Sleep fragmentation and hypoxias a cause of depression.

The two major pathological events that occur in association in OSA with upper airway obstruction are: (1) fragmentation of normal sleep because of ‘micro-arousals’ occurring due to recurrent apneas and hypopneas leading to (2) recurrent, intermittent hypoxemia causing diminished saturation of oxyhemoglobin. These then lead to reduced daytime wakefulness, impaired cognitive function and low mood. Sleep fragmentation has been hypothesized as the principal cause of excessive daytime sleepiness (EDS) in OSA and patients with EDS and OSA are more likely to be depressed than patients with OSA without EDS [32].

Animal studies suggest that recurrent, intermittent hypoxemia, a central feature of OSA, is associated with a dose-dependent cell loss in the areas rich in noradrenergic and dopaminergic pathways important for both sleep/wake and mood regulation including the hippocampus and cortex. Concomitant depression can worsen neuronal injury accompanying OSA. Effective treatment of OSA with continuous positive airway pressure (CPAP) treatment leads to neuronal regeneration evidenced by gray matter volume increase in the hippocampus and frontal cortex volume [33]. This results in improvement in memory, attention and executive functions. Antidepressants have been shown to cause similar effects (increase in hippocampus volume via neurogenesis) [34].

Obstructive sleep apnea is associated with elevated levels of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF). It has been hypothesized that these compounds are mediators of daytime sleepiness since administration of a tumor necrosis factor antagonist has been shown to dramatically reduce the level of daytime sleepiness in patients with OSA [35].

A vast body of literature has also documented the close association between major depression and the inflammatory immune response involving the proinflammatory cytokines IL-1, IL-6 and interferon [36]. While none of the studies are confirmatory for causation, they do suggest shared pathways between these conditions.

Further, obesity, particularly visceral obesity (a known risk factor for OSA), is also associated with an elevation in these cytokines [37].

Patients with OSA while awake are able to ‘prop open’ the upper airway through activation of the upper airway dilator muscles; when asleep, however, the neurochemical ‘tonic’ stimulation to upper airway motoneurons is lost as is muscle tone, resulting in pharyngeal collapse [38]. Abnormalities in central and peripheral neurotransmission of Serotonin have been implicated as a potential cause of major depression. It is now established that during wakefulness Serotonin, most probably acting through 5-HT2A receptors, provides a tonic excitatory input to hypoglossal motor neurons innervating the genioglossus and other upper airway dilating muscles. It is hypothesized that withdrawal of this serotonergic input during sleep might predispose to airway obstruction in the form of apnea or hypopnea [38, 39]. If we conceptualize a central pathology in OSA as easy upper airway collapsibility during sleep, then anything decreasing the activation of upper airway dilator muscles during sleep can potentially cause the disorder. The activation of Serotonin receptors innervating the genioglossus and other upper airway dilator muscles, particularly 5-HT2A receptors, is excitatory. The release of Serotonin from the raphe neurons steadily declines with the transition from wakefulness to NREM sleep and is minimal during REM sleep. Thus, loss of ‘tonic’ serotonergic activity is one potential basis for the reduced upper airway muscle activation and increased collapsibility of the upper airway characteristic of OSA [38, 39]. However, this pathway is extremely complex, with multiple receptor subtypes, and there may be other pathways shared with other neurotransmitters.

Norepinephrine has several similarities with Serotonin as a neuromodulator of motoneuronal function although studies suggest that its role is complementary [38]. Hypoxia secondary to OSA also alters motoneuronal and extracellular levels of the purines Adenosine and ATP, specifically reducing ATP and increasing Adenosine. Adenosine injected into the hypoglossal nucleus suppresses hypoglossal motoneuronal activity. This association needs to be explored further [38].

A similar inhibition of hypoglossal nerve activity is observed with Acetylcholine (ACh) which targets two specific groups of receptors: muscarinic and nicotinic. Activation of the muscarinic receptors inhibits hypoglossal and can be blocked with atropine, a muscarinic antagonist. This likely occurs via presynaptic suppression of glutamate release. ACh also causes excitation through activation of nicotinic receptors that is masked by the overwhelming muscarinic effect [38].

In addition GABA and glycine are the primary inhibitory neurotransmitters acting at these areas. Glycine plays an essential role in REM sleep postural atonia. However, the actions of these neurotransmitters on hypoglossal muscles are still under debate [38]. In one study, strychnine, a glycine antagonist, completely abolished apneas and regulated ventilator effort in OSA [40].

Hypocretin (orexin-A) increases electromyographic activity in the genioglossus muscle and reductions in orexin in upper airway motor nuclei in NREM sleep could contribute to the suppression of upper airway dilator activity in NREM sleep [38].

In addition to the above, a number of lesser studied neuropeptides modulate brain stem motoneuron activity. Many of these have significant excitatory effects, e.g., Vasopressin binds to the V1A receptor on facial and hypoglossal motoneurons [41]. It may play a greater role in newborns as the receptor density declines with age [42].

There is binding of Substance P to the NK-1 receptor in the hypoglossal nucleus, and this declines with recurrent hypoxia [43]. Substance P (NK-1) agonists have been shown to be excitatory [44]. Hypoglossal motoneurons also possess Oxytocin binding sites [45], but their physiological significance is currently unknown. Histamine activity is also increased in the brain while awake and it is thus excitatory [38]. There may be more, as yet undiscovered substances that may have additional roles to play.

Hormonal factors may also influence the activity of upper airway muscles. The genioglossal musculature in younger women is highly active compared to postmenopausal women and men of the same age. Thus, progesterone might be protective against sleep apnea. Exogenous progesterone administration has been shown to improve ventilation during sleep in men and women with sleep apnea [46]. Estrogen administration has been shown to decrease plasma levels of interleukin-6, which are higher in patients with sleep apnea [47]. Thus, postmenopausal women undergoing hormone replacement therapy (receiving progesterone and estrogen, both protective against OSA) have lower rates of OSA.

On the other hand, the exogenous administration of testosterone in women and healthy men can induce sleep apnea secondary to greater upper airway collapsibility independent of weight gain [48]. One cause might be greater deposition of soft tissue in the pharynx causing relaxation of the pharyngeal dilator muscles. This can because of redistribution of body fat under the influence of testosterone. This usually resolves if the exogenous testosterone is withdrawn.

Testosterone can also play a role in central apneas by altering the sensitivity of the central chemoreceptors to PaCO₂ [49].

Obese young females with polycystic ovary syndrome (POS) (who generally have higher circulating levels of androgens) develop sleep apnea at a higher rate than controls, and women with OSA have a higher level of circulating androgens hormones than do normal women paired by age and weight [48].

Thus, in relations to OSA, female hormones are protective and vice versa for male hormones.