Medical Physiology A Cellular and Molecular Approach, Updated 2nd Ed.

CONTROL OF VENTILATION

George B. Richerson and Walter F. Boron

OVERVIEW OF THE RESPIRATORY CONTROL SYSTEM

Breathing is one of those things in life that you almost never think about until something goes wrong with it. However, those with pulmonary disease become intensely aware of breathing, as do people who overexert themselves, especially at high altitude. The feeling of dyspnea that they experience (see the box on this topic) is one of the most unpleasant sensations in life. Swimmers and SCUBA divers, professional singers, practitioners of the Lamaze technique, and anyone with a bed partner who snores also focus intensely on breathing. It is common for respiratory output to be the last brain function to be lost in comatose patients, in which case its cessation marks the onset of brain death. Thus, despite our common tendency to ignore it, control of ventilation is one of the most important of all brain functions. (See Note: Brain Death)

The ventilatory control mechanism must accomplish two tasks. First, it must establish the automatic rhythm for contraction of the respiratory muscles. Second, it must adjust this rhythm to accommodate changing metabolicdemands (as reflected by changes in blood P_O2, P_CO2, and pH), varying mechanical conditions (e.g., changing posture), and a range of episodic, nonventilatory behaviors (e.g., speaking, sniffing, eating).

Automatic centers in the brainstem activate the respiratory muscles rhythmically and subconsciously

The rhythmic output of the central nervous system (CNS) to muscles of ventilation normally occurs automatically, without any conscious effort. Neurons within the medulla generate signals that are distributed appropriately to various pools of cranial and spinal motor neurons (see Chapter 9), which directly innervate the respiratory muscles (Fig. 32-1). The specific site containing the neurons that generate the respiratory rhythm—the central pattern generator (CPG; see Chapter 16)—under normal conditions is still unknown. A vast array of neurons—located primarily in the medulla but also in the pons and other brainstem regions—fire more action potentials during specific parts of the respiratory cycle. For example, some neurons have peak activity during inspiration, and others, during expiration. These neurons are called respiratory-related neurons (RRNs) because their activity patterns correlate with breathing. Some RRNs are interneurons (i.e., making local connections), others are premotor neurons (i.e., innervating motor neurons), and still others are motor neurons (i.e., innervating muscles of respiration).

Figure 32-1 Control of ventilation.

The most important respiratory motor neurons are those that send axons through the phrenic nerve to innervate the diaphragm (Table 32-1), one of the primary muscles of inspiration. When respiratory output increases (e.g., during exercise), activity also appears in motor neurons that innervate a wide variety of accessory muscles of inspiration and expiration. (See Chapter 26.)

Table 32-1 Innervation of the Primary and Some Secondary Muscles of Respiration

Muscles	Nerve	Location of Cell Body of Motor Neuron
Primary Muscles of Inspiration
Diaphragm	Phrenic nerve	Phrenic motor nuclei in ventral horn of spinal cord, C3-C5
Intercostal muscles	Intercostal nerves	Ventral horn of thoracic spinal cord
Secondary Muscles of Inspiration
Larynx and pharynx	Vagus (CN X) and glossopharyngeal (CN IX) nerves	Primarily within the nucleus ambiguus
Tongue	Hypoglossal nerve (CN XII)	Hypoglossal motor nucleus
Sternocleidomastoid and trapezius muscles	Accessory nerve (CN XI)	Spinal accessory nucleus, C1-C5
Nares	Facial nerve (CN VII)	Facial motor nucleus
Secondary Muscles of Expiration
Intercostal muscles	Intercostal nerves	Ventral horn of thoracic spinal cord
Abdominal muscles	Spinal nerves	Ventral horn of lumbar spinal cord

Each of these muscles is active at different times within the respiratory cycle, and the brain can alter this timing, depending on prevailing conditions. It is the job of the premotor neurons to orchestrate the appropriate patterns of activity among the different pools of motor neurons. The pattern of alternating inspiratory and expiratory activity that occurs under normal conditions during non-rapid eye movement (NREM) sleep, at rest, and during mild exercise is called eupnea. During eupnea, neural output to respiratory muscles is highly regular, with rhythmic bursts of activity during inspiration only to the diaphragm and certain intercostal muscles. Expiration occurs purely as a result of cessation of inspiration and passive, elastic recoil of the chest wall and lungs. During more intense exercise, the amplitude and frequency of phrenic nerve activity increase, and additional activity appears in nerves that supply accessory muscles of inspiration. With this increased effort, the accessory muscles of expiration also become active (see Chapter 26), thereby producing more rapid exhalation and permitting the next inspiration to begin sooner (i.e., increasing respiratory frequency).

Peripheral and central chemoreceptors—which sense P_O2, P_CO2, and pH—drive the central pattern generator

The CPG for breathing is the clock that times the automatic cycling of inspiration and expiration. In some cases, the CPG stops “ticking” in the absence of tonic drive inputs, resulting in the absence of ventilation, or apnea. Although this tonic drive comes from many sources, the most important are the central and peripheral chemoreceptors, which monitor the arterial blood gases—O₂, CO₂, and pH. Unlike a clock, the frequency of the respiratory CPG changes with the strength of the drive from the chemoreceptors, resulting in changes in both depth and frequency of ventilation.

The peripheral chemoreceptors, located in the carotid bodies in the neck and aortic bodies in the thorax, are primarily sensitive to decreases in arterial P_O2, although high P_CO2 and low pH also stimulate them and enhance their sensitivity to hypoxia. They convey their sensory information to the medulla through the glossopharyngeal nerve (CN IX) and vagus nerve (CN X). The central chemoreceptors, located on the “brain” side of the blood-brain barrier (see Chapter 11), sense increases in arterial P_CO2 and—much more slowly—decreases in arterial pH but not in arterial P_O2. All three signals trigger an increase in alveolar ventilation that tends to return these arterial blood gas parameters to normal. Thus, the peripheral and central chemoreceptors, in addition to supplying tonic drive to the CPG, form the critical sensory end of a negative feedback system that uses respiratory output to stabilize arterial P_O2, P_CO2, and pH (Fig. 32-1).

Dyspnea

Dyspnea is the feeling of being short of breath, or the unpleasant conscious awareness of difficulty in breathing. In some cases, dyspnea is an adaptive response. For example, when arterial P_O2 falls or P_CO2 rises from breath-holding, asphyxia, or pulmonary disease, dyspnea leads to efforts to increase ventilation and thus to restore blood gases to normal. However, dyspnea can occur even with a normal arterial P_O2 and P_CO2. For example, increased airway resistance can cause dyspnea, even if blood gases do not change. Intense exercise also causes dyspnea, even though P_CO2 usually falls. Other causes of dyspnea seem maladaptive. For example, claustrophobia and panic attacks can induce the feeling of suffocation—that is, dyspnea—despite normal ventilatory parameters. The central neural mechanisms and pathways responsible for dyspnea are unknown.

Other receptors and higher brain centers also modulate ventilation

Left alone, the respiratory CPG would tick regularly for an indefinite period. However, many inputs to the CPG reset the clock. For example, respiratory output is often highly irregular during many behaviors that use the respiratory muscles (e.g., eating, talking, and yawning). During NREM sleep or quiet wakefulness and with anesthesia, the CPG is unperturbed and does run regularly; it is under these conditions that neuroscientists usually study mechanisms of respiratory control.

A variety of receptors in the lungs and airways provide sensory feedback that the medulla integrates and uses to alter respiratory output. Stretch receptors monitor pulmonary mechanics (e.g., lung volume, muscle length) and may help optimize breathing parameters during changes in posture or activity. Activation of pulmonary stretch receptors also can terminate inspiratory efforts, thereby preventing overinflation. Other sensors that detect the presence of foreign bodies or chemicals in the airways are important for protecting the lungs by triggering a cough or a sneeze. Still others detect the movement of joints, which may be important for raising ventilation with exercise. The mechanoreceptors and chemoreceptors from the lungs and lower (i.e., distal conducting) airways send their sensory information to the respiratory neurons of the medulla through CN X, and those from the upper airways send information through CN IX.

Nonrespiratory brainstem nuclei and higher centers in the CNS also interact with respiratory control centers, allowing the ventilatory system to accommodate such activities as speaking, playing a musical instrument, swallowing, and vomiting. These interconnections also allow respiratory control to be highly integrated with the autonomic nervous system, the sleep-wake cycle, emotions, and other aspects of brain function.

In the remainder of this chapter, we examine (1) respiratory neurons, (2) how these neurons generate the automatic rhythm of ventilation, (3) the control of ventilation by arterial blood gases, and (4) how afferent feedback and higher CNS centers modulate ventilation.

NEURONS THAT CONTROL VENTILATION

The neurons that generate the respiratory rhythm are located in the medulla

A classic method for determining which parts of the CNS are responsible for controlling respiratory output is to transect the neuraxis at different levels and to observe changes in breathing. Using this approach in the 2nd century, Galen performed the first experiments to determine the location of the respiratory controller. As a physician for gladiators in the Greek city of Pergamon, he observed that breathing stopped after a sword blow to the high cervical spine. A similar blow to the lower cervical spine paralyzed the arms and legs but allowed respiration to continue. He reproduced these lesions in live animals and correctly concluded that the brain sends information through the midcervical spinal cord to the diaphragm. (See Note: Experimental Preparations for Studying the Neural Control of Ventilation)

Eighteen centuries later, Lumsden used a similar approach in cats. He found that transection of the CNS between the medulla and spinal cord (Fig. 32-2; spinomedullary transection) causes ventilation to cease as a result of loss of the descending input to phrenic and intercostal motor neurons in the spinal cord. However, even after a spinomedullary transection, respiratory activity continues in muscles innervated by motor neurons whose cell bodies reside in the brainstem. During the period that would have been an inspiration, the nostrils continue to flare, and the muscles of the tongue, pharynx, and larynx continue to maximize airway caliber—although this respiratory activity cannot sustain life. Thus, spinomedullary transection blocks ventilation by interrupting output to the diaphragm, not by eliminating the respiratory rhythm. In other words, the neural machinery driving ventilation lies above the spinal cord.

