The Respiratory Generator

Considering the importance of the respiratory generator in this scheme of respiratory control, its anatomy and mode of action are described here. Much of the work clarifying the location of the respiratory generator involved animal experiments with transections at various levels of the CNS and assessment of the effects on ventilation. Because transection between the brain and brainstem does not significantly alter ventilation, the generator apparently resides somewhere at the level of the brainstem or lower and does not require interaction with higher cortical centers. When transections are made at various points within the brainstem, the breathing pattern is substantially altered, but ventilation is not eliminated. Only when a transection is made between the medulla and the spinal cord does ventilation cease, indicating that the respiratory generator resides within the medulla.

Although the respiratory center (or generator) has been referred to as a single region, it appears that more than one network of neurons within the medulla is involved in initiating and coordinating respiratory activity. According to a popular model, one group of neurons is responsible for initiating inspiration and regulating its speed as a result of the intensity of neuronal activity; another group of neurons controls “switching off” inspiration and hence determines the onset of expiration.

Therefore, there are two aspects of ventilatory control: (1) the degree of inspiratory drive or central inspiratory activity (which regulates the inspiratory flow rate), and (2) the timing mechanism (which controls the termination of inspiration). These two determining factors act in concert to set the respiratory rate and tidal volume and thus the minute ventilation and specific pattern of breathing.

Input from Other Regions of the Central Nervous System

Even though the medullary respiratory center does not require additional input to drive ventilation, it does receive other information that contributes to a regular pattern of breathing and more precise ventilatory control. For example, input from the pons appears to be necessary for a normal, coordinated breathing pattern. When the influence of the pons is lost, irregularities in the breathing pattern ensue.

In addition to pathways involved in the “automatic” or involuntary control of ventilation, the cerebral cortex exerts a conscious or voluntary control over ventilation. Cortical overriding of automatic control can be seen with either voluntary breath holding or hyperventilation. Its usefulness is readily apparent in a person’s need for voluntary control of breathing during such activities as speaking, eating, and swimming. Interestingly, the automatic control of ventilation may be disturbed while conscious control remains intact. In these cases, during wakefulness the cerebral cortex exerts sufficient voluntary control over ventilation to maintain normal arterial blood gas values. During periods when the patient is dependent on automatic ventilatory control (e.g., during sleep), marked hypoventilation or apnea may occur. This rare condition, called congenital central hypoventilation syndrome, has also been known as Ondine’s curse, after a mythologic tale in which the suitor of Neptune’s daughter was cursed to lose automatic control over all bodily functions when he fell asleep. Defects in the PHOX2b gene mapped to chromosome 4p12 have been identified in most cases. PHOX2b encodes a highly conserved domain for transcription factors important in neural development. Further research into the pathogenesis of this condition undoubtedly will lead to better understanding of the mechanisms of normal ventilatory control.

Chemoreceptors

Maintenance of arterial blood gases is the ultimate goal of ventilatory control, and an important feedback loop adjusts respiratory center output if blood gases are not maintained at the appropriate level (see Fig. 17-1). Elevation of PCO₂ (hypercapnia) and depression of PO₂ (hypoxemia) both are capable of stimulating ventilation. In each case, one or more chemoreceptors detect alterations in PCO₂ or PO₂ and accordingly vary their input to the medullary respiratory center.

The primary sensor for CO₂ is located near the ventrolateral surface of the medulla and is called the central chemoreceptor. Even though it is located in the medulla, the central chemoreceptor is clearly separate from the medullary respiratory center and should not be confused with it. The central chemoreceptor does not appear to respond directly to blood PCO₂ but rather to the pH of the extracellular fluid (ECF) surrounding the chemoreceptor. The pH level, in turn, is determined by the level of hydrogen (H⁺) and bicarbonate (HCO₃⁻) ions as well as PCO₂ (see Appendix C for further discussion). The blood-brain barrier, the permeability properties of which influence the composition of cerebrospinal fluid (CSF) and brain ECF, prevents free movement of either H⁺ or HCO₃⁻ from blood to brain ECF, whereas CO₂ passes freely. The feedback loop for changes in PCO₂ can be summarized as follows: