Respiratory and Autonomic Plasticity Following Intermittent Hypoxia

Approximately 8 % of the Veteran population in the United States suffers from sleep apnea.
Consequences of untreated sleep apnea include increased daytime fatigue, hypertension and
stroke. Thus, sleep apnea is a major health concern. One of the primary hallmarks of sleep
apnea is exposure to intermittent hypoxia (IH) which occurs as a consequence of central or
obstructive apneas. Exposure to IH may lead to neural plasticity (i.e. a change in system
performance based on prior experience) of the respiratory and autonomic nervous system. One
adaptation that has been shown to manifest itself in animals following exposure to IH is
long-term facilitation (LTF) of ventilation and sympathetic nervous system activity (SNSA).
This phenomenon is characterized by a gradual increase in respiratory motor activity and SNSA
during successive periods of normoxia that separate hypoxic episodes and by activity that
persists above baseline levels for up to 90 minutes following exposure to IH. Although LTF of
minute ventilation has been well established in animals it has not been observed consistently
in healthy humans or in individuals with obstructive sleep apnea. Similarly, although a few
studies have shown that exposure to IH leads to increases in SNSA in healthy individuals the
magnitude of the response has varied significantly. Findings from animal studies suggest that
the manifestation of LTF in humans might in part be dependent on a variety of factors,
including prior exposure to IH, arousal state (wake vs. sleep) and gender. Thus, the initial
aim of our proposal will establish whether LTF can be induced in healthy humans and
individuals with obstructive sleep apnea and whether the magnitude of the response is
dependent on those factors mentioned above. Moreover, the initial aim will explore whether
the presence of LTF of minute ventilation promotes or mitigates apnea severity. Animal
studies have also indicated that LTF of respiratory and autonomic activity may in part be
induced by increases in oxidative stress. Thus, the second objective of our proposal will
explore whether administration of an antioxidant cocktail impacts respiratory and autonomic
nervous system plasticity during wakefulness and sleep following IH. Likewise, the second aim
will explore whether administration of an antioxidant cocktail alters apnea severity
following exposure to IH. Establishing whether LTF of minute ventilation exists in
individuals with sleep apnea is important since activation of this phenomenon could impact on
apnea severity across the night. Similarly, LTF of SNSA activity and possibly long-term
depression (LTD) of parasympathetic nervous system activity (PNSA) could ultimately lead to
persistent increases in blood pressure and heart rate. Furthermore, given that exposure to IH
may lead to long-term plasticity of respiratory and autonomic activity that are
physiologically detrimental, exploring mechanisms that ultimately lead to treatments that may
mitigate or prevent the manifestation of this phenomenon are important.

Inclusion Criteria:

Characteristics of OSA subject population:

- Body mass index < 30 kg/m2.

- 20 to 40 years old.

- Newly diagnosed never-treated mild to moderate sleep apnea (i.e. 50 > apnea/hypopnea
index >10 events per hour - average nocturnal oxygen saturation > 90%).

- Not pregnant.

- Free of any other known medical conditions.

- Not taking any medication.

- Non-smokers with normal lung function.

- Minimal alcohol consumption (i.e. no more than the equivalent of a glass of wine/day).

Characteristics of control group population:

- Body mass index < 30 kg/m2.

- 20 to 40 years old.

- Apnea/hypopnea index < 5 events per hour.

- Not pregnant.

- Free of any known medical conditions.

- Not taking any medication.

- Non-smokers with normal lung function.

- Minimal alcohol consumption (i.e. no more than the equivalent of a glass of wine/day).

Exclusion Criteria:

- Anything not in inclusion criteria.