Inherent vs. Induced Loop Gain Abnormalities in Obstructive Sleep Apnea

Abstract

Unstable ventilatory chemoreflex control, quantified as loop gain, is recognized as one of four key pathophysiological traits that contribute to cause obstructive sleep apnea (OSA). Novel treatments aimed at reducing loop gain are being investigated, with the intention that future OSA treatment may be tailored to the individual's specific cause of apnea. However, few studies have evaluated loop gain in OSA and non-OSA controls and those that have provide little evidence to support an inherent abnormality in either overall chemical loop gain in OSA patients vs. non-OSA controls, or its components (controller and plant gain). However, intermittent hypoxia may induce high controller gain through neuroplastic changes to chemoreflex control, and may also decrease plant gain via oxidative stress induced inflammation and reduced lung function. The inherent difficulties and limitations with loop gain measurements are discussed and areas where further research are required are highlighted, as only by understanding the mechanisms underlying OSA are new therapeutic approaches likely to emerge in OSA.

Children with Upper Airway Dysfunction: At Risk of Obstructive Sleep Apnea

“…46,47 Loop gain has been shown to have a causal relationship with OSA, complementing the theory that OSA has both structural and functional components of the upper airways that need to be considered during the clinical evaluation and treatment. [47][48][49] Finally, another pathological disturbance that decreases the nervous system from compensating for hypoxia or airway obstruction is reduced arousal threshold, leading to premature termination of the obstructive events, which impedes the central ventilatory drive from acting on the upper airway, reducing stable breathing during sleep. 50…”

The Role of Animal Models in Developing Pharmacotherapy for Obstructive Sleep Apnea

“…During wakefulness, breathing is regulated by both conscious respiratory drive from supra-pontine brain structures, and autonomic chemoreflex control [99]. During sleep, respiratory drive is mainly governed by chemoreflexes, with the fluctuations in CO 2 levels representing the major stimulus to breathe [11,99]. The magnitude of the ventilatory response to CO 2 during sleep can drive oscillations in breathing, leading to arousals during respiratory disturbances [11].…”

“…The magnitude of the ventilatory response to CO 2 during sleep can drive oscillations in breathing, leading to arousals during respiratory disturbances [11]. "Loop gain" (an engineering concept) describes the amplitude of ventilation in response to a disturbance, as might occur with obstruction of the upper airway [99]. There are two major components that regulate loop gain: (1) A controller gain and (2) plant gain [100].…”

“…However, it is still unclear if (1) OSA patients have a higher loop gain compared to non-OSA individuals and (2) whether a high loop gain is inherent to OSA or is induced by OSA traits. As extensively reviewed by Deacon-Diaz and Malhotra [99], the findings comparing loop gain between OSA and non-OSA patients are still contradictory. However, evidence from studies controlling for key confounding factors (i.e., obesity and CPAP status) have suggested a higher loop gain in apneic individuals [104].…”

“…The sustained increase in ventilatory neural activity induced by intermittent hypoxia that persists after hypoxic stimulation has been termed long-term facilitation (LTF). LTF reduces CO 2 levels below eupnea, leading to an increase in the controller gain [99,[109][110][111]. Prabhakar's laboratory has examined LTF and its contribution the development of an OSA phenotype in rodents.…”