Figure 32-2 Effect of brainstem transections. A dorsal view of the brainstem and spinal cord, with the cerebellum removed, and records of integrated nerve activity during one respiratory cycle, following the indicated transection. During inspiration, integrated nerve activity (a moving average of the amplitude of action potentials) increases in the nerves to the tongue (e.g., CN XII) and the diaphragm (phrenic nerve). CN, cranial nerve; DRG, dorsal respiratory group; VRG, ventral respiratory group.

When Lumsden, in the 1940s, made a transection between the pons and the medulla (Fig. 32-2; pontomedullary transection), he noticed that breathing continued, but with an abnormal “gasping” pattern. Others have since observed relatively normal breathing after a transection at this level and concluded that the gasping seen by Lumsden is due to surgical damage to the respiratory CPG in the rostral medulla. Today, some respiratory neurophysiologists believe, like Lumsden, that the medulla can generate only gasping and that eupnea requires the pons as well as the medulla. However, the consensus is that the respiratory CPG is located in the medulla but that other sites, including the pons, shape the respiratory output to produce the normal pattern. (See Note: Evolution of the Respiratory Central Pattern Generator)

The pons modulates—but is not essential for—respiratory output

Although the medulla alone can generate a basic respiratory rhythm, both higher CNS centers and sensory inputs fine-tune this rhythm. For example, the pons contains neurons that affect respiratory output.

Lumsden found that a midpons transection has only a modest effect—an increase in tidal volume and a slight decrease in respiratory rate. A bilateral vagotomy—interrupting the two vagus nerves, which carry sensory information from pulmonary stretch receptors—has a similar but smaller effect. However, combining a midpons transection with a bilateral vagotomy causes the animal to make prolonged inspiratory efforts (inspiratory apneuses) that are interrupted by only brief expirations. A brainstem transection above the pons did not alter the basic respiratory pattern of eupnea. These observations led Lumsden to propose that (1) the caudal pons contains an apneustic center(i.e., it can cause apneuses) and (2) the rostral pons contains a pneumotaxic center that prevents apneuses (i.e., it promotes coordinated respirations). He believed that these regions and the medulla are required for normal breathing. (See Note: Role of the Pons in the Control of Ventilation)

What is the modern view? We now appreciate that the apneustic center is not a specific nucleus but is distributed diffusely throughout the caudal pons. The pneumotaxic center is located in the nucleus parabrachialis medialisand adjacent Kölliker-Fuse nucleus in the rostral pons. However, the pneumotaxic center is not unique in preventing apneuses because simply increasing the temperature of the animal can reverse apneuses induced by lesions in the pneumotaxic center. Moreover, by making lesions in many locations outside the pneumotaxic center, apneuses can also be induced. Today, we still do not understand the role of the apneustic center, and the consensus is that the pneumotaxic center plays a general role in a variety of brainstem functions—including breathing—but is not required for eupnea. Thus, the terms apneustic center and pneumotaxic center are used primarily because of their historical significance.

The dorsal and ventral respiratory groups contain many neurons that fire in phase with respiratory motor output

In the 1930s, Gesell and colleagues used extracellular microelectrode recordings to monitor single neurons, finding that many neurons within the medulla increase their firing rate during one of the phases of the respiratory cycle. Some of these neurons fire more frequently during inspiration (inspiratory neurons), whereas others fire more often during expiration (expiratory neurons). (See Note: Robert Gesell)

Not all neurons that fire in phase with the respiratory cycle are involved in respiration. For example, because they are located within the chest cavity, aortic baroreceptors (see Chapter 23) produce an output that varies with lung inflation, but they are primarily involved in the control of cardiovascular—not respiratory—function. Conversely, some neurons whose firing does not correlate with the respiratory cycle may be essential for respiratory control. For example, central chemoreceptors may fire tonically (i.e., they do not burst during inspiration) and yet are critical for maintaining respiratory output by providing tonic drive. Thus, not all RRNs (e.g., those stimulated by the aortic baroreceptor) play a direct role in respiration, and respiratory control involves more than just RRNs (e.g., chemoreceptor neurons).

Normal and Abnormal Respiratory Patterns

Respiratory output can change for a variety of reasons. Many patterns, both normal and abnormal, have recognizable characteristics summarized here. Figure 32-3 illustrates some of these.

Eupnea Normal breathing.

Sighs Larger than normal breaths that occur automatically at regular intervals in normal subjects, possibly to counteract collapse of alveoli (atelectasis).

Yawn An exaggerated sigh.

Tachypnea An increase in respiratory rate.

Hyperventilation An increase in alveolar ventilation—caused by an increase in respiratory frequency or an increase in tidal volume—that decreases arterial P_CO2. Seen in pregnancy and liver cirrhosis (due to increased progesterone), in panic attacks, and as a compensation to metabolic acidosis.

Kussmaul breathing Refers to extremely deep, rapid breathing seen with metabolic acidosis, such as in diabetic ketoacidosis (see Chapter 51 for the box on diabetes mellitus).

Central neurogenic hyperventilation Rapid, deep breathing causing a decrease in arterial P_CO2. Although described in some patients with focal brain lesions, this pattern may actually reflect coexisting lung disease or other systemic illness.

Cheyne-Stokes respiration A benign respiratory pattern. Cycles of a gradual increase in tidal volume, followed by a gradual decrease in tidal volume, and then a period of apnea. Seen with bilateral cortical disease or congestive heart failure or in healthy people during sleep at high altitude.

Gasping Maximal, brief inspiratory efforts separated by long periods of expiration. Seen in severe anoxia, as well as a terminal, agonal breathing pattern in patients with brainstem lesions.

Apneusis (inspiratory) Prolonged inspirations separated by brief expirations. Rarely seen in humans.

Apnea Cessation of respiration.

Vagal breathing Slow, deep inspirations caused by interruption of vagus nerve input to the brainstem. Rarely seen in humans.

Cluster breathing Similar to ataxic breathing, with groups of breaths, often of differing amplitude, separated by long periods of apnea. Seen with medullary or pontine lesions.

Ataxic breathing Highly irregular inspirations, often separated by long periods of apnea. Seen mainly with medullary lesions.

Biot breathing First described in patients with meningitis by Biot (in 1876) as a variant of cluster breathing (see above), with breaths of nearly equal volume separated by periods of apnea. Biot breathing is also considered to be a variant of ataxic breathing.

Figure 32-3 Respiratory patterns. These records are typical of either integrated phrenic nerve activity or lung volume. Those on the left come from experimental animals, and those on the right, from humans. All of the patterns, theoretically, could occur in experimental animals or humans, and many occur in clinical settings.

Although electrical recordings from RRNs cannot identify all neurons necessary for producing respiratory output, this mapping has proved very useful in defining neurons that are candidates for controllingventilation. On each side of the medulla, two large concentrations of RRNs—the dorsal and ventral respiratory groups—are grossly organized into sausage-shaped columns, oriented along the long axis of the medulla (Fig. 32-4). Many neurons of these two regions tend to fire exclusively during either inspiration or expiration. (See Note: Role of the Pons in the Control of Ventilation)

Figure 32-4 Dorsal and ventral respiratory groups and their motor output. A, Inspiratory output. B, Expiratory output. These are dorsal views of the brainstem and spinal cord, with the cerebellum removed. The dorsal respiratory group (DRG) includes the nucleus tractus solitarii (NTS). The ventral respiratory group (VRG) includes the Bötzinger complex (BötC), pre-Bötzinger complex (preBötC), nucleus ambiguus (NA), nucleus para-ambigualis (NPA), and nucleus retroambigualis (NRA). The color coding indicates whether the neurons are primarily inspiratory (red) or primarily expiratory (green).

The pons also contains RRNs. Although, as discussed before, pontine neurons may not be needed to produce a normal respiratory rhythm, they can influence respiratory output.

The dorsal respiratory group processes sensory input and contains primarily inspiratory neurons

The dorsal respiratory group (DRG) primarily contains inspiratory neurons (Table 32-2). It extends for about one third of the length of the medulla and is located bilaterally in and around the nucleus tractus solitarii (NTS), which receives sensory input from all viscera of the thorax and abdomen and plays an important role in control of the autonomic nervous system (see Chapter 14). The NTS is viscerotopically organized, with the respiratory portion of the NTS ventrolateral to the tractus solitarius, just beneath the floor of the caudal end of the fourth ventricle (Fig. 32-4). These NTS neurons, as well as some immediately adjacent neurons in the dorsal medulla, make up the DRG.

