of other genes. The low expression of these genes during sleep may be associated with the fact that learning and memory formation are largely absent in this state. Increased expression of these genes may play a role in satisfying the higher metabolic demands of the awake brain. A different group of genes was most highly expressed during sleep, and some of them might contribute to increased protein synthesis and synaptic plasticity mechanisms that complement those most prevalent during waking. An important point is that the sleep-related changes in gene expression were specific to the brain, and they did not change in other tissues, such as the liver and skeletal muscle. This is consistent with the widely held hypothesis that sleep is a process generated by the brain for the benefit of the brain. Some animals are active during daylight hours, others only at night, and others mainly at the transitional periods of dawn and dusk. In humans, there is an approximately inverse relationship between the propensity to sleep and body temperature. Now and then you readjust your watch to keep it in sync with the rest of the world (or at least the time on your computer). Alertness and core body temperature vary similarly, but growth hormone and cortisol levels in the blood are highest during sleep, although at different times. The bottom graph shows the excretion of potassium by the kidneys, which is highest during the day. Brain clocks are an interesting example of the link between the activity of specific neurons and behavior. Biological Clocks the first evidence for a biological clock came from a brainless organism, the mimosa plant. It seemed obvious to many people that the plant simply reacted to sunlight with some kind of reflex movement. This implied that the plant was not responding to the sun and very likely had an internal biological clock. Environmental time cues (light/dark, temperature and humidity variations) are collectively termed zeitgebers (German for "time givers"). Obviously, even small, consistent errors of timing could not be tolerated for long. When mammals are completely deprived of zeitgebers, they settle into a rhythm of activity and rest that often has a period more or less than 24 hours, in which case their rhythms are said to free-run. In mice, the natural free-running period is about 23 hours, in hamsters it is close to 24 hours, and in humans it tends to be 24. Each horizontal line is a day; solid lines indicate sleep, and dashed lines indicate waking. The subject was first exposed to 9 days of natural 24-hour cycles of light and dark, noise and quiet, and air temperature. During the middle 25 days, all time cues were removed, and the subject was free to set his own schedule. Notice also that the low point of body temperature shifted from the end of the sleep period to the beginning. During the last 11 days, a 24-hour cycle of light and meals was reintroduced, the subject again entrained to a day-long rhythm, and body temperature gradually shifted back to its normal point in the sleep cycle. When people in caves are allowed to set their own schedules of activity for months on end-waking and sleeping, turning lights on and off, and eating when they choose-they initially settle into roughly a 25-hour rhythm. They may stay awake for about 20 hours straight, then sleep for about 12 hours, and this pattern seems perfectly normal to them at the time. In isolation experiments, behavior and physiology do not always continue to cycle together. Recent studies have found that body temperature and other physiological measures may continue to change reliably over a 24-hour cycle, even if people are entrained on a 20-hour or 28-hour "day" with artificial lighting. In the cave experiments described earlier, there can be even larger differences in the periods of behavioral and physiological cycles, when people are allowed to set their own schedules. Normally, our lowest body temperature occurs shortly before we awaken in the morning, but when desynchronized, this temperature nadir can drift, first moving earlier into the sleep period, and then into waking time. This is the familiar experience known as jet lag, and the best cure is bright light, which helps resynchronize our biological clocks. One or more input pathways are sensitive to light and dark and entrain the clock and keep its rhythm coordinated with the circadian rhythms of the environment. The clock itself continues to run and keep its basic rhythm even when the input pathway is removed. Output pathways from the clock allow it to control certain brain and body functions according to the timing of the clock. Sleep appears to be regulated by a mechanism other than the circadian clock, which depends primarily on the amount and timing of prior sleep. When placed in constant darkness, they and waking, running on their wheels, and eating and drinking over an average period of 24. It was this dependability that made neuroscientists Martin Ralph and Michael Menaker, then working at the University of Oregon, notice when one of the hamsters in their laboratory began punching in with 22. This maverick male was bred with three females of unimpeachable circadian character (their freerunning periods were 24. When 20 pups from the three resulting litters were tested in the dark, their free-running periods were evenly split into two narrow groups. Further cross-breeding showed that the hamsters with the shorter circadian periods had one mutant copy of a gene (tau) that was dominant over their normal gene. After further breeding, Ralph and Menaker found that animals with two copies of the mutant tau gene had free-running periods of only 20 hours! Due to an age-dependent