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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 p. 701 ) is one of the most unpleasant sensations in life ( Box 32-1 ). Swimmers and SCUBA divers, musicians who sing or play wind instruments, Lamaze practitioners, 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. N32-1 Thus, despite our common tendency to ignore breathing, control of ventilation is one of the most important of all brain functions.
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 falls or rises from breath holding, asphyxia, or pulmonary disease, dyspnea leads to efforts to increase ventilation and thus to restore arterial blood gas levels to normal. However, dyspnea can occur even with a normal arterial and . For example, increased airway resistance can cause dyspnea, even if arterial blood gas levels do not change. Exercise also causes dyspnea, even though is usually normal and 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 or even a drop in . The central neural mechanisms and pathways responsible for dyspnea are unknown, although many of the forebrain regions involved have been identified.
As stated in the text, respiratory output is often the last brain function to be lost in comatose patients, in which case its cessation marks the onset of brain death. In the United States, the legal definition of “brain death” is the irreversible loss of clinical function of the entire brain—which does not include the spinal cord. Brain death is legally equivalent to other forms of death. The declaration of brain death requires a careful neurological examination testing all reflexes mediated by cranial nerves, evaluating the patient for evidence of behaviors that require brain function, and ruling out any reversible cause such as hypothermia or drug overdose.
The ventilatory control mechanism must accomplish two tasks. First, it must establish the automatic rhythm for contraction of respiratory muscles. Second, it must adjust this rhythm to accommodate changing metabolic demands (as reflected by changes in blood , , and pH), varying mechanical conditions (e.g., changing posture), and a range of episodic nonventilatory behaviors (e.g., speaking, sniffing, eating).
The rhythmic output of the central nervous system (CNS) to muscles of ventilation normally occurs automatically, without any conscious effort. This output depends upon a vast array of interconnected neurons—located primarily in the medulla oblongata, but also in the pons and other brainstem regions. These neurons are called respiratory-related neurons (RRNs) because they fire more action potentials during specific parts of the respiratory cycle. For example, some neurons have peak activity during inspiration, and others, during expiration. Some RRNs are interneurons (i.e., they make local connections), others are premotor neurons (i.e., they innervate motor neurons), and still others are motor neurons (i.e., they innervate muscles of respiration). A subset of these neurons, thought to be in the medulla oblongata, is able to independently generate a respiratory rhythm—and is known as the central pattern generator ( CPG; see p. 396 ). Together the neurons of the respiratory network distribute signals appropriately to various pools of cranial and spinal motor neurons (see pp. 241–242 ), which directly innervate the respiratory muscles ( Fig. 32-1 ).
The most important respiratory motor neurons are those that send axons via the phrenic nerve to innervate the diaphragm ( Table 32-1 ), one of the primary muscles of inspiration (see p. 607 ). 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 p. 607 ).
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 |
External 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 ambiguous |
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 | ||
Internal 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 (see p. 606 ) 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 p. 608 ), thereby producing more rapid exhalation and permitting the next inspiration to begin sooner (i.e., increasing respiratory frequency).
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, which results 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 gas parameters—O 2 , CO 2 , and pH levels. Unlike the frequency of a clock, that 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 , although high and low pH also stimulate them and enhance their sensitivity to hypoxia. They convey their sensory information to the medulla via the glossopharyngeal nerve (cranial nerve [CN] IX) and vagus nerve (CN X). The central chemoreceptors, located on the brain side of the blood-brain barrier (see pp. 284–287 ), sense increases in arterial and—much more slowly—decreases in arterial pH, but not arterial . All three signals trigger an increase in alveolar ventilation that tends to return these arterial blood-gas parameters to normal. Thus, the 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 , , and pH (see Fig. 32-1 ).
Left alone, the respiratory CPG would tick regularly for an indefinite period. However, many inputs to the CPG cause the clock to speed up or slow down. 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 in the lungs and lower (i.e., distal) airways send their sensory information to the respiratory neurons of the medulla via CN X, and those in the upper airways send information via CN IX.
