Central Nervous System Control of the Viscera PDF

Central Nervous System Control of the Viscera **Sympathetic output can be massive and nonspecific, as in the fight-or-flight response, or selective for specific target organs** --------------------------------------------------------------------------------------------------------------------------...

Central Nervous System Control of the Viscera **Sympathetic output can be massive and nonspecific, as in the fight-or-flight response, or selective for specific target organs** ---------------------------------------------------------------------------------------------------------------------------------- In 1915, Walter Cannon proposed that the entire sympathetic division is activated together and has a uniform effect on all target organs. In response to fear, exercise, and other types of stress, the sympathetic division produces a massive and coordinated output to all end organs simultaneously, and parasympathetic output ceases. This type of sympathetic output is used to ready the body for life-threatening situations---the so-called **fight-or-flight** response. Thus, when a person is presented with a fearful or menacing stimulus, the sympathetic division coordinates all body functions to respond appropriately to the stressful situation. This response includes increases in heart rate, cardiac contractility, blood pressure, and ventilation of the lungs; bronchial dilatation; sweating; piloerection; liberation of glucose into the blood; inhibition of insulin secretion; reduction in blood clotting time; mobilization of blood cells by contraction of the spleen; and decreased GI activity. This mass response is a primitive mechanism for survival. In some people, such a response can be triggered spontaneously or with minimal provocation; each individual episode is then called a panic attack. The fight-or-flight response is an important mechanism for survival, but under normal nonstressful conditions, output of the sympathetic division can also be more discrete and organ specific. In contrast to Cannon\'s original proposal, the sympathetic division does not actually produce uniform effects on all visceral targets. Different postganglionic sympathetic neurons have different electrophysiological pro­perties and release other neurotransmitters in addition to norepinephrine. This specific distribution of neuroactive chemicals among neurons is called chemical coding. For example, depolarization of guinea pig postganglionic sympathetic neurons in the *lumbar* sympathetic chain ganglia causes a *brief* burst of action potentials in 95% of the neurons and release of norepinephrine together with ATP and neuropeptide Y. These neurons are thought to innervate arteries and to induce vasoconstriction (see [Fig. 14-10](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0055) ). In contrast, depolarization of postganglionic sympathetic neurons in the *inferior mesenteric ganglion* causes sustained firing in 80% of the neurons and release of norepinephrine together with somatostatin. These neurons appear to control gut motility and secretion. Thus, sympathetic neurons have cellular properties that are substantially variable. This variability permits the sympathetic division to produce different effects on targets with different functions. **Parasympathetic neurons participate in many simple involuntary reflexes** --------------------------------------------------------------------------- As opposed to neurons in the sympathetic division, neurons in the parasympathetic division function only in a discrete, organ-specific, and reflexive manner. Together with specific visceral afferents and a small number of interneurons, parasympathetic neurons mediate simple reflexes involving target organs. For example, the output of the baroreceptor reflex (see [pp. 537--539 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000239?scrollTo=%23u0045)) is mediated by preganglionic parasympathetic neurons in the dorsal motor nucleus of the vagus. Other examples include urination in response to bladder distention (see [pp. 736--737 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000331?scrollTo=%23s0150)); salivation in response to the sight or smell of food (see [p. 895 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000434?scrollTo=%23p0520)); vagovagal reflexes (see [p. 857 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000410?scrollTo=%23p0175)) in the GI tract, such as contraction of the colon in response to food in the stomach; and bronchoconstriction in response to activation of receptors in the lungs (see [pp. 717--718 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B978145574377300032X?scrollTo=%23s0335)). The pupillary light reflex is an example of an involuntary parasympathetic reflex that can be tested at the bedside (see [p. 362 