shortening of the circadian rhythm, overwhelming sleepiness begins in early evening, and awakening comes at 3:00 or 4:00 in the morning. It had long been known that eyeless mice cannot use light to reset their clocks, but mutant mice with intact retinas that lack rods and cones can! Since rods and cones were the only known photoreceptors in mammals, it remained a mystery how light could affect the circadian clock without them. They discovered a new photoreceptor in the retina that was not at all like rods and cones but was, remarkably, a very specialized type of ganglion cell. Recall from Chapter 9 that ganglion cells are retinal neurons whose axons send visual information to the rest of the brain; ganglion cells, like nearly all other neurons in the brain, were not supposed to be directly sensitive to light. The light-sensitive ganglion cells, however, express a unique type of photopigment called melanopsin, which is not present in rods and cones. Each neuron generates a strong circadian rhythm that is well coordinated with the other neurons. Research in a wide range of species indicates that it is a molecular cycle based on gene expression. The molecular clock used in humans is similar to those found in mice, fruit flies (Drosophila), and even bread mold. Some of the more important genes in mammals are known as period (per), cryptochrome, and clock. Although the details vary across species, the basic scheme is a negative feedback loop. Many of the details were first worked out in experiments performed by Joseph Takahashi and his colleagues at Northwestern University, who named the clock gene (an acronym for circadian locomotor output cycles kaput). After a delay, the newly manufactured proteins send feedback and interact with the transcription mechanism, causing a decrease in gene expression. As a consequence of decreased transcription, less protein is produced, and gene expression again increases to start the cycle anew. Research has shown that nearly every cell of the body, including those in the liver, kidney, and lung, has a circadian clock. When cells from liver, kidney, or lung are grown in isolation, each exhibits a circadian rhythm of its own. Body temperature, for example, has a powerful effect on the clocks of peripheral tissues. According to local legend, in 200 years, these swallows have missed the date only twice. While the purpose of some rhythms is obvious, the functions of many neural rhythms are unknown. Indeed, some rhythms may have no function at all but arise as a secondary consequence of neural interconnections that are essential for other, nonrhythmic, purposes. Unlike most studies of single ion channels, single neurons, or the systems mediating perception and movement, sleep research begins with profound ignorance about a most basic question: Why Sleep and dreams may have no vital function, but they can be studied and enjoyed nevertheless. Ignoring the functional question will not be a satisfying approach for long, however. The human cerebral cortex is very large and must be folded extensively to fit within the skull. Does this mean that sleep performs a function essential for the life of these higher vertebrates What differences would there be in the behavioral consequences of a free-running circadian clock versus no clock at all Neuronal gamma-band synchronization as a fundamental process in cortical computation.

Soon I was inventing algorithms that enabled artificial neural networks to learn medications and grapefruit interactions cheap 10mg paroxetine visa, and I developed a mathematical theory of a hindbrain neural circuit called the oculomotor integrator 911 treatment order 10 mg paroxetine otc. I continued this work after moving to the Massachusetts Institute of Technology as an assistant professor medicine keri hilson lyrics order 20mg paroxetine free shipping. My theory of the oculomotor integrator was interesting and even plausible medications resembling percocet 512 best purchase paroxetine, judging from experimental tests by my collaborator David Tank at Princeton treatment tmj purchase paroxetine 20mg line. But others were continuing to propose alternative theories treatment of ringworm cheap 10mg paroxetine, and the field showed no sign of converging on a consensus. My theory assumed the existence of recurrent connections between integrator neurons. In the 1990s, we had both worked at Bell Labs with Winfried Denk, who had since moved to the Max Planck Institute of Biomedical Research in Heidelberg. There Winfried had built an ingenious automated device that could image the face of a block of brain tissue, and then shave off a thin slice to expose a new face. By repeatedly cutting deeper and deeper into the block, the device could acquire a three-dimensional (3D) image of brain tissue. The second type of neocortex consists of secondary sensory areas, so designated because of their heavy interconnections with the primary sensory areas. The third type of cortex consists of motor areas, which are intimately involved with the control of voluntary movement. These cortical areas receive inputs from thalamic nuclei that relay information from the basal telencephalon and the cerebellum, and they send outputs to motor control neurons in the brain stem and spinal cord. For example, because cortical area 4 sends outputs directly to motor neurons in the ventral horn of the spinal cord, it is designated the primary motor cortex, or M1. Manual reconstruction of the wiring diagram would be prohibitively time-consuming. I decided to work on the problem of speeding up image analysis by computer automation. This computational method significantly improved the speed and accuracy of 3D