With regard to OSA the modulatory mechanisms

during REM sleep could indeed explain not only decreased activation of the respiratory network but also a decrease in airway tone (Remmers et al., 1978 and Sauerland and Harper, 1976). Yet either mechanism can only partly explain how decreased XII motoneuronal activation predisposes the upper airways to a pharyngeal collapse. Thus, it remains uncertain how the apneas themselves are generated. Indeed, the possibility that modulators are causing the decreased tone but not the apnea itself is consistent check details with the well-known inefficiency of aminergic therapies that have largely failed to alleviate OSA (Dempsey et al., 2010 and Funk et al., 2011). Moreover, noradrenergic and serotonergic innervation is

strengthened following exposure to chronic intermittent hypoxia which may oppose the decreased muscle tone during sleep (Rukhadze et al., 2010), and OSA patients show a variety of neurogenic changes in the upper airways that could potentially compensate for decreased muscle tone. These adaptations include increased activation, earlier firing, and increased sprouting of the XII motoneurons (Saboisky Alisertib supplier et al., 2007 and Saboisky et al., 2012). As illustrated in Fig. 2 there is not a general suppression of the upper airways, but instead the airflow is “suddenly” disturbed for a few cycles and then the oral-nasal flow reappears and re-synchronizes with the respiratory abdominal muscles. Thus, ROS1 while a persistently decreased drive to the XII motoneurons may predispose the pharynx to sudden collapse, the sudden failure in XII motor activity cannot be entirely explained by altered modulatory tone generating persistent atonia during a specific sleep state. As illustrated in Fig. 2, genioglossus EMG activity is specifically weakened and less phasic during the airway occlusion but not before or after the occlusion. Thus, in addition to a neuromodulator- and transmitter-driven decrease in muscle tone, one needs to consider additional central nervous and reflex mechanisms that

contribute to the disconnect between the ongoing phasic respiratory activity that drives the diaphragmatic activity and the decrease in phasic respiratory drive to the XII motoneurons which is specifically associated with the airway occlusion. In OSA, airway occlusion also involves reflex mechanisms (Fig. 1) that are characterized by pathological gain changes in the mechano- and chemosensory reflex loops regulating ventilation. These reflex pathways become specifically dysregulated during sleep and could therefore destabilize the respiratory response to an airway obstruction resulting in pharyngeal collapse during sleep and not wakefulness (Douglas et al., 1982 and White, 2005). To prevent pharyngeal collapse, mechanoreceptors located within the pharyngeal walls specifically regulate the XII motoneurons (Fig. 1).