Rhythmic neural impulses responsible for ventilation originate in the medulla oblongata of the brainstem (Figure 11-1). Animal experiments show that transection of the brainstem just below the medulla (see level IV, Figure 11-1) stops all ventilatory activity. However, rhythmic breathing continues after the brainstem is transected just above the pons (see level I, Figure 11-1).

Figure 11-1 Dorsal view of the brainstem. Phases I to IV refer to transections at different levels.

Physiologists previously thought that separate inspiratory and expiratory neuron “centers” in the medulla were responsible for the cyclical pattern of breathing. It was believed that inspiratory and expiratory neurons fired by self-excitation and that they mutually inhibited one another. It is now known that inspiratory and expiratory neurons are anatomically intermingled and do not necessarily inhibit one another.¹ These neurons are widely dispersed in the medulla; the dorsal respiratory groups (DRG) contain mainly inspiratory neurons, whereas the ventral respiratory groups (VRG) contain intermingled inspiratory and expiratory neurons.

As shown in Figure 11-1, the DRG consist of mainly inspiratory neurons located bilaterally in an area called the nucleus of the tractus solitarius. These neurons send impulses to the phrenic and external intercostal motor nerves in the spinal cord, providing the main stimulus for inspiration.¹ Many DRG nerves extend into the VRG, but few VRG fibers extend into the DRG. Thus, reciprocal inhibition is an unlikely explanation for rhythmic, spontaneous breathing.¹ The DRG consists of two neuron populations, one of which is inhibited by deep lung inflation (causing cessation of inspiratory effort), whereas the other is excited by lung inflation (causing continued inspiratory effort).¹ These neurons are involved in the Hering-Breuer and Head’s reflexes described later in this chapter.

The vagus and glossopharyngeal nerves transmit many sensory impulses to the DRG from the lungs, airways, peripheral chemoreceptors, and joint proprioceptors. These impulses modify the basic breathing pattern generated in the medulla.

Ventral Respiratory Groups

VRG neurons are located bilaterally in the medulla in two separate nuclei that contain both inspiratory and expiratory neurons (see Figure 11-1). Some inspiratory VRG neurons send motor impulses through the vagus nerve to the laryngeal and pharyngeal muscles, abducting the vocal cords and increasing the diameter of the glottis. Other VRG inspiratory neurons transmit impulses to the diaphragm and external intercostal muscles. Still other VRG neurons have mostly expiratory discharge patterns and send impulses to the internal intercostal and abdominal expiratory muscles. The most rostral (toward the head) part of the VRG, Bötzinger’s complex (see Figure 11-1), contains the only expiratory neurons known to inhibit the inspiratory VRG and DRG impulses.²

CLINICAL FOCUS 11-1 Use of Dorsal Respiratory Group Neural Impulses to Trigger Mechanical Ventilation: Neurally Adjusted Ventilatory Assist

Critically ill patients in hospital intensive care units often cannot breathe adequately on their own and require mechanical ventilation. The electrical impulses of the DRG neurons can be used to adjust the mechanical ventilator’s inspiratory gas flow to meet the patient’s inspiratory demands precisely. One challenge of mechanical ventilation is to ensure that the patient and the ventilator are in synchrony, such that the ventilator senses the patient’s slightest inspiratory effort and immediately provides gas flow to the patient in an amount proportional to the inspiratory effort.

Neurally adjusted ventilatory assist (NAVA) is a mode that accomplishes this task by measuring the diaphragm’s electrical activity in response to phrenic nerve impulses; this kind of measurement is called electromyography (EMG). A specially designed thin tube (nasogastric tube) with a series of EMG electrodes at one end is inserted into the patient’s esophagus by way of the nasal cavity and advanced until the electrodes are adjacent to the diaphragm. When the patient wants to take a breath, electrical impulses from the medulla’s DRG neurons travel down the phrenic nerves to the diaphragm causing it to contract, which produces an electrical current proportional to the level of muscle activity. The nasogastric tube’s EMG electrodes sense the electrical current and transmit this information to the ventilator’s microprocessor, which instructs the ventilator to generate an inspiratory gas flow rate that is proportional to the signal strength. Through the ventilator’s control panel, the clinician can set how much pressure the ventilator applies to the patient’s airway for each millivolt of EMG activity. The ventilator assists the patient’s inspiratory efforts in a way that is precisely matched to the EMG signal strength—that is, proportional to the patient’s inspiratory effort. The greater the inspiratory effort, the more pressure the ventilator applies; with less effort, the less pressure is applied. In theory, NAVA should provide the patient with a more natural and comfortable mode of mechanical ventilation because it recognizes the inspiratory signal high up in the neural pathway that controls breathing.¹⁴

