PATTERN OF MOTOR OUTFLOW TO THE INSPIRATORY MUSCLES

The firing of the bulbospinal inspiratory neurons projecting to the diaphragm and intercostal muscles increases progressively throughout inspiration and is terminated abruptly (off-switching). The ramplike increase in activity of these bulbospinal neurons (the central inspiratory activity) causes a progressive increase in excitation of the inspiratory muscles and hence their force of contraction (Fig. 2). The electrical and mechanical analogues of central inspiratory activity are, respectively, the integrated activity of the phrenic neurogram and diaphragmatic electromyogram (EMG) and the pleural pressure waveform. The progressively augmenting shape of central inspiratory activity allows the inspiratory musculature to overcome the progressive increase in elastic recoil of the lung during inspiration despite progressive shortening and a decrease in the intrinsic ability of the inspiratory muscles to generate force (i.e., the length-tension relationship).

FIG. 2. Effect of hypercapnia on the duration of the phrenic nerve electrical activity integrated as a moving time average and its rate of increase and the pleural pressure waveform. Note the similarity in shape of the integrated phrenic neurogram and the pleural pressure tracing. Following bilateral vagotomy, the duration of inspiration remains relatively constant despite the progressive increase in PCO2.

Control of the rate of rise in central inspiratory activity and hence the rate of lung inflation differs from control of inspiratory off-switching. Both chemical (e.g., hypoxia and hypercapnia) and nonchemical (e.g., thermal and mechanoreceptor afferents) inputs affect the steepness of the ramp of central inspiratory activity. On the other hand, the timing of inspiratory off-switching depends largely on inputs from pulmonary stretch receptors and from higher CNS structures, such as the NPBM and the KFN.

In anesthetized animals, phasic increases in lung volume resulting from the ramp of central inspiratory activity progressively increase pulmonary stretch-receptor activity. Integration of inputs from pulmonary stretch receptors and projections reflecting the intensity of the central inspiratory activity by as yet incompletely described pools of neurons terminates inspiration. Vagotomy eliminates stretch-receptor input, prolonging inspiration and increasing tidal volume, but the rate of rise in central inspiratory activity and hence the rate of inspiratory air flow are virtually unchanged. On the other hand, hypoxia and hypercapnia increase the steepness of the ramp of inspiratory activity and hence increase the rate of inspiratory air flow and tidal volume, but they have little effect on the duration of inspiration and frequency of breathing.

When the vagus is intact, so that respiratory neurons receive input from the stretch receptors as well as inputs reflecting central inspiratory activity, the duration of inspiration is reduced, because the inspiratory off-switch is activated earlier. Because central inspiratory activity increases with time, more stretch-receptor input (i.e., a greater change in lung volume) is needed early in inspiration to terminate a breath. This accounts for the curvilinear relationship between tidal volume (Vt) and inspiratory time (tinsp) that has been noted in studies of anesthetized animals (Fig. 3).

FIG. 3. Effect of lung volume information in determining off-switch and, hence, tinsp. Vagal input allows the off-switch threshold to be reached earlier in inspiration. The numbers refer to the PCO2 with the vagi intact. Inspiratory time declines and tidal volume rises with increasing hypercapnia. Without lung volume information (vagotomy), tinsp is fixed.

Consistent with these observations is the idea that ventilatory responses to hypercapnia and hypoxia depend on the sensitivity of both stretch receptors and chemoreceptors. Chemoreceptor sensitivity, because it influences the rate of increase in central inspiratory activity, is more closely related to the average level of air flow during inspiration than to minute ventilation. That is, the change in the ratio of tidal volume to inspiratory time, rather than the change in ventilation itself, most closely reflects chemical drive. On the other hand, the change in inspiratory time as a fraction of total breath duration indicates the activity of stretch receptors.

Although ventilation is conventionally thought to be equal to tidal volume times frequency (f), the concept of central respiratory neuronal organization suggests that ventilation should more realistically be considered to be the product of the following:

where tinsp is inspiratory time and texp is expiratory time.

Some studies in humans have tried to separate neural and chemical responses to hypoxia and hypercapnia by analyzing ventilatory responses with this approach. In some cases, depressed ventilatory responses to CO2 seem to be caused by altered mechanoreceptor function rather than by depressed chemosensitivity.

It is important to remember that this concept originated from experiments carried out in anesthetized animals and accordingly does not include the effects on breathing of inputs eliminated by anesthesia. These additional inputs, occurring during both wakefulness and sleep, may greatly distort the basic relationships between the medullary respiratory neurons observed in animals during anesthesia. Thus, in awake humans, increases in breathing frequency produced by hypercapnia and hypoxia are associated mainly with a shortening of expiratory time, whereas inspiratory time remains relatively constant. Rapid-eye-movement (REM) sleep is associated with an irregular breathing pattern and seems to eliminate ventilatory increases to hypercapnia, but not to hypoxia. In non-REM sleep, breathing is more regular, but responses to changes in CO2 remain lower than during wakefulness.

Even in anesthetized animals, influences from thermal and circulatory receptors can affect breathing. For example, temperature increases accelerate the frequency of breathing without changing tidal volume.