Table 32-2 Properties of the DRG and VRG

(See Note: Origin of the Terms Bötzinger Complex and Pre-Bötzinger Complex; The Ventral Respiratory Group)

As might be surmised from the sensory role of the NTS, one of the major functions of the DRG is the integration of sensory information from the respiratory system. Indeed, some of the DRG neurons receive sensory input—through the glossopharyngeal (CN IX) and vagus (CN X) nerves—from peripheral chemoreceptors as well as from receptors in the lungs and airways (see earlier). Some of the RRNs in the DRG are local interneurons. Others are premotor neurons, projecting directly to various pools of motor neurons—primarily inspiratory—in the spinal cord and ventral respiratory group (Fig. 32-4). (See Note: DRG Neurons)

The ventral respiratory group is primarily motor and contains both inspiratory and expiratory neurons

The ventral respiratory group (VRG) contains both inspiratory and expiratory neurons (Table 32-2). It is ventral to the DRG, about midway between the dorsal and ventral surfaces of the medulla. The VRG lies within and around a series of nuclei that form a column of neurons extending from the pons nearly to the spinal cord and is thus considerably longer than the DRG (Fig. 32-4). Like the DRG, the VRG contains local interneurons and premotor neurons. In contrast to the DRG, the VRG also contains motor neurons that innervate muscles of the pharynx and larynx as well as viscera of the thorax and abdomen. Sensory information related to pulmonary function comes indirectly through the DRG. Thus, the VRG plays more of an efferent role, whereas the DRG primarily plays an afferent role. (See Note: The Ventral Respiratory Group)

The VRG consists of three regions that perform specific functions. (1) The rostral VRG (or Bötzinger complex, BötC) contains interneurons that drive the expiratory activity of the caudal region. (2) The intermediate VRGcontains somatic motor neurons whose axons leave the medulla through CN IX and CN X. These fibers supply the pharynx, larynx, and other structures, thus maximizing the caliber of the upper airways during inspiration. The intermediate VRG also contains premotor neurons that project to inspiratory motor neurons in the spinal cord and medulla. Within the rostral pole of the intermediate VRG is a group of inspiratory neurons defined as the pre-Bötzinger complex (preBötC), which, as we will see later, is involved in generating the respiratory rhythm. (3) The caudal VRG contains premotorneurons that travel down the spinal cord to synapse on motor neurons that innervate accessory muscles of expiration, such as abdominal and certain intercostal muscles (see Chapter 27). (See Note: Neural Activity during the Respiratory Cycle; Properties of the DRG versus VRG)

GENERATION OF THE RESPIRATORY RHYTHM

Different RRNs fire at different times during inspiration and expiration

Eupneic breathing is highly stereotyped and consists of two phases—inspiration and expiration (Fig. 32-5A, B). During the inspiratory phase, phrenic nerve output to the diaphragm gradually increases in activity during 0.5 to 2 seconds and then declines precipitously at the onset of expiration (Fig. 32-5C). The ramp increase in activity helps ensure a smooth increase in lung volume. During the expiratory phase, the phrenic nerve is inactive, except—in some cases—for a brief burst at the onset.

Figure 32-5 Neural activity during the respiratory cycle. The activity of respiratory-related neurons in the medulla (examples of which are shown in D and E) leads to the phasic activity of the phrenic nerve (C) and other respiratory nerves, which produces airflow (B), causing lung volume to change (A). ENG, electroneurogram; Exp, expiration; FRC, functional residual capacity; Insp, inspiration; TV, tidal volume; V_m, membrane potential. (See Note: Origin of the Terms Bötzinger Complex and Pre-Bötzinger Complex)

Underlying the activity of the phrenic nerve—and the other motor nerves supplying the muscles of inspiration and expiration—is a spectrum of firing patterns of different RRNs located within the DRG and VRG (see earlier). RRNs can be broadly classified as inspiratory or expiratory, but each class includes many subtypes, based on how their firing patterns correlate with the respiratory cycle. Figure 32-5D, E shows two such patterns. Each subtype presumably plays a unique role in generating and shaping respiratory output—that is, the activity of the nerves to each respiratory muscle. RRNs may be further subclassified on the basis of their responses to afferent inputs, such as lung inflation and changes in arterial P_CO2. (See Note: Neural Activity during the Respiratory Cycle)

The firing patterns of RRNs depend on the ion channels in their membranes and the synaptic inputs they receive

What are the mechanisms for generating so many types of activity in RRNs? For example, if the RRN is a premotor neuron, its firing pattern must be appropriate for driving a motor neuron, such as one in the phrenic nerve nucleus. Two complementary mechanisms appear to contribute to the firing patterns necessary for the neuron to do its job. (1) The intrinsic membrane properties of RRNs—the complement and distribution of ion channels present in a neuron—influence the firing pattern of that neuron. (2) The synaptic input—excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs)—changes with an appropriate pattern during the respiratory cycle and thereby generates a specific firing pattern.

Intrinsic Membrane Properties Many neurons in respiratory nuclei have intrinsic membrane properties that influence the types of firing patterns they are able to produce. For example, many DRG neurons have a K⁺ current called a transient A-type current (see Chapter 7). If we first hyperpolarize and then depolarize such a neuron, it begins firing action potentials, but only after a delay. The hyperpolarization removes the inactivation of the A-type current, and the subsequent depolarization transiently activates the A-type K⁺ current and transiently slows depolarization of the membrane and inhibits generation of action potentials (see Fig. 7-18C). If the A-type current is large, the neuron cannot begin to fire until after the A-type current sufficiently inactivates (see Fig. 7-18D). The delay in firing of a neuron with A-type current can explain why some RRNs fire only late during inspiration, even though they receive EPSPs continuously during inspiration. As we will see, other neurons have pacemaker properties due to their complement of ion channels, allowing them to fire action potentials spontaneously without synaptic input. (See Note: DRG Neuron with Ca²⁺-Activated K⁺ Current)

Synaptic Input The most obvious explanation for a neuron’s having a specific firing pattern is that it receives excitatory synaptic input when it is supposed to fire action potentials and receives inhibitory synaptic input when it is quiet. Indeed, some RRNs fire only during early inspiration, when they receive strong excitatory synaptic input. These early inspiratory neurons also inhibit late-onset inspiratory neurons, and vice versa (Fig. 32-6). As a result of this reciprocal inhibition, only one of the two subtypes of inspiratory neurons can be maximally active at a time. (See Note:  Patterned input)

Figure 32-6 Patterned synaptic input: reciprocal inhibition. Because of reciprocal inhibition between the early-burst neuron and the late-onset inspiratory neuron, only one can be maximally active at a time.

In addition to synaptic input from RRNs that occurs rhythmically, in phase with breathing, respiratory neurons also receive input from other neuronal systems. This input can either interrupt regular breathing or control the level of ventilation, allowing the respiratory system to respond appropriately to challenges and to be integrated with many different brain functions.

Pacemaker properties and synaptic interactions may both contribute to the generation of the respiratory rhythm

Perhaps the most important questions that still need to be answered about the neural control of breathing revolve around the mechanism and identity (or location) of the respiratory CPG. We address the mechanism in this section and which cells are involved in the next.

Two general theories have evolved for the mechanism of the respiratory CPG. The first posits that subsets of neurons have pacemaker activity; the second, that synaptic interactions create the rhythm.

Pacemaker Activity Some cells have ion channels that endow them with pacemaker properties (see Chapter 16). For example, isolated cardiac myocytes produce rhythmic activity by “pacemaker currents” (see Chapter 21). Some neurons have similar pacemaker activity and repeatedly fire one spike at a time (i.e., beating pacemakers). Other pacemaker neurons repeatedly generate bursts of spikes (i.e., bursting pacemakers).

The first evidence for pacemaker activity in a mammalian respiratory nucleus came from the laboratory of Peter Getting. In brain slices from the guinea pig, putative premotor respiratory neurons in the NTS fire erratically at a low rate, with no apparent respiratory rhythm. However, adding thyrotropin-releasing hormone (TRH; see Chapter 49) to the bathing medium causes these neurons to generate bursts of action potentials (Fig. 32-7A), similar to inspiratory bursts in RRNs of the DRG during eupnea in an intact animal (Fig. 32-7B). Indeed, axons that come from the medullary raphe nuclei (see Chapter 13) project to the NTS, where they release TRH and thereby could induce bursting pacemaker activity in NTS neurons. This pacemaker activity might either contribute to generation of the respiratory rhythm or augment respiratory output generated within another site. Pacemaker activity is also present in neurons within another respiratory nucleus—the pre-Bötzinger complex (see later).

Figure 32-7 Pacemaker activity in respiratory-related neurons. (A, Data from Dekin MS, Richerson GB, Getting PA: Thyrotropin-releasing hormone induces rhythmic bursting in neurons of the nucleus tractus solitarii. Science 1985; 229:67. B, Data from Richerson GB, Getting PA: Maintenance of complex neural function during perfusion of the mammalian brain. Brain Res 1987; 409:128.)

Synaptic Interactions Even neural circuits without pacemaker neurons can generate rhythmic output (see Chapter 16). Indeed, synaptic connections within and between the DRG and VRG establish neural circuits and generate EPSPs and IPSPs with a timing that could explain the neurons’ oscillatory behavior during the respiratory cycle (Fig. 32-5). Computational neurobiologists have proposed a variety of pure network models of respiratory rhythm generation. According to these models, the CPG that produces the respiratory rhythm depends solely on synaptic connections between subtypes of RRNs and not at all on the pacemaker activity of individual neurons. Thus, the rhythm would be an emergent property of the network. (See Note: The Central Pattern Generator as an "Emergent Property")

One of the difficulties with network models of breathing is that not all of the neurons within the respiratory network are known. Network models also must take into account the presence of the rich complement of intrinsic membrane properties that exist in the component neurons, but also not all of these are fully characterized. As a result, pure network models must be very complex to explain all aspects of the normal respiratory rhythm. Supplementing network models with intrinsic membrane properties (e.g., pacemaker activity) allows the models to be simpler. Moreover, from an evolutionary perspective, it is reasonable to infer that pacemaker cells may have driven primitive respiratory systems (e.g., gills). In higher organisms, both pacemaker activity and synaptic interactions are probably important for generating the normal respiratory rhythm.