reconstruction of neurons. However, the method still made errors, so it could not completely replace human intelligence. In 2008, we started creating software that would enable humans to work with the machines to reconstruct neural circuits. In 2014, Nature published the first EyeWire-assisted discovery: a new wiring diagram for a neural circuit in the retina. The discovery suggests a new solution to a problem that has eluded neuroscientists for 50 years: How does the retina detect moving visual stimuli It is plain to see that when we speak of the expansion of the cortex in mammalian evolution, what has expanded is the region that lies in between these areas. Much of the "in-between" cortex reflects expansion of the number of secondary sensory areas devoted to the analysis of sensory information. Notice the expansion of the human cortex that is neither strictly primary sensory nor strictly motor. However, even after we have assigned primary sensory, motor, and secondary sensory functions to large regions of cortex, a considerable amount of area remains in the human brain, particularly in the frontal and temporal lobes. Association cortex is a more recent evolutionary development, a noteworthy characteristic of the primate brain. The emergence of the "mind"-our unique ability to interpret behavior (our own and that of others) in terms of unobservable mental states, such as desires, intentions, and beliefs- correlates best with the expansion of the frontal cortex. Clearly, the brain deserves its status as the most complex piece of matter in the universe. What we have presented here is a shell, or scaffold, of the nervous system and some of its contents. This statement is just as true for an undergraduate firsttime neuroscience student as it is for a neurologist or a neurosurgeon. An Illustrated Guide to Human Neuroanatomy appears as an appendix to this chapter. Labeling exercises are also provided to help you learn the names of the parts of the nervous system you will encounter in this book. Is the myelin sheath of optic nerve axons provided by Schwann cells or oligodendroglia Imagine that you are a neurosurgeon, about to remove a tumor lodged deep inside the brain. Thus, the olfactory system consists of those parts of the brain that are devoted to the sense of smell, the visual system includes those parts that are devoted to vision, and so on. While this functional approach to investigating nervous system structure has many merits, it can make the "big picture"-how all these systems fit together inside the box we call the brain-difficult to see. The goal of this Illustrated Guide is to help you learn, in advance, about some of the anatomy that will be discussed in the subsequent chapters. Here, we concentrate on naming the structures and seeing how they are related physically; their functional significance is discussed in the remainder of the book. The first part covers the surface anatomy of the brain-the structures that can been seen by inspection of the whole brain, as well as those parts that are visible when the two cerebral hemispheres are separated by a cut in the midsagittal plane. Next, we explore the cross-sectional anatomy of the brain, using a series of slabs that contain structures of interest. The brief third and fourth parts cover the spinal cord and the autonomic nervous system. The fifth part of the Guide illustrates the cranial nerves and summarizes their diverse functions. In this Guide, we focus on those structures that will appear later in the book when we discuss the various functional systems. Nonetheless, even this abbreviated atlas of neuroanatomy yields a formidable list of new vocabulary. Therefore, to help you learn the terminology, an extensive self-quiz review is provided at the end, in the form of a workbook with labeling exercises. Flipping the brain over shows the complex ventral surface that normally rests on the floor of the skull. The brain stem is shown more clearly if we slice the brain right down the middle and view its medial surface. In the part of the guide that follows, we will name the important structures that are revealed by such an inspection of the brain. Notice the magnification of the drawings: 1 is life-size, 2 is twice life-size, 0. Gross inspection reveals the three major parts: the large cerebrum, the brain stem that forms its stalk, and the rippled cerebellum. The diminutive olfactory bulb of the cerebrum can also be seen in this lateral view. The bumps are called gyri, and the grooves are called sulci or, if they are especially deep, fissures. The precise pattern of gyri and sulci can vary considerably from individual to individual, but many features are common to all human brains. Notice that the postcentral gyrus lies immediately posterior to the central sulcus, and that the precentral gyrus lies immediately anterior to it. The neurons of the postcentral gyrus are involved in somatic sensation (touch; Chapter 12), and those of the precentral gyrus control voluntary movement (Chapter 14). Neurons in the superior temporal gyrus are involved in audition (hearing; Chapter 11). By convention, the cerebrum is subdivided into lobes named after the bones of the skull that lie over them. The occipital lobe lies at the very back of the cerebrum, bordering both parietal and temporal lobes. A buried piece of the cerebral cortex, called the insula (Latin for "island"), is revealed if the margins of the lateral fissure are gently pulled apart (inset). On the inferior surface of the parietal lobe (the operculum) and buried in the insula is the gustatory cortex, devoted to the sense of taste (Chapter 8). In addition to the analysis of sensory information, the cerebral cortex plays