Nonrespiratory brainstem nuclei and higher centers in the CNS also interact with respiratory control centers, which allows 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-gas levels, and (4) how afferent feedback and higher CNS centers modulate ventilation.
A classical method for determining which parts of the CNS N32-2 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 second century, Galen was the first 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 via the midcervical spinal cord to the diaphragm.
One of the most difficult challenges in neurobiology today is to understand how neurons function within neural networks to generate normal behaviors. Although it is one of the most primitive in the mammalian brain, the neural network controlling respiration is still highly complex. The experimental preparations and techniques used to study respiration are also shared by neuroscientists studying other neural networks and include the following:
Intact, awake, behaving animals and humans are used to permit direct correlation of results with behavior. Investigators primarily use this approach to measure body movements, lung volume changes, or electrical activity in muscles or peripheral nerves.
Anesthetized, paralyzed, mechanically ventilated animals are used to permit better control of experimental variables and more intensive surgical techniques. Paralysis reduces movement of the brain so that individual neurons can be studied using extracellular recordings of single neurons.
The whole brain or large portions of the brain can be isolated in vitro by perfusing the brain via the arterial system, or by removing the spinal cord and lower brainstem of a neonatal rat from the body and keeping them alive submerged in artificial CSF. Because the brainstem circuitry is intact, a respiratory rhythm may still be produced. Elimination of the lungs and heart results in reduction of movement, which makes intracellular recording easier.
Brain slices are prepared by cutting the medulla into thin slices and are kept alive in artificial CSF. These slices can be used to study individual neurons in relative isolation; for example, with intracellular microelectrodes or patch-clamp recordings. Simple synaptic connections, limited to a restricted subset of those present in vivo, can also be studied.
Dissociated neurons can be studied immediately or after days or weeks in tissue culture. These approaches isolate neurons from synaptic input and permit highly stable recordings so that their biophysical properties can be studied with a high degree of precision and control.
These approaches to studying neural networks are at the same time very powerful and very limited. Results can vary depending on the species studied, on age, and on whether the subject is awake or anesthetized. Each experimental preparation has advantages for answering specific questions, as well as disadvantages. For example, it is not possible to define the properties of individual neurons while they are still part of a complex neural network. On the other hand, the respiratory rhythm is usually no longer present in “reduced” preparations, which makes it difficult to know if a given neuron is actually involved in respiratory control. All of these approaches suffer, more or less, from effects due to measurement of the responses—the biological equivalent of the Heisenberg uncertainty principle. There is ischemia in the center of en-bloc tissue, traumatic damage of neurons in brain slices, dedifferentiation of some neuronal properties in culture, and effects of anesthetics and prolonged surgery in vivo. For this reason, it is important that each result be verified and each theory be tested using many of these approaches, instead of relying on only one.
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. We can conclude that the neural machinery driving ventilation lies above the spinal cord.
When Lumsden, in the 1940s, made a transection between the pons and the medulla (see 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 was due to surgical damage to the respiratory CPG in the rostral medulla. Today, most respiratory neurophysiologists believe that the respiratory CPG is located in the medulla and that other sites, including the pons, only shape the respiratory output to produce the normal pattern. N32-3
The medulla actually has two identical respiratory CPGs—one on each side. All of the elements of the respiratory controller—drive inputs, sensory feedback, RRNs, and motor neurons—are bilateral. Thus, after a midsagittal transection, each side of the medulla generates an independent respiratory rhythm. As noted in the textbook, the location of the respiratory CPG is not universally agreed upon.
The respiratory CPG probably evolved in fish, where blood-gas exchange across the gills requires pumping by branchial structures; this necessity explains why the CPG is located in the medulla. CPGs generate all repetitive motor activities (see pp. 396–397 ). In invertebrates, these include swimming in sea slugs and movements of the stomach in lobsters. The mechanisms of rhythm generation discovered in these systems have led to establishment of general principles that have been valuable in promoting understanding of CPGs in mammals.