The respiratory CPG for eupnea could reside in a single site or in multiple sites or could emerge from a complex network

Where is the respiratory CPG for eupnea? In 1851, Flourens proposed a noeud vital (“vital node”) in the medulla, a small region that is the sole site producing respiratory output. In 1909, the neuroanatomist Santiago Ramón y Cajal reported that neurons in the NTS receive afferents from pulmonary stretch receptors and that NTS neurons project directly to the phrenic motor nucleus. He concluded that the NTS is the site of respiratory rhythm generation. However, today—in spite of considerable progress—the question of where in the medulla the CPG is located remains unanswered. Here we discuss three major proposals for the location of the respiratory CPG.

Restricted-Site Model Toshihiko Suzue first introduced the in vitro brainstem/spinal cord preparation from the neonatal rat, and Jeffrey Smith and Jack Feldman further developed this preparation to study the generation of respiratory output. In this preparation, a small region in the rostral VRG—the pre-Bötzinger complex (Fig. 32-4)—generates rhythmic motor output in the phrenic nerve and hypoglossal nerve (CN XII, which innervates the tongue, an accessory muscle of inspiration). Destroying the pre-Bötzinger complex in the isolated brainstem causes respiratory output to cease. In a slice preparation, the pre-Bötzinger complex generates rhythmic bursts of activity that one can record from the hypoglossal nerve rootlets (Fig. 32-8). These experiments have led to the hypothesis that the pre-Bötzinger complex is the site of the respiratory CPG. (See Note: Site of the Respiratory CPG)

Figure 32-8 Possible role of pre-Bötzinger complex as the respiratory central pattern generator. The recordings were made in a brain slice containing the pre-Bötzinger complex, a piece of the hypoglossal nucleus, and some rootlets of the hypoglossal nerve. (Data from Smith JC, Ellenberger HH, Ballanyi K, et al: Pre-Bötzinger complex: A brainstem region that may generate respiratory rhythm in mammals. Science 1991; 254:726.)

Distributed Oscillator Models Another possibility is that there is more than one CPG, any one of which could take over the job of generating the respiratory rhythm, depending on the conditions. As already noted, TRH can induce bursting pacemaker activity in DRG neurons. Moreover, a group of neurons in the parafacial respiratory group near the ventral surface of the medulla can also produce rhythmic activity. One interpretation is that various groups of respiratory neurons are latent CPGs and that the location of the dominant CPG can shift during different behaviors. A second interpretation is that the presence of rhythmicity in multiple areas represents a redundancy, ensuring that respiratory output does not fail. This design would be analogous to initiation of the heartbeat, in which many cells within the sinoatrial node can be the first to fire, and cells in other parts of the heart can take over if the sinoatrial node fails (see Chapter 21). In this model, some respiratory neurons with intrinsic oscillatory behavior would contribute to rhythm generation only under unusual conditions (e.g., hypoxia, anesthesia, early in development); under these conditions, the neurons might generate abnormal or pathological respiratory output (e.g., gasping). A third interpretation is that only one CPG exists for eupnea and that other regions augment the rhythm (and make it more robust) but are unable to generate a rhythm on their own.

Emergent Property Model The most common early explanation for generation of the respiratory rhythm (e.g., that proposed by Lumsden) is that no individual region of the DRG or VRG is sufficient to generate the rhythm but that many of them are necessary. A normal rhythm would require the component neurons in multiple brainstem regions to be “wired up” in a specific way. Some still believe that this view is essentially correct, arguing that none of the individual regions proposed to contain the CPG can produce a pattern of activity with all of the features described during eupnea.

None of the models we have discussed is universally accepted, and some of their elements are not mutually exclusive. The challenges in testing these hypotheses include the complexity of the CNS even at the level of the medulla, the technical difficulty in studying neurons of the mammalian brainstem, and the large number of nonrespiratory neurons in the medulla. Yet, because it is primitive both ontogenetically and phylogenetically, the respiratory CPG will probably prove to be far easier to define than most other mammalian neural networks, such as those responsible for consciousness or memory.

CHEMICAL CONTROL OF VENTILATION

In fulfilling its mission to exchange O₂ and CO₂ between the atmosphere and the capillaries of the systemic circulation, the respiratory system attempts to regulate the blood gas parameters, that is, the arterial levels of O₂, CO₂, and pH. These are overwhelmingly the most important influences on breathing. The body senses these parameters through two sets of chemoreceptors—the peripheral chemoreceptors and the central chemoreceptors. Hypoxia, hypercapnia, and acidosis all cause an increase in ventilation, which tends to raise P_O2, to lower P_CO2, and to raise pH, thereby correcting deviations in the three blood-gas parameters. Although small variations in arterial P_CO2 and P_O2occur with activities such as sleep, exercise, talking, and panting, the control of blood gases is so tight in normal individuals that it is rare for arterial P_CO2 to change from the normal 40 mm Hg by more than a few millimeters of mercury. Thus, the peripheral and central chemoreceptors form the vital sensory arm of a negative feedback mechanism that stabilizes arterial P_O2, P_CO2, and pH.

PERIPHERAL CHEMORECEPTORS

Peripheral chemoreceptors (carotid and aortic bodies) respond to hypoxia, hypercapnia, and acidosis

A decrease in arterial P_O2 is the primary stimulus for the peripheral chemoreceptors. Increases in P_CO2 and decreases in pH also stimulate these receptors and make them more responsive to hypoxia.

Sensitivity to Decreased Arterial P_O2 Perfusion of the carotid body with blood having a low P_O2—but a normal P_CO2 and pH—causes a prompt and reversible increase in the firing rate of axons in the carotid sinus nerve. Figure 32-9A shows a comparable experiment on an isolated chemoreceptor cell of the carotid body. Under normal acid-base conditions, increase of P_O2 above the normal value of ~100 mm Hg has only trivial effects on the firing rate of the nerve. However, at normal values of P_CO2 and pH (Fig. 32-9B, blue curve), decrease of P_O2 to values below 100 mm Hg causes a progressive increase in the firing rate.

Figure 32-9 Chemosensitivity of the carotid body. A, Effect of anoxia on a single, isolated glomus cell. Anoxia elicits a depolarization and small action potentials, as measured with a patch pipette. B, Effect of respiratory acid-base disturbances on O₂ sensitivity. C, Effect of pH changes on CO₂ sensitivity. In B and C, the y-axis represents the frequency of action potentials in single sensory fibers from the carotid body. (A, Data from Buckler KJ, Vaughan-Jones RD: Effects of hypoxia on membrane potential and intracellular calcium in rat neonatal carotid body type I cells. J Physiol 1994; 476:423-428. B, Data from Cunningham DJC, Robbins PA, Wolff CB: Integration of respiratory responses to changes in alveolar partial pressures of CO₂ and O₂ and in arterial pH. In Cherniack NS, Widdicombe J: Handbook of Physiology, Section 3: The Respiratory System, vol II, pp 475-528. Bethesda, MD: American Physiological Society, 1986. C, Data from Biscoe TJ, Purves MJ, Sampson SR: The frequency of nerve impulse in single carotid body chemoreceptor afferent fibers recorded in vivo with intact circulation. J Physiol 1970; 208:121-131.)

Sensitivity to Increased Arterial P_CO2 The carotid body can sense hypercapnia in the absence of hypoxia or acidosis. It is possible to maintain a constant extracellular pH (pH_o) while increasing P_CO2 by keeping the ratio [HCO⁻₃]/P_CO2constant (see Chapter 28). The maroon curve in Figure 32-9C shows the results of experiments in which graded increases in P_CO2—at a fixed blood pH of 7.45 and a fixed P_O2 of 80 mm Hg—produced graded increases in the firing rate of the carotid sinus nerve.

Sensitivity to Decreased Arterial pH The carotid body also can sense acidosis in the absence of hypoxia or hypercapnia. The green curve in Figure 32-9C shows the results of experiments that are the same as those represented by the maroon curve, except that blood pH was fixed at 7.25 rather than at 7.45. Over the entire range of P_CO2 values, the firing rate of the carotid sinus nerve is greater at a pH of 7.25 than at 7.45. Thus, metabolic acidosis (see Chapter 28) stimulates the carotid body.

In summary, besides being sensitive to hypoxia, the carotid body is sensitive to both components of respiratory acidosis (see Chapter 28)—high P_CO2 and low pH. In fact, respiratory acidosis makes the carotid body more sensitive to hypoxia (Fig. 32-9B, orange curve), whereas respiratory alkalosis has the opposite effect (Fig. 32-9B, red curve).

The glomus cell is the chemosensor in the carotid and aortic bodies

The body has two sets of peripheral chemoreceptors: the carotid bodies, one located at the bifurcation of each of the common carotid arteries; and the aortic bodies, scattered along the underside of the arch of the aorta (Fig. 32-10A). The carotid bodies should not be confused with the carotid sinus (see Chapter 23), which is the bulbous initial portion of the internal carotid artery that serves as a baroreceptor. Similarly, the aortic bodies should not be confused with baroreceptors of the aortic arch.