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B978145574377300015X?scrollTo=%23p0285)). **A variety of brainstem nuclei provide basic control of the ANS** ------------------------------------------------------------------ In addition to nuclei that contain parasympathetic preganglionic neurons (see [Fig. 14-5](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/f0030) ), a variety of other brainstem structures are also involved in visceral control. These structures include the nucleus tractus solitarii, area postrema, ventrolateral medulla, medullary raphé, reticular formation, locus coeruleus, and parabrachial nucleus. These nuclei within the lower part of the brainstem mediate autonomic reflexes, control specific autonomic functions, or modulate the general level of autonomic tone. In some cases, these nuclei play a well-defined role in one specific autonomic function. For example, stimulation of a group of neurons in the rostral portion of the ventrolateral medulla increases sympathetic output to the cardiovascular system---without affecting respiration or sympathetic output to other targets. In other cases, these nuclei are linked to more than one autonomic function. For example, the medullary raphé contains serotonergic neurons that project to cardiovascular, respiratory, and GI neurons, the reticular activating system, and pain pathways. Therefore, these neurons can affect the background level of autonomic tone. The specific functions of some nuclei are not known, and their involvement in autonomic control is inferred from their anatomical connections, a correlation between neuron activity and activity in autonomic nerves, or the effect of lesions. One of the most important lower brainstem structures is the **nucleus tractus solitarii (NTS)** in the medulla. The NTS contains second-order sensory neurons that receive all input from peripheral chemoreceptors (see [pp. 710--713 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B978145574377300032X?scrollTo=%23s0240)) and baroreceptors (see [p. 534 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000239?scrollTo=%23f0010)), as well as non-nociceptive afferent input from every organ of the thorax and abdomen. Visceral afferents from the vagus nerve make their first synapse within the NTS, where they combine with other visceral (largely unconscious) afferent impulses derived from the glossopharyngeal (CN IX), facial (CN VII), and trigeminal (CN V) nerves. These visceral afferents form a large bundle of nerve fibers---the **tractus solitarius** ---that the NTS surrounds. Afferent input is distributed to the NTS in a viscerotopic manner, with major subnuclei devoted to respiratory, cardiovascular, gustatory, and GI input. The NTS also receives input and sends output to many other CNS regions ( [Table 14-4](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0025) ), including the brainstem nuclei described above as well as the hypothalamus and the forebrain. These widespread interconnections allow the NTS to influence and to be influenced by a wide variety of CNS functions. Thus, the NTS is the major lower brainstem command center for visceral control. It integrates multiple inputs from visceral afferents and exerts control over autonomic output, thereby participating in autonomic reflexes that maintain the homeostasis of many basic visceral functions. **Receives Input from** -------------------------------------------------------------------------------------------------------------------------------------------------------------------- Vagus nerve (peripheral chemoreceptor/aortic bodies and aortic baroreceptor, as well as non-nociceptive afferent input from every organ of the thorax and abdomen) Glossopharyngeal nerve (taste and peripheral chemoreceptors/carotid bodies, carotid baroreceptor) Facial nerve (taste) Trigeminal nerve (teeth, sinuses) Ventrolateral medulla Medullary raphé Area postrema Periaqueductal gray substance Parabrachial nucleus Hypothalamus Cerebral cortex **Sends Output to** Intermediolateral cell column (preganglionic sympathetic neurons) and sacral parasympathetic neurons Phrenic motor nucleus and other respiratory output pathways Dorsal motor nucleus of the vagus (preganglionic parasympathetic neurons from the vagus nerve) Nucleus ambiguus (preganglionic parasympathetic neurons from the vagus nerve) Ventrolateral medulla Medullary raphé Area postrema Parabrachial nuclei Reticular formation Forebrain nuclei Hypothalamus Table: 14-4. Connections to and from the Nucleus Tractus Solitarii **The forebrain can modulate autonomic output, and reciprocally, visceral sensory input integrated in the brainstem can influence or even overwhelm the forebrain** ------------------------------------------------------------------------------------------------------------------------------------------------------------------- Only a subset of the nervous system is necessary to maintain autonomic body homeostasis under most conditions. The necessary structures include (1) the brainstem nuclei discussed in the preceding section, (2) the brainstem nuclei that contain the parasympathetic preganglionic neurons, (3) the spinal cord, and (4) the peripheral ANS. These components are capable of acting autonomously, even without input from higher (i.e., rostral) forebrain regions. How­ever, forebrain regions do play a role in coordinating and modulating activity in the lower centers. Many rostral CNS centers influence autonomic output; these centers include the hypothalamus, amygdala, prefrontal cortex, entorhinal cortex, insula, and other forebrain nuclei. The **hypothalamus,** especially the paraventricular nu­cleus, is the most important brain region for coordination of autonomic output. The hypothalamus projects to the parabrachial nucleus, medullary raphé, NTS, central gray matter, locus coeruleus, dorsal motor nucleus of the vagus, nucleus ambiguus, and intermediolateral cell column of the spinal cord. Thus, the hypothalamus can initiate and coordinate an integrated response to the body\'s needs, including modulation of autonomic output as well as control of neuroendocrine function by the pituitary gland (see [p. 978 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000471?scrollTo=%23p0160)). The hypothalamus coordinates autonomic function with feeding, thermoregulation, circadian rhythms, water balance, emotions, sexual drive, reproduction, motivation, and other brain functions and thus plays a dominant role in the integration of higher cortical and limbic systems with autonomic control. The hypothalamus can also initiate the fight-or-flight response The hypothalamus often mediates interactions between the forebrain and the brainstem. However, a number of forebrain regions also have direct connections to brainstem nuclei involved in autonomic control. Most of these forebrain regions are part of the **limbic system** rather than the neocortex. The paucity of direct neocortical connections probably explains why individuals trained to control autonomic output by biofeedback can generally produce only relatively minor effects on overall autonomic activity rather than regulate output to specific organs. Most individuals are incapable of even limited cortical control over the ANS. However, even though we may have only minimal *conscious* control of autonomic output, cortical processes can strongly modulate the ANS. Emotions, mood, anxiety, stress, and fear can all alter autonomic output ( [Table 14-5, top](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0030) section). The pathways for these effects are unknown, but they could be mediated by direct connections or through the hypothalamus. **Examples of Descending Cortical Control of Autonomic Output** --------------------------------------------------------------------------------------------------------------------------------------------------------------- Fear---initiates fight-or-flight response Panic attacks---initiate activation of sympathetic division, increased breathing, and feeling of suffocation Emotional stress (e.g., first day in gross anatomy lab) or painful stimuli---lead to massive vasodilation and hypotension, i.e., vasovagal syncope (fainting) Seizures---can induce sudden cardiac death from massive sympathetic output and arrhythmias or sudden respiratory death from apnea Chronic stress---can lead to peptic ulcers from increased gastric acid secretion Sleep deprivation---in rats leads to death from loss of thermoregulation and cardiovascular control Cognitive activity---can initiate sexual arousal Nervousness (e.g., before an exam) can lead to diarrhea **Examples in Which Visceral Afferents Overwhelm Cortical Function (i.e., Nothing Else Seems to Matter)** Hunger Nausea Dyspnea Visceral pain Bladder and bowel distention Hypothermia/hyperthermia Table 14-5. Interactions between cortical and autonomic functions. Not only does forebrain function influence the ANS, visceral activity also influences forebrain function. Visceral afferents reach the neocortex. However, because these afferents are not represented viscerotopically, they cannot be well localized. Nevertheless, visceral afferents can have profound effects on cortical function. Visceral input can modulate the excitability of cortical neurons ( [Box 14-2](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/b0055) ) and, in some cases, can result in such overpowering sensory stimuli that it is not possible to focus cortical activity on anything else (see [Table 14-5](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0030) , bottom section). Box 14-2 [Vagus Nerve Stimulation in the Treatment of Epilepsy] It is often not appreciated just how much effect the ANS can have on cortical function. [Table 14-5](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0030) (bottom section) lists several examples in which strong input from visceral afferents can overwhelm cortical function to the point that concentrating on anything else is nearly impossible. As we have already noted, not only does the vagus nerve contain parasympathetic preganglionic *motor* fibers, it also contains a wide variety of *sensory* fibers from viscera in the thorax and abdomen. Discovery of the influence of vagal afferent input on seizures has led to development of the vagus nerve stimulator, which is used clinically. The surgically implanted device electrically stimulates the vagus nerve for 30 seconds every 5 minutes, 24 hours per day. In addition, when patients feel a seizure coming on (an aura), they can activate the device with a hand-held magnet to deliver extra pulses. Clinical studies have shown that this treatment reduces the number of seizures by about half in about one in four patients. It remains to be determined whether a subgroup of patients may be particularly responsive to this treatment. Side effects include hoarseness, coughing, and breathlessness. That this approach works at all indicates how important visceral input is to cortical function. Vagal input can influence many rostral brain structures, but it is not yet clear whether stimulation of peripheral chemoreceptor afferents, pulmonary afferents, or other visceral afferent pathways is important for the anticonvulsant effect. If the specific pathways could be identified, it might be possible to selectively stimulate these pathways or to activate them pharmacologically to produce an anticonvulsant effect with fewer side effects. **CNS control centers oversee visceral feedback loops and orchestrate a feed-forward response to meet anticipated needs** ------------------------------------------------------------------------------------------------------------------------- The ANS maintains physiological parameters within an optimal range by means of **feedback loops** made up of sensors, afferent fibers, central autonomic control centers (discussed in the preceding section), and effector systems. These feedback loops achieve homeostasis by monitoring input from visceral receptors and adjusting the output of both the sympathetic and parasympathetic divisions to specific organs so that they maintain activity at a set-point determined by involuntary CNS control centers. As we have already noted, the sympathetic and parasympathetic divisions usually act in opposite ways to make these adjustments. Blood pressure control is an example of a visceral feedback loop in which the CNS monitors current blood pressure through afferents from baroreceptors, compares it with an internally determined set-point, and appropriately adjusts output to the heart, blood vessels, adrenal gland, and other targets. An increase in blood pressure (see [pp. 537--539 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000239?scrollTo=%23u0045)) causes a reflex decrease in sympathetic output to the heart and an increase in parasympathetic output. Instead of merely responding through feedback loops, the ANS also anticipates the future needs of the individual. For example, when a person begins to exercise, sympathetic output increases before the increase in metabolic need to prevent an exercise debt from occurring (see [p. 1214 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000604?scrollTo=%23p0400)). Because of this anticipatory response, alveolar ventilation rises to such an extent that blood levels of CO ~2~ (a byproduct of exercise) actually drop at the onset of exercise. This response is the opposite of what would be expected if the ANS worked purely through feedback loops, in which case an obligatory increase in CO ~2~ levels would have preceded the increase in respiratory output (see [pp. 716--717 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B978145574377300032X?scrollTo=%23s0325)). Similarly, a trained athlete\'s heart rate begins to increase several seconds before the starting gun fires to signal the beginning of a 100-m dash. This anticipation of future activity, or **feed-forward** stimulation prior to (and during) exercise, is a key component of the regulation of homeostasis during stress because it prevents large changes in physiological parameters that could be detrimental to optimal function. This type of response probably resulted in an evolutionary advantage that permitted the body to respond rapidly and more efficiently to a threat of danger. A system relying solely on feedback could produce a response that is delayed or out of phase with respect to the stimulus. The central neuronal pathways responsible for this anticipatory or feed-forward response are not known. **The ANS has multiple levels of reflex