an important role in the control of voluntary, willful movement. The major motor control areas lie in the frontal lobe, anterior to the central sulcus (Chapter 14). In the human brain, large expanses of cortex cannot be simply assigned to sensory or motor functions. Some of the more important areas are the prefrontal cortex (Chapters 21 and 24), the posterior parietal cortex (Chapters 12, 21, and 24), and the inferotemporal cortex (Chapters 24 and 25). The various areas, first identified by Brodmann, differ from one another in terms of microscopic structure and function. Splitting the brain down the middle exposes the medial surface of the cerebrum, shown in this life-size illustration. This view also shows the midsagittal, cut surface of the brain stem, consisting of the diencephalon (thalamus and hypothalamus), the midbrain (tectum and tegmentum), the pons, and the medulla. These are "phantom views" of these structures since they cannot be observed directly from the surface. The amygdala (from the Latin word for "almond") is an important structure for regulating emotional states (Chapter 18), and the hippocampus is important for memory (Chapters 24 and 25). Shown here are the important forebrain structures that can be observed by viewing the medial surface of the brain. Notice the cut surface of the corpus callosum, a huge bundle of axons that connects the two sides of the cerebrum. The unique contributions of the two cerebral hemispheres to human brain function can be studied in patients in which the callosum has been sectioned (Chapter 20). The fornix (Latin for "arch) is another prominent fiber bundle that connects the hippocampus on each side with the hypothalamus. Cingulate gyrus Corpus callosum (cut edge) Fornix Olfactory bulb Calcarine fissure Optic chiasm (0. The lateral walls of the unpaired parts of the ventricular system-the third ventricle, the cerebral aqueduct, the fourth ventricle, and the spinal canal-can be observed in the medial view of the brain. These are handy landmarks because the thalamus and hypothalamus lie next to the third ventricle; the midbrain lies next to the aqueduct; the pons, cerebellum, and medulla lie next to the fourth ventricle; and the spinal cord forms the walls of the spinal canal. The lateral ventricles are paired structures that sprout like antlers from the third ventricle. A phantom view of the right lateral ventricle, which lies underneath the overlying cortex, is shown in the lower illustration. The bundles lying posterior to the chiasm, which disappear into the thalamus, are called the optic tracts (Chapter 10). The paired mammillary bodies (Latin for "nipple") are a prominent feature of the ventral surface of the brain. These nuclei of the hypothalamus are part of the circuitry that stores memory (Chapter 24) and are a major target of the axons of the fornix (seen in the medial view). The Ventral Surface of the Brain the underside of the brain has a lot of distinct anatomical features. Notice the nerves emerging from the brain stem; these are the cranial nerves, which are illustrated in more detail later in the Guide. The chiasm is the place where many axons from the eyes decussate (cross) from one side to another. These are connected by the axons of the corpus callosum (Chapter 20), which can be seen if the hemispheres are retracted slightly. The medial view of the brain, illustrated previously, showed the callosum in cross section. The cerebellum dominates the dorsal view of the brain if the cerebrum is removed and the brain is tilted slightly forward. The cerebellum is an important motor control structure (Chapter 14), and is divided into two hemispheres and a midline region called the vermis (Latin for "worm"). The top surface of the brain stem is exposed when both the cerebrum and the cerebellum are removed. The major divisions of the brain stem are labeled on the left side, and some specific structures are labeled on the right side. The pineal body, lying atop the thalamus, secretes melatonin and is involved in the regulation of sleep and sexual behavior (Chapters 17 and 19). The superior colliculus receives direct input from the eyes (Chapter 10) and is involved in the control of eye movements (Chapter 14), while the inferior colliculus is an important component of the auditory system (Chapter 11). Cross sections can be made physically with a knife or, in the case of noninvasive imaging of the living brain, digitally with a magnetic resonance imaging or a computed tomography scan. For learning the internal organization of the brain, the best approach is to make cross sections that are perpendicular to the axis defined by the embryonic neural tube, called the neuraxis. Forebrain Sections 2 1 the neuraxis bends as the human fetus grows, particularly at the junction of the midbrain and thalamus. Consequently, the best plane of section depends on exactly where we are along the neuraxis. The telencephalon surrounds the lateral ventricles, and the thalamus surrounds the third ventricle. Notice that in this section, the lateral ventricles can be seen sprouting from the slit-like third ventricle. Notice that the insula (Chapter 8) lies at the base of the lateral (Sylvian) fissure, here separating the frontal lobe from the temporal lobe. The heterogeneous region lying deep within the telencephalon, medial to the insula and lateral to the thalamus, is called the basal forebrain. Notice that the internal capsule is the large collection of axons connecting the cortical white matter with the brain stem, and that the corpus callosum is the enormous sling of axons connecting the cerebral cortex of the two hemispheres.

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