Figure 32-10 Anatomy of the peripheral chemoreceptors. (B, Data from Williams PL, Warwick R [eds]: Splanchnology. In Gray’s Anatomy. Philadelphia: WB Saunders, 1980.)

The major function of the carotid and aortic bodies is to sense hypoxia in the arterial blood and signal cells in the medulla to increase ventilation. This signaling occurs through afferents of the glossopharyngeal nerve (CN IX) for the carotid bodies and of the vagus nerve (CN X) for the aortic bodies. The carotid bodies have been more extensively studied than the aortic bodies, which are smaller and less accessible. The first description of their function as chemoreceptors was provided by Corneille Heymans, for which he was awarded the 1938 Nobel Prize for Physiology or Medicine. (See Note: Corneille Jean François Heymans)

Aside from their chemosensitivity, three features characterize the carotid bodies. First, they are extremely small: each weighs only ~2 mg. Second, for their size, they receive an extraordinarily high blood flow—the largest of any tissue in the body. Their blood flow, normalized for weight, is ~40-fold higher than that of the brain. Third, they have a very high metabolic rate, 2-to 3-fold greater than that of the brain. Thus, even though the metabolic rate is high, the blood flow is so much higher that the composition of the blood (e.g., P_O2, P_CO2, and pH) in the carotid body capillaries is virtually the same as in the systemic arteries.

The chemosensitive cells of the carotid body are the type I or glomus cells. They are ~10 μm in diameter, are roughly spherical, and occur in clusters (Fig. 32-10B). Adjacent glomus cells may communicate with each other through gap junctions. Embryologically, the glomus cell is neuroectodermal in origin and shares many characteristics with neurons of the peripheral nervous system as well as with adrenal chromaffin cells (see Chapter 49). Indeed, glomus cells have four neuron-like characteristics. (1) Some are innervated by preganglionic sympathetic neurons. (2) Glomus cells have a variety of voltage-gated ion channels. (3) Depolarization triggers action potentials. (4) Glomus cells have numerous intracellular vesicles containing a variety of neurotransmitters—acetylcholine, dopamine, norepinephrine, substance P, and met-enkephalin. Stimulation causes the release of these neurotransmitters and controls the firing of the sensory nerve endings.

Sensory endings of the carotid sinus nerve (a branch of CN IX) impinge on carotid body glomus cells. Neurotransmitter release from the glomus cells triggers action potentials in the carotid sinus nerve, which makes its first synapse on neurons of the NTS (part of the DRG), thereby signaling the medulla that the systemic arterial blood has a low P_O2, a high P_CO2, or a low pH. (See Note: The Glomus Cell)

Surrounding individual clusters of glomus cells are the type II or sustentacular cells (Fig. 32-10B), which are supporting cells similar to glia. Also close to the glomus cells is a dense network of fenestrated capillaries. This vascular anatomy as well as the exceptionally high blood flow puts the glomus cells in an ideal position to monitor the arterial blood gases with fidelity.

Both the sympathetic and parasympathetic divisions of the autonomic nervous system innervate the carotid body. As already noted, preganglionic sympathetic neurons synapse on glomus cells and presumably can alter their function. Autonomic fibers also contact blood vessels; increased sympathetic tone decreases local blood flow. Because the metabolic rate of the carotid body is high, a large decrease in blood flow produces a local fall in P_O2 near the glomus cells, even when systemic arterial P_O2 remains constant. Increased sympathetic tone thus “fools” the carotid body into behaving as if a hypoxic state existed. Hence, by modulating blood flow to the carotid body, the autonomic nervous system can fine-tune the response of the peripheral chemoreceptors.

The aortic bodies also include scattered glomus cells that presumably have a function similar to that of glomus cells in the carotid bodies. However, there are distinct differences between their responses to stimuli and the effects they have on ventilation. For the purposes of this section, we focus our discussion here on the carotid bodies, about which more is known.

Hypoxia, hypercapnia, and acidosis inhibit K⁺ channels, raise glomus cell [Ca²⁺]_i, and release neurotransmitters

The sensitivity of the glomus cell to hypoxia, hypercapnia, and acidosis is a special case of chemoreception that we discussed in connection with sensory transduction (see Chapter 15). It is interesting that one cell type—the glomus cell—is able to sense all three blood-gas modalities. The final common pathway for the response to all three stimuli (Fig. 32-11) is an inhibition of BK K⁺ channels, depolarization of the glomus cell, possible firing of action potentials, opening of voltage-gated Ca²⁺ channels, increase in [Ca²⁺]_i, secretion of neurotransmitters, and stimulation of the afferent nerve fiber. What differs among the three pathways is how the stimulus inhibits K⁺ channels.

Figure 32-11 Response of glomus cell to hypoxia, hypercapnia, and acidosis. cAMP, cyclic adenosine monophosphate; GSH, reduced glutathione; GSSG, oxidized glutathione.

Hypoxia Investigators have proposed three mechanisms by which low P_O2 might inhibit K⁺ channels. First, some evidence suggests that a heme-containing protein responds to a decrease in P_O2 by lowering the open probability of closely associated K⁺ channels. Second, in rabbit glomus cells, hypoxia raises [cAMP]_i, which inhibits a cAMP-sensitive K⁺ current. Third, small decreases in P_O2 inhibit NADPH oxidase in mitochondria, thus increasing the ratio of reduced glutathione versus oxidized glutathione, which directly inhibits certain K⁺ channels. The relative roles of the three pathways may depend on the species. Regardless of how hypoxia inhibits which K⁺ channels, the resulting depolarization activates voltage-gated Ca²⁺ channels. (See Note: Peripheral Chemoreceptors)

Hypercapnia An increase in P_CO2 causes CO₂ to move into the glomus cell, thereby generating H⁺ (see Chapter 28) and leading to a virtually instantaneous fall of intracellular pH (pH_i). As pH_i decreases, the protons appear to inhibit high-conductance BK K⁺ channels by displacing Ca²⁺ from their binding sites. The result is a depolarization, a rise in [Ca²⁺]_i, and the release of neurotransmitter.

Extracellular Acidosis A decrease in pH_o inhibits acid-base transporters (e.g., Na-H exchangers) that elevate pH_i and stimulates acid-base transporters (e.g., Cl-HCO₃ exchangers) that lower pH_i, thereby leading to a slow fall in pH_i(see Chapter 28). Thus, even at a constant P_CO2, extracellular acidosis (i.e., metabolic acidosis) triggers the same cascade of events outlined for hypercapnia, albeit more slowly.

CENTRAL CHEMORECEPTORS

When the blood-gas parameters are nearly normal, the central chemoreceptors are the primary source of feedback for assessing the effectiveness of ventilation and also the major source of tonic drive for breathing. Just as the peripheral chemoreceptors are primarily sensitive to arterial hypoxia, the neurons that act as central chemoreceptors are primarily sensitive to arterial hypercapnia, which generally presents itself as respiratory acidosis (i.e., a decrease in pH_o brought about by a rise in P_CO2; see Chapter 28). However, the actual parameter sensed appears to be a low pH in or around the chemoreceptor neurons.

The blood-brain barrier separates the central chemoreceptors in the medulla from arterial blood

In the 1950s, Isidore Leusen—working on dogs with denervated peripheral chemoreceptors—found that ventilation increased when he perfused the cerebral ventricles with an acidic solution having a high P_CO2. Because the resultant hyperventilation caused a respiratory alkalosis in the blood, it must have been the local acidosis in the brain that raised ventilation. From this and later experiments, we now believe that the primary stimulus driving respiration during respiratory acidosis is not actually an increase in arterial P_CO2 but probably the ensuing pH decrease within brain tissue. Most evidence indicates that the central chemoreceptors are at a site within the brain parenchyma that responds to changes both in arterial P_CO2 and in cerebrospinal fluid (CSF) pH.

Starting from normal blood gas parameters, an increase in the arterial P_CO2 from 40 to ~45 mm Hg (an increase of only ~12.5%) doubles ventilation. By contrast, hypoxia doubles ventilation only if P_O2 falls by ~50%. If P_CO2increases suddenly, the increase in ventilation begins rapidly, augmenting first the depth and later the frequency of inspirations. However, the response may take as long as 10 minutes to develop fully (Fig. 32-12A). If, instead, the acid-base disturbance in arterial blood is a metabolic acidosis (i.e., a decrease in pH_o and [HCO⁻₃]_o at a fixed P_CO2; see Chapter 28) of comparable magnitude, ventilation increases much more slowly and the steady-state increase is substantially less.

Figure 32-12 Effect of arterial hypercapnia on brain pH and ventilation. (A, Data from Padget P: The respiratory response to carbon dioxide. Am J Physiol 1928; 83:384-389. B, Data from Fencl V: Acid-base balance in cerebral fluids. In Cherniack NS, Widdicombe J: Handbook of Physiology, Section 3: The Respiratory System, vol II, part 1, pp 115-140. Bethesda, MD: American Physiological Society, 1986. C, Data from Fencl V, Miller TB, Pappenheimer JR: Studies on the respiratory response to disturbances of acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid. Am J Physiol 1966; 210:459-472.)

The reason for these observations is that the central chemoreceptors are located within the brain parenchyma (Fig. 32-12B) and are bathed in brain extracellular fluid (BECF), which is separated from arterial blood by the blood-brain barrier (BBB). The BBB has a high permeability to small, neutral molecules such as O₂ and CO₂ but a low permeability to ions such as Na⁺, Cl⁻, H⁺, and [HCO⁻₃]_o (see Chapter 11). An increase in arterial P_CO2 rapidly leads to a P_CO2 increase of similar magnitude in the BECF, in the CSF, and inside brain cells. The result is an acidosis in each of these compartments. In fact, because the protein concentration of CSF or BECF is lower than that of blood plasma (see Table 11-1), the non-HCO⁻₃ buffering power (see Chapter 28) of CSF and BECF is also substantially less. Thus, at least initially, raising P_CO2 produces a larger signal (i.e., pH decrease) in the CSF and BECF than in the blood. (See Note: CO₂-Induced pH Changes in CSF and BECF)

Although raising arterial P_CO2 causes the pH of the BECF and CSF to fall rapidly, the choroid plexus (see Chapter 11) and perhaps the BBB partially restore the pH of these compartments by actively transporting HCO⁻₃ from the blood into the CSF. Thus, after many hours of respiratory acidosis in the arterial blood, the low-pH signal in the BECF and CSF gradually wanes. Even so, respiratory acid-base disturbances lead to substantial changes in the steady-state pH of the BECF and CSF (Fig. 32-12C, purple curve).

In contrast to its high CO₂ permeability, the BBB’s permeability to ions such as H⁺ and HCO⁻₃ is low. For this reason, and because the BBB actively regulates the pH of the BECF and CSF, metabolic acid-base disturbances alter steady-state brain pH only 10% to 35% as much as identical blood pH changes during respiratory acid-base disturbances (Fig. 32-12C, red curve). Therefore, ventilation is much less sensitive to changes in arterial pH and [HCO⁻₃] at constant arterial P_CO2. Ventilation correlates uniquely with the pH of the BECF (Fig. 32-12D), regardless of whether respiratory or metabolic acid-base disturbances produce the pH changes in the BECF.

Central chemoreceptors are located in the ventrolateral medulla and other brainstem nuclei or areas

Early work on the central chemoreceptor by Hans Loeschcke, Marianne Schläfke, and Robert Mitchell identified candidate regions near the surface of the ventrolateral medulla (VLM; Fig. 32-13A). The application of acidic solutions to the rostral or caudal VLM leads to a prompt increase in ventilation. Moreover, focal cooling of these areas to 20°C to reversibly inhibit neurons—or placement of lesions to permanently destroy the neurons—blunts the ventilatory response to respiratory acidosis. This and other work led to the conclusion that the central chemoreceptors are located near the surface of the VLM.

Figure 32-13 Chemosensitive neurons in the ventrolateral medulla and raphe. Illustrated in A is a ventral view of a cat medulla showing chemosensitive areas named after the three physiologists who first described them. The slice to the right shows the location of serotonergic neurons in the ventrolateral medulla and medullary raphe nuclei. B, Patch pipette recordings of neurons cultured from the medullary raphe of rats. Those that are stimulated by acidosis are serotonergic. D, Transverse section of rostral medulla, near the ventral surface, with blood vessels colored red and serotonergic neurons colored green. Yellow shows the overlap of red and green. B, basilar artery; P, pyramidal tracts. (A, Data from Dermietzel R: Central chemosensitivity, morphological studies. In Loeschcke HH [ed]: Acid-Base Homeostasis of the Brain Extracellular Fluid and the Respiratory Control System, pp 52-66. Stuttgart: Thieme, 1976. B, Data from Wang W, Pizzonia JH, Richerson GB: Chemosensitivity of rat medullary raphe neurones in primary tissues culture. J Physiol 1998; 511:433-450). D, Data from Risso-Bradley A, Pieribone VA, Wang W, et al: Chemosensitive serotonergic neurons are closely associated with large medullary arteries. Nat Neurosci 2002; 5:401-402.)

More recent work indicates that the VLM is not the only location of central chemoreceptors. For example, studies on brain slices and cultured cells show that acidosis stimulates neurons in many brainstem nuclei. Besides the VLM, these include the medullary raphe (Fig. 32-13A, inset), the nucleus ambiguus, and the NTS—all in the medulla—as well as the locus coeruleus and hypothalamus. Experiments in the laboratory of Eugene Nattie show that focal acidosis within many of these areas stimulates breathing in intact animals. It is not clear whether all of these chemosensitive areas play a role in the control of ventilation. If they do, multiple sensors may be another example of redundancy in a critical system. Some may come into play only under special circumstances, such as during severe acid-base disturbances; others may be responsible for arousal from sleep only when airways are obstructed. (See Note: Central Chemoreceptor)

Some neurons of the medullary raphe and ventrolateral medulla are unusually pH sensitive

Certain medullary raphe neurons are unusually pH sensitive. In brain slices and in tissue culture, small decreases in extracellular pH raise the firing rate of one subset of medullary raphe neurons (Fig. 32-13B) and lower the firing rate of another. In both types of chemosensitive neurons, metabolic and respiratory disturbances have similar effects on firing, indicating that the primary stimulus is a decrease in either extracellular or intracellular pH, rather than an increase in P_CO2. (See Note: Medullary Raphé Neurons)

The two types of chemosensitive neurons have other distinguishing properties, including different shapes, basal firing patterns, and neurotransmitter content. For example, the neurons stimulated by acidosis contain the stimulatoryneurotransmitter serotonin, whereas those that are inhibited by acidosis may contain the inhibitory neurotransmitter GABA. Serotonergic neurons are also present in the VLM. When arterial P_CO2 rises, acidosis-stimulated neurons may stimulate breathing like an accelerator on a car, whereas acidosis-inhibited neurons may decrease the inhibition of breathing, as when one is letting off on the brake (Fig. 32-13C).

The serotonergic neurons in the medullary raphe are in close apposition to branches of the basilar artery (Fig. 32-13D), which puts them—like the glomus cells of the peripheral chemoreceptors—in a position to sense arterial P_CO2with fidelity. Thus, serotonergic neurons of the raphe and VLM have many properties that would be expected of central respiratory chemoreceptors. Many infants who have died of sudden infant death syndrome (SIDS) have a deficit of serotonergic neurons, which is consistent with a prevailing theory that a subset of SIDS infants have a defect in central respiratory chemoreception. (See Note: Sudden Infant Death Syndrome)

INTEGRATED RESPONSES TO HYPOXIA, HYPERCAPNIA, AND ACIDOSIS

In real life, it is rare for arterial P_O2 to fall without accompanying changes in P_CO2 and pH. In addition, changes in individual blood-gas parameters may independently affect both the peripheral and the central chemoreceptors. How does the respiratory system as a whole respond to changes in multiple blood-gas parameters?

Hypoxia accentuates the acute response to respiratory acidosis

Respiratory Acidosis When the blood gas parameters are nearly normal, respiratory acidosis (increased P_CO2/decreased pH) stimulates ventilation more than does hypoxia. If an animal breathes an air mixture containing CO₂, the resultant respiratory acidosis causes ventilation to increase rapidly. Because both peripheral and central chemoreceptors respond to respiratory acidosis, both could contribute to the response. It is possible to isolate the function of the two sets of chemoreceptors by (1) denervating the peripheral chemoreceptors to study the response of the central chemoreceptors alone or (2) perfusing the carotid bodies to study the response of the peripheral chemoreceptors alone. On the basis of approaches such as these, it appears that the central chemoreceptors account for 65% to 80% of the integrated response to respiratory acidosis under normoxic conditions. However, the response of the peripheral chemoreceptors is considerably more rapid than that of the central chemoreceptors, which require several minutes to develop a full-blown response.

At an alveolar P_O2 that is somewhat higher than normal, raising the alveolar P_CO2 causes a linear increase in steady-state ventilation (Fig. 32-14A, red curve). Lowering the alveolar P_O2 has two effects (Fig. 32-14A, other two curves). First, at a given P_CO2, hypoxia increases ventilation, reflecting the response of the peripheral chemoreceptors to hypoxia. Second, hypoxia increases the sensitivity of the integrated response to respiratory acidosis. That is, the slopes of the curves increase. At least part of the explanation for this increase in slopes is that the peripheral chemoreceptor itself—as judged by the activity of the carotid sinus nerve—becomes more sensitive to respiratory acidosis with coexisting hypoxia.

Figure 32-14 Integrated ventilatory response to changes in P_CO2 (A) and P_O2 (B). The shaded triangles indicate the slopes. (A, Data from Nielsen M, Smith H: Studies on the regulation of respiration in acute hypoxia. Acta Physiol Scand 1952; 24:293-313. B, Data from Loeschcke HH, Gertz KH: Einfluss des O₂-Druckes in der Einatmungsluft auf die Atemtätigkeit der Menschen, gepruüft unter Konstanthaltung des alveolaren CO₂-Druckes. Pflugers Arch Gesamte Physiol 1958; 267:460-477.)

Metabolic Acidosis Severe metabolic acidosis (e.g., diabetic ketoacidosis) leads to profound hyperventilation, known as Kussmaul breathing. This hyperventilation can drive arterial P_CO2 down to low levels, in an attempt to compensate for the metabolic acidosis. Acutely, the main stimulus for hyperventilation comes from peripheral chemoreceptors. Because a severe decrease in arterial pH does produce a small fall in CSF pH, central chemoreceptors also participate in this response. If the insult persists for many hours, CSF pH falls even farther, and central chemoreceptor drive becomes more prominent.