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 a prolonged inspiratory effort— inspiratory apneusis —that is terminated by a brief expiration. A brainstem transection above the pons does 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 apneusis), and (2) the rostral pons contains a pneumotaxic center that prevents apneusis (i.e., it promotes coordinated respirations). He believed that these two regions and the medulla are required for normal breathing. N32-4 Although this viewpoint is common in current literature, it is held by only a minority of respiratory physiologists.
See the special issue of Respiratory Physiology and Neurobiology dealing with pontine influences in breathing. The following is the lead/introductory article:
McCrimmon DR, Milsom WK, Alheid GF: The rhombencephalon and breathing: A view from the pons. Respir Physiol Neurobiol 143:103–104, 2004.
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 medialis and adjacent Kölliker-Fuse nucleus in the rostral pons. However, the pneumotaxic center is not unique in preventing apneusis because simply increasing the temperature of the animal can reverse apneusis induced by lesions in the pneumotaxic center. Moreover, lesions in many locations outside the pneumotaxic center can also induce apneusis. 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 ( Box 32-2 ). Thus, the terms apneustic center and pneumotaxic center are generally of only historical significance.
Respiratory output can change for a variety of reasons. Many patterns, both normal and abnormal, have recognizable characteristics summarized below. Figure 32-3 illustrates some of these.
Normal breathing.
Larger than normal breaths (see Box 32-4 ) that occur automatically at regular intervals in normal subjects, possibly to counteract collapse of alveoli (atelectasis).
An exaggerated sigh (see Box 32-4 ).
An increase in respiratory rate.
An increase in alveolar ventilation (see pp. 675–676 )—caused by an increase in respiratory frequency or an increase in tidal volume—that decreases arterial . Seen in pregnancy and liver cirrhosis (due to increased progesterone), in panic attacks, and as a compensation to metabolic acidosis (see p. 642 ).
Extremely deep, rapid breathing seen with metabolic acidosis, such as in diabetic ketoacidosis (see p. 1185 ).
Rapid, deep breathing causing a decrease in arterial . Although first described in a small number of patients with focal brain lesions, it is now believed that this pattern reflected coexisting lung disease or other systemic illness in the majority of these patients.
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.
Maximal, brief inspiratory efforts separated by long periods of expiration. Seen in severe anoxia, as well as in terminal, agonal breathing exhibited by patients with brainstem lesions or cardiac arrest.
Prolonged inspirations separated by brief expirations, typically seen in animals with lesions of the rostral pons plus bilateral vagotomy. Rarely seen in humans.
Cessation of respiration.
Slow, deep inspirations caused by interruption of vagus nerve input to the brainstem. Rarely seen in humans.
Highly irregular inspirations, often separated by long periods of apnea. Seen mainly with medullary lesions.
Similar to ataxic breathing, with groups of breaths, often of differing amplitude, separated by long periods of apnea. Seen with medullary or pontine lesions.
First described in patients with meningitis by Biot (in 1876), with breaths of nearly equal volume separated by periods of apnea. Biot breathing is also considered to be a variant of ataxic or cluster breathing.
In the 1930s, Gesell N32-5 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 the following reference:
Gesell R: Respiration and its adjustments. Annu Rev Physiol 1:185–216, 1939.
Not all neurons that fire in phase with the respiratory cycle are involved in control of breathing. For example, because they are located within the chest cavity, aortic baroreceptors (see p. 534 ) 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 (see pp. 700–701 ). Thus, not all RRNs (e.g., those stimulated by the aortic baroreceptors) play a direct role in respiration, and respiratory control involves more than just RRNs (e.g., chemoreceptor neurons).
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 controlling ventilation. 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.
The pons also contains RRNs. N32-4 Although, as discussed above, pontine neurons may not be needed to produce a normal respiratory rhythm, they can influence respiratory output.
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 p. 348 ). 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 (see Fig. 32-4 ). These NTS neurons, as well as some immediately adjacent neurons in the dorsal medulla, make up the DRG.