Respiratory Rhythm Generation

The exact origin of the basic rhythmic pattern of breathing is unknown; no single group of pacemaker cells have been identified. The Bötzinger complex and a structure located between it and the VRG, the pre-Bötzinger complex, are thought to be responsible for rhythmic breathing.² Two predominant theories of rhythm generation are the pacemaker hypothesis and the network hypothesis. The pacemaker hypothesis holds that certain medullary cells have intrinsic pacemaker properties—that is, rhythmic self-exciting characteristics—and that these cells drive other medullary neurons. The network hypothesis suggests that rhythmic breathing is the result of a particular pattern of interconnections between neurons dispersed throughout the rostral VRG, the pre-Bötzinger complex, and the Bötzinger complex. This hypothesis assumes that certain populations of inspiratory and expiratory neurons inhibit one another and that one of the neuron types fires in a self-limiting way, such that it becomes less responsive the longer it fires. There is no definitive proof of either hypothesis; the precise origin of respiratory rhythm generation remains elusive.

Inspiratory Ramp Signal

The dorsal and ventral inspiratory neurons do not send an abrupt burst of impulses to the inspiratory muscles; instead, their firing rate increases gradually after expiration ceases, creating a smoothly increasing ramp signal (Figure 11-2). This ramp signal leads to a progressively stronger contraction of inspiratory muscles, smoothly and gradually inflating the lungs instead of filling them in an abrupt inspiratory gasp. During exercise, various peripheral reflexes and receptors influence the medullary neurons, steepening the inspiratory ramp signal and filling the lungs more rapidly.

As the inspiratory ramp signal strengthens, inhibitory neurons begin to fire with increasing frequency.² After approximately 2 seconds, these restraining impulses become strong enough to switch off the inspiratory signal abruptly. Expiration proceeds for about 3 seconds.³ As expiration begins, inspiratory neurons fire briefly, “braking” the early phase of expiration by maintaining some inspiratory muscle tone (see Figure 11-2). Inspiratory neuronal activity completely stops in the last phase of expiration. The inhibitory neurons that switch off the inspiratory ramp arise from the pneumotaxic center and pulmonary stretch receptors, which are discussed in the next section.

CONCEPT QUESTION 11-1

What effect does the lack of pneumotaxic and stretch receptor neurons have on ventilation?

Pontine Centers

If the brainstem is transected above the medulla (see Figure 11-1, level III), spontaneous respiration continues, although in a more irregular pattern; thus, the pons promotes rhythmic breathing by modifying the output of the medullary centers. Figure 11-1 shows two groups of neurons in the pons: (1) the apneustic center and (2) the pneumotaxic center.

Apneustic and Pneumotaxic Centers

The two respiratory centers in the pons (apneustic and pneumotaxic) have been identified through animal brain transection experiments. If the brainstem is severed at the midpons level (see Figure 11-1, level II), and the vagus nerves connecting this area with the lower parts of the brain and spinal cord are also cut, a breathing pattern called apneusis results (Figure 11-3). Apneusis consists of prolonged inspiratory gasps interrupted by occasional expirations. The apneustic center is thought to be in a region in the lower pons, but it has never been anatomically identified with certainty.² Its existence and function can be demonstrated only if its connections to the higher pneumotaxic center are severed and the vagus nerves are cut. Under these circumstances, the area in the lower pons (i.e., the apneustic center) sends signals to the DRG neurons, preventing the inspiratory ramp signal from being switched off.³ Apparently, vagal and pneumotaxic center impulses hold the apneustic center’s stimulatory effect on DRG neurons in check because apneusis does not occur if the vagus is left intact (see Figure 11-3).

Figure 11-3 Breathing patterns produced by transections of the brainstem at different levels. These levels correspond with phases I to IV shown in Figure 11-1. (From Berne RM, Levy MN: *Principles of physiology,* ed 2, St Louis, 1996, Mosby.)