Respiratory acidosis accentuates the acute response to hypoxia

If an animal breathes an O₂-free air mixture, the resulting hypoxia causes ventilation to increase rapidly. As already discussed, the peripheral chemoreceptors respond primarily to hypoxia. To what extent do central mechanisms contribute to the integrated response to acute hypoxia? In an animal with denervated peripheral chemoreceptors, hypoxia actually depresses respiratory output. Thus, the integrated response actually underestimates the stimulatory contribution of the peripheral chemoreceptors.

At an arterial P_CO2 that is slightly lower than normal, lowering of alveolar P_O2 has very little effect on ventilation until P_O2 falls below 50 mm Hg (Fig. 32-14B, red curve). The eventual response at very low P_O2values indicates that the peripheral chemoreceptors play a vital, fail-safe role in responding to extreme hypoxia, as at high altitudes (see Chapter 61). Raising the arterial P_CO2 (i.e., respiratory acidosis) has two effects (Fig. 32-14B, other two curves). First, at a given P_O2, respiratory acidosis increases ventilation, reflecting the dual contributions of the peripheral and central chemoreceptors to hypercapnia and acidosis. Second, respiratory acidosis increases the sensitivity of the integrated response to hypoxia. That is, the curves become steeper. These effects on the integrated response (Fig. 32-14B) are similar to—although more exaggerated than—the effects of respiratory acidosis on the response of the peripheral chemoreceptor to hypoxia (Fig. 32-9B).

Chronic Hypercapnia in Pulmonary Disease

Chronic hypercapnia occurs in many people with lung disease (e.g., emphysema—destruction of alveoli and loss of proper gas exchange) or with muscle weakness (e.g., amyotrophic lateral sclerosis, neuropathies, and myopathies). An increase in P_CO2 leads to an immediate respiratory acidosis in the arterial blood and brain. If CO₂ remains elevated, the pH of the CSF/BECF slowly recovers (i.e., increases) during the following 8 to 24 hours. The mechanism of this pH_CSF increase is probably an increase in HCO⁻₃ flux into the CSF/BECF across the choroid plexus and BBB, representing a metabolic compensation to the respiratory acidosis (see Chapter 28). The increased CSF pH shifts the CO₂ response curves in Figure 32-14A to the right because, compared with reference conditions, a higher P_CO2 is needed to produce a given degree of CSF acidity (i.e., ventilatory drive). Such a resetting of the central chemoreceptors may be important clinically for patients who chronically retain CO₂. Even though P_CO2 may be quite high, adaptation of the CSF/BECF restores pH_CSF toward normal. With central chemoreceptor drive for ventilation now decreased, the main drive for ventilation may become hypoxia through peripheral chemoreceptors. Administration of supplemental O₂ to such a patient may remove the hypoxic drive as well, causing ventilation to decrease and P_CO2 to rise to very high levels (e.g., P_CO2 > 100 mm Hg). At such high levels, CO₂ acts as a narcotic, depressing respiration. This “CO₂ narcosis” then directly inhibits ventilation and can cause death from hypoventilation—a classic example of “too much of a good thing.”

MODULATION OF VENTILATORY CONTROL

The major parameters that feed back on the respiratory control system are the blood gases—P_O2, P_CO2, and pH. In addition, the respiratory system receives input from two other major sources: (1) a variety of stretch and chemical/irritant receptors that monitor the size of the airways and the presence of noxious agents and (2) higher CNS centers that modulate respiratory activity for the sake of nonrespiratory activities.

Stretch and chemical/irritant receptors in the airways and lung parenchyma provide feedback about lung volume and the presence of irritants

Sensors within the lungs and upper airways detect foreign bodies, chemical irritants, or immunological challenges and help protect the lungs—one of the few organs that have direct access to the outside world. Sensors also detect changes in lung volume to help control output to the respiratory muscles. These sensors are part of respiratory afferent fibers from the thorax that travel with CN X, and those from the upper airways travel with CN IX. Both synapse within the DRG in the medulla.

Slowly Adapting Pulmonary Stretch Receptors (PSRs) Within the tracheobronchial tree are mechanoreceptors that detect changes in lung volume by sensing stretch of the airway walls. One type of PSR—the slowly adapting PSR—responds to stretch with an increase in firing that then decays very slowly over time. One of their functions may be to inform the brain about lung volume to optimize respiratory output. (See Note: Slowly Adapting Pulmonary Stretch Receptors)

A reflex that involves slowly adapting PSRs is the Hering-Breuer reflex, one of the first examples in physiology of negative feedback. In 1868, Hering and Breuer found that lung inflation inhibits the output of phrenic motor neurons (Fig. 32-15), thereby protecting the lungs from overinflation. Because the reflex also increases respiratory frequency, it maintains a constant alveolar ventilation. This reflex may be important in controlling tidal volume during eupnea in human infants. In adults, this reflex does not occur until lung volume is greater than during a normal inspiration. However, the sensor may provide feedback that the medulla uses to choose a combination of tidal volume and respiratory frequency that minimizes the work of breathing.

Figure 32-15 The Hering-Breuer reflex. In a paralyzed and artificially ventilated animal, prevention of lung inflation during inspiratory activity (blue curves) leads to prolonged phrenic nerve output (i.e., if the animal were not paralyzed, then tidal volume would be large). Inflation of the lungs during inspiratory activity (red curves) produces feedback that shortens the duration of inspiratory activity (i.e., if the animal were not paralyzed, then the tidal volume would be smaller) and also causes the next breath to occur earlier (respiratory frequency would increase). (Data from von Euler C: Brainstem mechanisms for generation and control of breathing pattern. In Cherniack NS, Widdicombe J: Handbook of Physiology, Section 3: The Respiratory System, vol II, part 1, pp 1-67. Bethesda, MD: American Physiological Society, 1986.)

Rapidly Adapting Pulmonary Stretch (Irritant) Receptors This PSR responds to a sudden, maintained inflation with a rapid increase in firing rate, which then decreases by 80% or more within 1 second. Unlike slowly adapting PSRs, rapidly adapting PSRs are very sensitive to a variety of chemical stimuli, hence the term irritant receptors. These agents include serotonin, prostaglandins, bradykinin, ammonia, cigarette smoke, and ether. An important function of these receptors may be to detect pathophysiological processes in the airway, such as chemical irritation, congestion, and inflammation. These receptors also detect histamine, which produces bronchoconstriction in asthma. (See Note: Rapidly Adapting Pulmonary Stretch Receptors)

C-Fiber Receptors A rich network of small, unmyelinated axons (C fibers) have nerve endings in the alveoli (juxtacapillary or J receptors) and conducting airways. Like slowly adapting PSRs, which are extensions of myelinated axons, C-fiber receptors respond to both chemical and mechanical stimuli. Stimulation of C-fiber receptors elicits a triad of rapid and shallow breathing, bronchoconstriction, and increased secretion of mucus into airways—all of which may be defense mechanisms. Bronchoconstriction and rapid, shallow breathing enhance turbulence (see Chapter 27), favoring the deposition of foreign substances in mucus higher up in the bronchial tree, where mucus-secreting cells are located.

Higher brain centers coordinate ventilation with other behaviors and can override the brainstem’s control of breathing

The role of the CNS in controlling ventilation is far more complex than generating a regular pattern of inspirations and expirations and then modifying this pattern in response to input from mechanical and chemical sensors. The CNS also must balance the need to control P_O2, P_CO2, and pH with the need to control ventilation for nonrespiratory purposes, such as speaking, sniffing, and regulating temperature (e.g., panting in dogs). In addition, the CNS must coordinate breathing with behaviors that require the absence of airflow, such as chewing, swallowing, and vomiting.

Many nonrespiratory regions of the CNS tonically stimulate or inhibit respiration. For example, the reticular activating system (see Chapter 10) in the brainstem is one of the sources of tonic drive to the respiratory CPG. An increase in this drive occurs during arousal from sleep, when a general alerting reaction increases ventilation and heart rate and activates the brain as evidenced on an electroencephalogram.

Coordination with Voluntary Behaviors That Use Respiratory Muscles Numerous voluntary actions initiated in the cerebral cortex involve a change in airflow—voluntarily hyperventilating, breath-holding, speaking, singing, whistling, and playing musical wind instruments. Although voluntary control over muscles of respiration can be exquisitely precise, this control is not absolute. For example, voluntary breath-holding can last only so long before being overwhelmed by ventilatory drive from chemoreceptors. The cerebral cortex controls the respiratory system by at least two major mechanisms. First, some cortical neurons send axons to respiratory centers in the medulla. Second, some cortical premotor neurons send axons to motor neurons that control muscles of respiration. One consequence of this dual control mechanism is that lesions in specific areas of the cerebral cortex can abolish voluntary breath-holding, a condition known as respiratory apraxia. Another consequence is that small CNS lesions may specifically knock out one set of connections. For example, patients with intractable pain are sometimes treated with partial transection of the upper cervical ventrolateral spinal cord to cut axons carrying pain sensation to the thalamus (spinothalamic tract). When this procedure inadvertently damages respiratory projections within the reticulospinal tract, patients breathe properly while awake but experience respiratory failure while asleep (Ondine’s curse; see the box on this topic). The lesion may cut automatic premotor neurons descending to the spinal cord from respiratory centers in the medulla, but not voluntary ones from the cortex.

Sighs, Yawns, Coughs, and Sneezes

The respiratory apparatus engages in a variety of motor behaviors that help maintain normal lung function and gas exchange by protecting the alveoli from collapse or preventing obstruction of the upper airways.

