This pilot study is the first that describes the effects of subacute intermittent nocturnal hypoxia on alertness and cognition in healthy human volunteers. Our major findings were that 1) multiple nights of intermittent nocturnal hypoxia can be safely and effectively induced in humans; 2) the exposure provokes a spectrum of respiratory abnormalities; 3) sleep quality was relatively well-maintained under intermittent hypoxia; 4) the exposed subjects showed no significant deficits in subjective or objective alertness, objective vigilance, verbal learning, or working memory. These results are limited by the small sample size, and that on a background of hypoxia, episodic reversal was achieved by brief boluses of oxygen, somewhat the inverse of sleep apnea.
Our model is a reasonable approximation of clinical sleep-disordered breathing, as exposure is intermittent, associated with re-oxygenation, and occurs only during the sleep period. Sleep respiration at altitude is typically characterized by periodic breathing, dominant in NREM sleep.22, 23, 24
Besides the expected periodic breathing, we also saw central apneas induced by the oxygen bolus and respiratory instability immediately following the oxygen bolus. Central apneas following return to normoxia or hyperoxia have been described under a variety of relatively brief experimental conditions.25,26–28
Hypoxia can increase the sleep CO2
apneic threshold and hyperoxia can lower it.29
A combination of hypocapnia and hyperoxia has previously been demonstrated to produce central apnea during NREM sleep.25, 30, 31
Cortical activity plays a role in maintaining respiratory rhythm,32
but in our model instability occurred even without cortical arousals. As we did not measure end-tidal CO2
, the exact genesis of the changes noted is not known.
Our results were surprising as there is ample supportive evidence that hypoxia may be directly linked to cognitive dysfunction, such as chronic obstructive lung disease,33
and altitude exposure.14
Hypoxia has direct effects on sleep in rodents, including increased wake and stage I sleep, associated with reduced delta power and decreased REM sleep.34, 35
Veasey and colleagues exposed mice to intermittent hypoxia during the lights-on period daily for eight weeks and demonstrated reduced sleep latency, oxidative injury in wake-promoting regions of the brain, and increased sensitivity to sleep deprivation.2
Murine models of sleep intermittent hypoxia have demonstrated executive dysfunction, excessive sleepiness, oxidative injury to basal forebrain structures, and brainstem motor neurons.2, 36–38
Prior models of intermittent hypoxia also demonstrate executive and learning dysfunction and hippocampal injury.9, 12, 39
Results using brain morphometric techniques in humans are mixed,40, 41
with both extensive and limited hippocampal signal reductions in hypoxic sleep-disordered breathing. In addition, healthy volunteers may be more resistant to the adverse effects of intermittent hypoxia and sleep fragmentation on cognition than patients with sleep apnea. The duration of exposure remains important, as we evaluated 4 weeks vs. years of exposure that occur in sleep apnea patients.
Our model has several important limitations. The pattern of hypoxia and re-oxygenation does not exactly mimic that seen in sleep apnea, where the background is typically not hypoxic. The piezo effort bands are less accurate in estimating respiratory effort than respiratory inductance plethysmography or esophageal manometry. The expense and degree of labor of the experiment at the pilot stage did not allow for a perfect design – randomized, sham arm, control arm of placebo intermittent hypoxia, counterbalanced design, retesting several weeks after hypoxia, and control for learning and habituation effects. The sample size is small, but powered to detect moderate changes in vigilance. The tests used may not have been sensitive enough, but we did use field standards shown to be sensitive to increases in sleep drive and sleep debt. Subjective assessments of sleepiness and mood following sleep deprivation are progressively inaccurate over time even if performance is deteriorating, but the complete absence of subjective change argues against this explanation. The Psychomotor Vigilance Test used has been shown in numerous publications to be sensitive to the effects of excessive sleepiness.18
We have used the 2-back working memory task to assess the effects of single night sleep deprivation and auditory sleep fragmentation, and cognitive function in sleep apnea and narcolepsy, with a consistent demonstration of slowing of performance.42
The Multiple Sleep Latency Test19
is a standardized objective test of sleepiness. The Rey verbal learning test is sensitive to hippocampal function. It is thus unlikely that a major component of sleepiness-induced brain function was not sampled by our methods. More subtle effects, however, cannot be excluded. The average age of our subjects is less than the majority of patients with sleep apnea, and younger individuals may be more tolerant to intermittent nocturnal hypoxia or simply have greater reserve to adapt. Our subjects, who continued their usual daytime jobs during the experimental period, were not monitored during the day but were instructed not to nap (and verified on return to the GCRC). While this design may result in imperfect control of the experimental environment, it is a more real-life condition.
In conclusion, we report the absence of significant subjective or objective sleepiness, or objective vigilance and working memory impairment, following 4 weeks of nocturnal intermittent hypoxia in healthy adult volunteers, using a model of episodic reoxygenation in a controlled hypoxic environment. Technical improvements in the model, such as longer periods of normoxia, and tracking / control of CO2 to minimize periodic breathing, and a sham / placebo controlled design may yield more precise assessments of the effects of sleep hypoxia on human cognitive function.