VRG | ||||
---|---|---|---|---|
PROPERTY | DRG | ROSTRAL | INTERMEDIATE | CAUDAL |
Location | Dorsal medulla | Midway between dorsal and ventral surfaces of medulla | ||
Major component | Nucleus tractus solitarii (NTS) | Nucleus retrofacialis (NRF) or Bötzinger complex (BötC) N32-8 | Pre-Bötzinger complex (preBötC), nucleus ambiguus (NA), and nucleus para-ambigualis (NPA) | Nucleus retroambigualis (NRA) |
Dominant activity | Inspiratory | Expiratory | Inspiratory | Expiratory |
eTable 32-2 is an expansion of Table 32-2 .
VRG | ||||
---|---|---|---|---|
PROPERTY | DRG | ROSTRAL | INTERMEDIATE | CAUDAL |
Location | Dorsal medulla | Midway between dorsal and ventral surfaces of medulla | ||
Major component | Nucleus tractus solitarii (NTS) | Nucleus retrofacialis (NRF) or Bötzinger complex (BötC) | Pre-Bötzinger complex (preBötC), nucleus ambiguus (NA), and nucleus para-ambigualis (NPA) | Nucleus retroambigualis (NRA) |
Dominant activity | Inspiratory | Expiratory | Inspiratory | Expiratory |
Major input | Sensory via CN IX and X | — | — | Rostral VRG |
Major output |
|
Interneurons → DRG and caudal VRG |
|
Premotor neurons→ spinal cord → accessory muscles of expiration |
|
|
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—via the glossopharyngeal (CN IX) and vagus (CN X) nerves—from peripheral chemoreceptors, as well as from receptors in the lungs and airways (see above). 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 (see Fig. 32-4 ). N32-6
For example, an interneuron in the DRG may synapse on a DRG premotor neuron, which, in turn, may descend into the spinal cord and reach one of the paired phrenic motor nuclei in the ventral horn of the spinal cord. There, the premotor neuron synapses on the cell bodies of phrenic motor neurons, whose axons follow the phrenic nerve to the diaphragm.
The ventral respiratory group (VRG) N32-7 contains both inspiratory and expiratory neurons (see 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 (see 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 via the DRG. Thus, the VRG plays more of an efferent role, whereas the DRG primarily plays an afferent role.
Aside from input from muscle spindle fibers (see p. 388 ), which provide feedback to pharyngeal and laryngeal motor neurons, the VRG does not receive any monosynaptic sensory input.
Within the nucleus retrofacialis is a region known as the Bötzinger complex. This region is the rostral VRG, which contains primarily expiratory interneurons projecting to other respiratory nuclei, including the caudal VRG.
Within and near the nucleus ambiguus and the nucleus para-ambigualis is the intermediate VRG. The majority of RRNs in the intermediate VRG are inspiratory . The nucleus ambiguus contains somatic motor neurons that leave the medulla via CN IX and X to supply the larynx and pharynx and prevent collapse of the upper airways during inspiration. In addition, this nucleus contains parasympathetic preganglionic neurons that supply airways in the lung and other structures via CN X. Finally, the nucleus ambiguus contains some motor neurons with respiration-related activity that send axons out the trigeminal nerve (CN V), presumably for opening the mouth; the facial nerve (CN VII), for flaring the nostrils; and the accessory nerve (CN XI), for activating other accessory muscles of respiration during strong inspirations.
The nucleus para-ambigualis surrounds the nucleus ambiguus and contains premotor neurons that project to inspiratory motor neurons in the spinal cord and interneurons that have local connections to other neurons of the medulla. Like some neurons in the DRG, the inspiratory premotor neurons in the nucleus para-ambigualis drive primary muscles of inspiration. However, unlike neurons in the DRG, the inspiratory premotor neurons in the nucleus para-ambigualis also drive accessory muscles.
The pre-Bötzinger complex (see p. 706 ) is in the rostral portion of the intermediate VRG. It is not yet well defined anatomically, but instead is defined by the electrophysiological properties of its component neurons, which continue to produce bursts of respiratory activity in brain slices. The anatomical location roughly corresponds to a region slightly ventral and lateral to the nucleus ambiguus just caudal to the Bötzinger complex. The pre-Bötzinger complex contains inspiratory neurons that include local interneurons and premotor neurons. There is evidence that this region may be the respiratory CPG.
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