Sigh or “Augmented Breath”

A sigh is a slow and deep inspiration, held for just a moment, followed by a longer than normal expiratory period (Fig. 32-3A). A normal person sighs ~6 times per hour. Local collapse of alveoli (atelectasis) may initiate a sigh, which is an important mechanism for stimulating release of surfactant (see Chapter 27) and thus reopening these alveoli. Hypoxia and respiratory acidosis increase sigh frequency, consistent with the idea that sighs counteract decreased alveolar ventilation.

Yawn

An exaggerated sigh, a yawn takes lung volume to total lung capacity for several seconds. The mouth is fully open. In the extreme case, the arms are stretched upward, the neck is extended to elevate the pectoral girdle, and the back is extended—maneuvers that maximize lung volume (see Chapter 27). Yawning is even more effective than sighing in opening up the most resistant atelectatic alveoli. Everyone “knows” that yawns are contagious, and some evidence suggests that this is actually true. Yawns may (1) minimize atelectasis as one prepares for a long period of sleep or anticipates sleep (as during a boring cell biology lecture) and (2) reverse—on arousal—the atelectasis that has accumulated during sleep.

Cough Reflex

Coughing is important for ridding the tracheobronchial tree of inhaled foreign substances. There is probably no single class of “cough receptors.” The tickling sensation that is relieved by a cough is analogous to the cutaneous itch and is probably mediated by C-fiber receptors. Thus, a cough is a respiratory scratch. (See Note: C Fibers)

When lower airway receptors trigger a cough, it begins with a small inspiration that increases the coughing force. Mechanosensitive and irritant receptors in the larynx can trigger either coughing or apnea. When they trigger a cough, the inspiration is absent, minimizing the chances that the offending foreign body will be pulled deeper into the lungs. In either case, a forced expiratory effort against a closed glottis raises intrathoracic and intra-abdominal pressures to very high levels. The glottis then opens suddenly, and the pressure inside the larynx falls almost instantaneously to near-atmospheric levels. This sudden drop in luminal pressure produces dramatic increases in the axial (alveolus to trachea) pressure gradient that drives airflow. In the trachea, this pressure drop also decreases the radial transmural pressure difference across the tracheal wall, thereby collapsing the trachea, especially the membranous (i.e., noncartilaginous) part of the trachea. (See Chapter 27.) As a result, tracheal cross-sectional area may fall to as little as one-sixth its original value. The net effect is a brief but violent rush of air out of the trachea at velocities near 800 km/hr (~65% of the speed of sound) that loosens mucus or foreign bodies and moves them upward. Protracted bouts of severe coughing can lead to syncope (lightheadedness) because the high intrathoracic pressure decreases venous return and reduces cardiac output (see Chapter 23). (See Note: External Compression of Thoracic Vessels)

Sneeze

Sensors in the nose detect irritants and can evoke a sneeze. Curiously, these same receptors are probably also responsible for apnea in response to water applied to the face or nose, which is part of the diving reflex that evolved in diving mammals such as the seal to prevent aspiration during submersion. A sneeze differs from a cough in that a sneeze is almost always preceded by a deep inspiration. Like a cough, a sneeze involves an initial buildup of intrathoracic pressure behind a closed glottis. Unlike a cough, a sneeze involves pharyngeal constriction during the buildup phase and an explosive forced expiration through the nose as well as the mouth. This expiration is accompanied by contraction of facial and nasal muscles, so that the effect is to dislodge foreign bodies from the nasal mucosa.

Coordination with Complex Nonventilatory Behaviors One of the jobs of the brain is to coordinate complex behaviors such as yawning, chewing, swallowing, sucking, defecating, grunting, and vomiting. During yawning and vomiting, for example, groups of neurons orchestrate an array of simultaneous actions, only some involving the respiratory system. The premotor neurons that project from medullary respiratory centers to respiratory motor neurons are probably distinct from descending pathways involved in these complex nonventilatory behaviors.

Modification by Affective States Fear, horror, rage, and passion can be associated with major and highly characteristic changes in the respiratory pattern. For example, if a child runs in front of a car you are driving, the sudden application of the brakes is almost always accompanied by an equally sudden and rapid inspiration, with mouth open wide, increasing lung volume to nearly total lung capacity. The tendency of prevarications to be associated with changes in the breathing pattern is the basis for one part of the polygraph test used as a lie detector. Descending pathways from the limbic system (see Chapter 14) of the forebrain may mediate these emotional effects on breathing.

Ondine’s Curse, Sleep, and Sleep Apnea

Ondine’s Curse

Ondine, a water nymph in a German legend, was immortalized in the 1811 fairy tale by Friedrich Heinrich Karl, Baron de la Motte-Fouqué. In the play Ondine by Jean Giraudoux in 1939, Ondine married a mortal man, Hans, with the understanding that Hans would never marry a mortal woman. However, when Ondine later returned to the sea, her husband did remarry. Ondine’s father punished Hans by requiring him to make a continuous conscious effort to maintain lung ventilation (and all other automatic body functions). If he fell asleep, he would stop breathing and die. Hans explained to Ondine how hard it is to live with his curse: “One moment of inattention and I shall forget to hear, to breathe. They will say he died because breathing bored him.” Rare patients have been identified who have the same disorder—minus the relationship with a water nymph. These patients can be treated with a ventilator when they sleep and can maintain normal ventilation on their own while awake.

Sleep

Sleep, or even closing one’s eyes, has powerful effects on the breathing pattern and CO₂ responsiveness. During non–rapid eye movement (NREM) sleep, the regularity of eupneic breathing increases; also, the sensitivity of the respiratory system to CO₂ decreases compared with wakefulness, and the outflow to the muscles of the pharynx decreases. During rapid eye movement (REM) sleep, the pattern of breathing becomes markedly irregular, sometimes with no discernible rhythm, and the sensitivity of the respiratory system to CO₂ decreases further. Thus, P_CO2 often increases during NREM sleep and usually even more so during REM sleep. Barbiturates at low doses depress drive to the respiratory system and, if superimposed on normal sleep, can halt ventilation altogether.

Sleep Apnea

The collection of disorders in which ventilation ceases during deeper stages of sleep, particularly during REM sleep, is known as sleep apnea. Some cases of sleep apnea are related to Ondine’s curse and are due to a lack of central drive (central sleep apnea). However, most cases are due to collapse of the airway with sleep (obstructive sleep apnea), usually in obese people. The airway collapse is due to an exaggeration of the normal decrease in airway tone during sleep, superimposed on the structural problem of reduced airway diameter due to obesity. This is a common disorder associated with severe and excessive snoring, poor and interrupted sleep, daytime somnolence, and behavioral changes, possibly leading ultimately to hypertension and cardiac arrhythmias.

Balancing Conflicting Demands of Gas Exchange and Other Behaviors Ventilation, or lack thereof, is involved in a wide variety of behaviors, many of which have nothing to do with alveolar gas exchange per se. How is it that the brain is able to weigh the need for alveolar gas exchange against these competing demands on the respiratory system? Playing of a musical wind instrument is an example in which respiratory and nonrespiratory needs are reconciled. Musicians must make rapid and deep inspirations, followed by slow and prolonged expirations that can lead to considerable breath-to-breath variations in alveolar P_CO2. Nevertheless, these variations balance out, so that professionals can follow a musical score for prolonged periods without significant changes in average alveolar ventilation.

In other cases, conflicting demands are not so easily resolved. In infants, suckling relegates alveolar ventilation to a lower priority, and P_CO2 rises. Subjects reading aloud tend to increase their alveolar ventilation by ~25%, and P_CO2falls. Thus, during speech, chemical drive is overwhelmed by voluntary behavior. On the other hand, when strenuous exercise increases the need for alveolar ventilation, the CNS permits only brief gasps for speech—the ability of voluntary behavior to subvert body homeostasis can go only so far.

REFERENCES

Books and Reviews

Coleridge JCG: Pulmonary reflexes: Neural mechanisms of pulmonary defense. Annu Rev Physiol 1994; 56:69-91.

Feldman JL: Neurophysiology of breathing in mammals. In Bloom FE: Handbook of Physiology, Section 1: The Nervous System, vol IV, pp 463-525. Bethesda, MD: American Physiological Society, 1986.

Loeschcke HH: Central chemosensitivity and the reaction theory. J Physiol 1982; 332:1-24.

Peers C, Buckler KJ: Transduction of chemostimuli by the type I carotid body cell. J Membrane Biol 1995; 144:1-9.

Richerson GB: Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 2004; 5:449-461.

Journal Articles

Gray PA, Janczewski WA, Mellen N, et al: Normal breathing requires pre-Bötzinger complex neurokinin-1 receptor–expressing neurons. Nat Neurosci 2001; 4:1-4.

Pappenheimer, JR, Fencl V, Heisey SR, Held D: Role of cerebral fluids in control of respiration as studied in unanesthetized goats. Am J Physiol 1965; 208:436-450.

Schläfke ME, See WR, Loeschcke HH: Ventilatory response to alterations of H⁺ ion concentration in small areas of the ventral medullary surface. Resp Physiol 1970; 10:198-212.

Wang W, Zaykin AV, Tiwari JK, et al: Acidosis-stimulated neurons of the medullary raphe are serotonergic. J Neurophysiol 2001; 85:2224-2235.

Williams SEJ, Wootton P, Mason HS, et al: Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science 2004; 206: 2093-2097.