loops** ----------------------------------------------- The human nervous system is built in a hierarchy that mirrors phylogenetic evolution (see [pp. 269--274 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000100?scrollTo=%23s0140)). Each of the successively more primitive components is capable of independent, organized, and adaptive behavior. In turn, the activity of each of the more primitive levels is modulated by rostral, more phylogenetically advanced components. The **enteric nervous system** of humans is homologous to the most primitive nervous system, the neural net of jellyfish. In both cases, the component neurons control motility and nutrient absorption and respond appropriately to external stimuli. The **autonomic ganglia** are homologous to ganglionic nervous systems, such as those of annelid worms. Autonomic ganglia were previously considered a simple relay station for signals from the CNS to the periphery, but it is now clear that they integrate afferent input from the viscera and have substantial independent control mechanisms. The largest of the sympathetic ganglia, the superior cervical ganglion, contains about 1 million neurons. In addition to postganglionic cell bodies, autonomic ganglia also contain interneurons. Axons from interneurons, sensory receptors located in the end organs, and preganglionic neurons converge with postganglionic neuron dendrites to form a dense network of nerve fibers, or a **neuropil,** within the ganglion. This neuropil confers considerable computational capability on the ganglia. Whereas feedback from skeletal muscle occurs only in the CNS, the peripheral synapses of visceral afferents result in substantial integration of autonomic activity at peripheral sites. This integration is enhanced by the variety of neurotransmitters released, for example, by interneurons in autonomic ganglia (see [Table 14-3](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/t0020) ). Thus, although fast neurotransmission from preganglionic neurons to postganglionic neurons is an important role of the autonomic ganglia, the ganglia are not simply relays. The **spinal cord,** which coordinates activity among different root levels, first appeared with the evolution of chordates. The CNS of amphioxus, a primitive chordate, is essentially just a spinal cord. In humans who experience transection of the low cervical spinal cord---and in whom the outflow of the respiratory system is spared (see [Chapter 32 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B978145574377300032X?scrollTo=%23c00032))---the caudal spinal cord and lower autonomic ganglia can still continue to maintain homeostasis. However, these individuals are incapable of more complex responses that require reflexes mediated by the cranial nerve afferents and cranial parasympathetic outflow. In many patients, this situation can lead to maladaptive reflexes such as autonomic hyper-reflexia, in which a full bladder results in hypertension and sweating ( [Boxes 14-3](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/b0065) and [14-4](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/b0070) ). All vertebrates have a brain that is segmented into three parts (see [p. 261 ](https://www-clinicalkey-com.utrechtuniversity.idm.oclc.org/#!/content/3-s2.0-B9781455743773000100?scrollTo=%23p0205)): the prosencephalon, mesencephalon, and rhombencephalon. With evolution, the more rostral parts took on a more dominant role. The brain of the ammocoete larva of the lamprey is dominated by the **medulla,** which is also the most vital part of the human brain; in contrast to destruction of more rostral structures, destruction of the medulla leads to instant death in the absence of life support. The medulla coordinates all visceral control and optimizes it for survival. In humans, normal body homeostasis can continue indefinitely with only a medulla, spinal cord, and peripheral ANS. In fish, the **midbrain** became the dominant CNS structure in response to the increasing importance of vision. The brain of primitive reptiles is only a brainstem and paleocortex, without a neocortex; the corpus striatum is the dominant structure. Thus, the brainstem is sometimes referred to as the reptilian brain. Finally, the **neocortex** appeared in mammals and became dominant. The phylogenetically advanced portions of the CNS rostral to the medulla---including the hypothalamus, limbic system, and cortex---coordinate activity of the ANS with complex behaviors, motivations, and desires, but they are not required for normal homeostasis. As a result of this hierarchy, impulses from most visceral afferents never reach the cortex, and we are not usually conscious of them. Instead, they make synapses within the enteric plexuses, autonomic ganglia, spinal cord, and brainstem, and they close reflex loops that regulate visceral output at each of these levels.