Medical Physiology, 3rd Edition

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 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. imageN32-1 Thus, despite our common tendency to ignore breathing, control of ventilation is one of the most important of all brain functions.

Box 32-1


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 image falls or image 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 image and image. For example, increased airway resistance can cause dyspnea, even if arterial blood gas levels do not change. Exercise also causes dyspnea, even though image is usually normal and image 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 image. The central neural mechanisms and pathways responsible for dyspnea are unknown, although many of the forebrain regions involved have been identified.


Brain Death

Contributed by George Richerson

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 imageimage, 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. 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).


FIGURE 32-1 Control of ventilation.

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).

TABLE 32-1

Innervation of the Primary and Some Secondary Muscles of Respiration




Primary Muscles of Inspiration


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


Hypoglossal nerve (CN XII)

Hypoglossal motor nucleus

Sternocleidomastoid and trapezius muscles

Accessory nerve (CN XI)

Spinal accessory nucleus, C1–C5


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).

Peripheral and central chemoreceptors—which sense imageimage, and pH—drive the CPG

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—O2, CO2, 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 image, although high image 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 image and—much more slowly—decreases in arterial pH, but not arterial image. 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 imageimage, and pH (see Fig. 32-1).

Other receptors as well as higher brain centers also modulate ventilation

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.