The pneumotaxic centers are bilateral groups of neurons in the upper pons (see Figure 11-1). These centers control the off-switch point of the DRG’s inspiratory ramp signal, sending inhibitory impulses to medullary inspiratory neurons; thus, pneumotaxic signals control the length of inspiration. Strong pneumotaxic signals shorten the inspiratory time and increase the respiratory rate. Weak signals produce prolonged inspiration and large tidal volumes. The primary function of the pneumotaxic center is to limit inspiration and hold apneustic center impulses in check. The exact nature of the interaction between the apneustic and pneumotaxic centers remains poorly understood; they apparently work together to control the depth of inspiration.³ The effect of the pontine centers on the lower medullary centers seems to be fine-tuning the respiratory pattern because the transection of the brainstem between the pons and medulla (see Figures 11-1, level III, and 11-3) results in an irregular breathing pattern.¹

Reflex Control of Breathing

The central ventilatory drive arising from the medulla is modified by various inputs from peripheral sensors. These sensors are located in the lungs, muscles, and joints.

Hering-Breuer Inflation Reflex

The Hering-Breuer inflation reflex, described by Hering and Breuer in 1868, is generated by stretch receptors located in smooth muscle of large and small airways. These receptors are called slowly adapting receptors because their activity continues as long as the stimulus persists (see Chapter 2). When stretched, these receptors send inhibitory impulses through the vagus nerve to the DRG neurons, stopping further inspiration. Thus, the Hering-Breuer reflex has an effect similar to that of the pneumotaxic center.³ The Hering-Breuer reflex in adults is activated only at large tidal volumes (≥800 to 1000 mL) and is apparently not an important control mechanism in quiet breathing. However, this reflex is important in regulating the respiratory rate and depth during moderate to strenuous exercise.²

Diseases associated with low lung compliance (i.e., strong elastic retractive forces) may stimulate the inflation stretch receptors by increasing the mechanical stress acting on the airways during inspiratory efforts.² This stimulation tends to increase the respiratory rate because it sends an early inhibitory signal, shortening the inspiratory phase.

Various combinations of respiratory rate and tidal volume can produce the level of ventilation needed to meet metabolic gas exchange demands, but there is always a specific combination that results in the least work. The information stretch receptors send to the medullary centers, which can be consciously sensed, probably helps to establish this optimal combination. The sensation of dyspnea is thought to be produced when the medullary centers demand a level of ventilation greater than the actual ventilation achieved.²

J-Receptors

C-fibers in the lung parenchyma near pulmonary capillaries are called juxtacapillary receptors, or J-receptors (see Chapter 1). They are stimulated by alveolar inflammatory processes (pneumonia), pulmonary vascular congestion (congestive heart failure), and edema. J-receptor stimulation causes rapid, shallow breathing; a sensation of dyspnea; and expiratory narrowing of the glottis. Expiratory narrowing of the glottis causes grunting on expiration, especially in infants.

Peripheral Proprioceptors

Proprioceptors (positional sensors) in muscles, tendons, and joints, and pain receptors in muscles and skin send stimulatory impulses to the medullary centers, increasing inspiratory activity and hyperpnea.² For this reason, moving the limbs, slapping the skin, and other painful stimuli stimulate ventilation in patients who have respiratory depression. Splashing cold water on the skin has a similar effect.

Proprioceptors in joints and tendons may be important in initiating and maintaining increased ventilation at the beginning of exercise. Passive limb movement around a joint increases the breathing rate in anesthetized animals and unanesthetized humans.³

Muscle Spindles

Muscle spindles in the diaphragm and intercostal muscles are part of a reflex arc that helps the muscles adjust to an increased load. Muscle spindles are stretch-sensing elements located on intrafusal muscle fibers, which are arranged in parallel with the main extrafusal muscle fibers (Figure 11-4). The extrafusal skeletal muscle fibers that elevate the ribs (see Figure 11-4) are innervated by different motor fibers (alpha motor fibers) than the intrafusal spindle fibers (gamma motor fibers). As the main extrafusal muscle fiber and the intrafusal fibers contract together in parallel, the spindle-sensing element stretches and sends impulses over spindle afferent nerves directly to the spinal cord (see Figure 11-4). The number of impulses sent is proportional to the spindle’s stretch. The spindle’s afferent (sensory) nerve synapses directly with the same alpha motor neuron in the spinal cord that sends motor impulses back to the main extrafusal muscle fiber; this creates a single synapse reflex arc. When stimulated by the spindle’s afferent nerve signal, the alpha motor neuron sends signals to only the main extrafusal muscle fibers, causing them to contract with greater force, which unloads and shortens the adjacent intrafusal muscle fibers. As a result, the stretch-sensitive spindle is unloaded, and its impulses cease. In this way, inspiratory muscle force automatically adjusts to the load imposed by decreased lung compliance or increased airway resistance.