Pushing and pulling with no end in sight! The role of cross‐talk between different forms of respiratory plasticity in modifying sleep apnoea

Abstract

Therapeutic exposure to intermittent hypoxia leads to long-term facilitation (LTF) of diaphragm and upper airway muscle activity, resulting in sustained increases in minute ventilation and improved upper airway stability (Mateika & Narwani 2009). These findings led to the hypothesis that exposure to intermittent hypoxia, which accompanies hypopnoeic or apnoeic events during sleep, could initiate LTF of chest wall (e.g. diaphragm and inspiratory intercostal muscles) and upper airway muscle activity. Initiation of LTF could serve to stabilize breathing and the upper airway, leading to reductions in breathing events across the night or life-span (Mateika and Narwani 2009). However, there is little support for this hypothesis, since many studies conducted over decades have reported that the severity of sleep apnoea increases from the evening to the early morning. The prevailing hypothesis is that LTF does not typically manifest itself in individuals with sleep apnoea because of the withdrawal of chemoreceptor input (Harris et al. 2006). This withdrawal is induced by the presence of hypocapnia that occurs in response to hyperventilation that is elicited when emerging from apnoeic events. However, there are other possibilities that could explain the ineffectiveness of respiratory plasticity in mitigating apnoeic events during sleep. Along these lines, in an article in this issue of The Journal of Physiology, Fields and colleagues (2019) explored if initiation of competing forms of plasticity, induced by repetitive apnoea, prevents the induction of sustained increases in phrenic nerve activity. In addition to LTF induced by intermittent hypoxia, recurrent reductions in respiratory neural activity initiate another form of plasticity, known as inactivity-induced inspiratory motor facilitation (iMF) (Streeter & Baker-Herman, 2014a). iMF is robustly expressed in phrenic, inspiratory intercostal and hypoglossal motor pools. Given that central sleep apnoea is characterized by periods of reduced or inactive motor activity, and mixed apnoeic events are characterized by motor inactivity at the onset of an event, the authors proposed that iMF may be initiated during sleep (Fields et al. 2019). Given that hypoxia typically accompanies motor inactivity, two forms of respiratory plasticity could theoretically be initiated in response to apnoeic events. However, there is little evidence in humans that compensatory breathing adaptations clearly manifest (Mateika & Narwani 2009). Thus, Fields et al. (2019) hypothesized that the simultaneous initiation of LTF and iMF prevents the expression of compensatory modifications. To test the hypothesis, a series of clever experiments using anaesthetized, neuromuscularly blocked, vagotomized and ventilated rats were employed (Fields et al. 2019). In one set of experiments, LTF of phrenic nerve activity was initiated by intermittent hypoxia, which was induced by ceasing mechanical ventilation five times for 25 s. In another series of experiments, iMF was initiated by eliminating motor activity by decreasing carbon dioxide levels five times for 25 s. Thereafter, the two perturbations were combined (i.e. carbon dioxide was reduced in the absence of mechanical ventilation). Although the separate stimuli initiated the two forms of plasticity as expected, there was no evidence of compensatory mechanisms when the two stimuli were combined (Fields et al. 2019). This observation is exciting and is tied in with our previous hypothesis, which suggested that increases in carbon dioxide levels are required for the manifestation of LTF (Harris et al. 2006). In other words, if hypocapnia reduces or eliminates respiratory motor activity during sleep, then iMF may be initiated concurrently with LTF leading to occlusion of compensatory mechanisms that mitigate apnoea severity (Fields et al. 2019). Fields and colleagues (2019) went a step further to explore the mechanistic underpinning of the interaction between LTF and iMF. Based on previous work (Streeter & Baker-Herman 2014b), they hypothesized that NMDA receptor activation could be responsible for the absence of compensatory breathing adaptations in individuals with sleep apnoea. This hypothesis was based on the understanding that spinal NMDA receptor activation is necessary for the induction and maintenance of LTF, but constrains iMF expression (Streeter & Baker-Herman 2014b). This possibility was supported by their findings that showed that administration of an NMDA receptor antagonist prevented the initiation of LTF and led to sustained increases in phrenic activity when intermittent hypoxia and respiratory motor inactivity were combined (Fields et al. 2019). Given these findings, the application of NMDA receptor antagonists could serve as a pharmacological intervention for sleep apnoea. However, Fields and colleagues (2019) recognized that the use of NMDA antagonists may not be useful therapeutically because of accompanying psychotropic side effects. Thus, the role of retinoic acid in promoting the initiation of compensatory responses following exposure to intermittent hypoxia and respiratory motor inactivity was explored (Fields et al. 2019). The inhibition of retinoic acid synthesis prevented iMF but had no effect on LTF (Fields et al. 2019). They also showed that the application of retinoic acid resulted in the manifestation of compensatory responses following intermittent motor inactivity combined with intermittent hypoxia (Fields et al. 2019). Thus, retinoic acid could serve as a therapeutic intervention to allow for the manifestation of compensatory forms of plasticity that might ultimately contribute to reducing the severity of sleep apnoea. Overall, Fields and colleagues (2019) have set the stage to explore if iMF is initiated in humans with sleep apnoea, which would complement our work that has shown that LTF can be initiated in men and women during wakefulness and sleep