Development of Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is common, affecting approximately 2–4% of middle-aged people in the USA (Young et al., 1993). In this disorder, the airway behind the tongue and soft palate collapse during sleep. This leads to a reduction in the level of oxygen in the blood, and an affected person must wake up briefly from sleep to reopen the airway. While the origin of this disorder is complex, most evidence suggests that patients with OSA have a smaller airway that predisposes them to collapse (Schwab et al., 1995). However, while they are awake, there are protective mechanisms that help to keep the airway open by increasing the activity of certain upper airway muscles. These muscles are called pharyngeal dilators. We believe that these protective mechanisms fail during sleep, which leads to collapse of the airway in those that are susceptible. Thus understanding the control of the upper airway muscles is paramount to understanding sleep apnea.

The human upper airway is a complex structure whose functions include breathing, speaking, and swallowing. The human upper airway is also able to move a fair bit and is quite flexible. Due to this fact, the airway depends on the activity of muscles for it to stay open. These muscles act to offset the negative (suction) pressure that develops when we inhale. The best-studied such muscle is the genioglossus (which makes up the bulk of the tongue).

The activity of the genioglossus is carefully controlled by a number of variables (Figure 1) including (a) the brain centers that drive breathing; (b) different levels of blood chemicals such as rising carbon dioxide or falling oxygen levels; and (c) a drive due to being awake called the "wakefulness drive." Finally, it appears that negative (suction) pressure in the airway is sensed and responded to. If either a rapid pulse of negative pressure is applied to the pharyngeal airway, or if breathing is made more difficult (increasing the amount of pressure generated) this leads to an immediate increase in activity of this muscle. In addition, if a person is placed in an iron-lung ventilator and the ventilator is turned up to generate high levels of negative pressure, genioglossal activity increases and remains proportional to the negative pressure generated by the iron-lung ventilator (Fogel et al., 2001).

This system thus provides a mechanism by which the airway muscles can respond on a moment-by-moment basis to changes. In the patient with OSA, who has a smaller upper airway, the genioglossus is more active during wakefulness than in healthy individuals, probably secondary to the reflex mechanisms outlined above. This increased activity helps keep the airway open while the apnea patient is awake.

However, sleep exerts a marked effect on these muscles. Studies suggest that during stable sleep the negative pressure reflex is substantially diminished (Wheatley et al., 1993). Furthermore if a person is placed in an iron-lung when they are asleep, and again turn the pressure up high, the genioglossus muscle is much less able to respond to this negative pressure asleep compared to wakefulness (Fogel et al., 2003). It is not known why this is the case.

However, we do know that almost all the brain chemical systems that are important in keeping us awake are also important in controlling the genioglossus and all lead to increased muscle activity. Thus, when these systems become less active during sleep, it is not surprising that muscle activity falls.

Thus it seems that the primary defect in obstructive sleep apnea is a small or collapsible pharyngeal airway. While awake, compensatory systems function to increase the activity of the dilator muscles, thus keeping the airway open, and the person can breathe without a problem.

However, this increased muscle activity is lost at sleep onset, and collapse of the upper airway occurs. The associated drop in oxygen and increased carbon dioxide ultimately lead to an arousal from sleep, thus reopening the airway and breathing resumes. Once the patient returns to sleep, the cycle begins again. The patient thus suffers the consequences of repeated sleep disruption as well as drops in oxygen level. As we learn more about the basic neural pathways that control upper airway muscle activity during wakefulness and sleep, we may be able to develop drug therapy for this important disorder.

Dr. Fogel is an Instructor in Medicine at the Harvard Medical School and an Associate Physician, Division of Sleep Medicine at Brigham and Women's Hospital. He is a 1999 NSF Pickwick Postdoctoral Fellow.