Determinants of Age Related Breathing Instability During Non-Rapid-Eye-Movement (NREM) Sleep

Sleep apnea-hypopnea syndrome (SAS) is a relatively common disorder in the US population
with significant adverse health consequences. Despite the high prevalence of SAS in elderly
individuals, the underlying mechanisms have remained elusive. Specifically, we do not know
whether the high prevalence of sleep apnea in older adults is due to increased central
breathing instability. This proposal focuses on investigating age-specific differences in
the susceptibility to central breathing instability in healthy individuals as well as
individuals with sleep apnea.

This project will investigate the following specific objectives:

- Determine age-specific changes in the hypocapnic apneic threshold during sleep in

- elderly vs young individuals without sleep apnea

- elderly vs young individuals with sleep apnea.

- Determine age-specific changes in long-term facilitation during sleep in

- elderly versus young individuals without sleep apnea

- elderly vs young individuals with sleep apnea.

- We will investigate the susceptibility to central breathing instability by mechanically
ventilating the subjects during NREM sleep using pressure support ventilation. We will
compare the hypocapnic apneic threshold in old (age>60-65 years) and young (age
18-40years) individuals who are healthy as well as in those with sleep-disordered
breathing. We will also measure the parameters over a continuum of age from 18 to 89y.

- We will investigate whether there is a difference in the susceptibility to long term
facilitation of genioglossus activity and ventilation between young and old healthy
individuals in response to episodic hypoxia, while maintaining isocapnia. We will
conduct similar experiments in young and old individuals with sleep apnea.

Sleep apnea is very common in older veterans and is associated with significant
cardiovascular complications. Greater insight into the pathogenesis will have a positive
impact on the health of veterans suffering from this condition. This proposal will further
our understanding of the pathogenesis of breathing instability leading to sleep-disordered
breathing during sleep. Thus, we anticipate our findings will provide a basis for new
approaches to prevention and management of SAS in veterans.

Inclusion Criteria:

- Normal subjects without sleep apnea (controls) and individuals with sleep apnea.

Exclusion Criteria:

- Pregnancy,

- history of active coronary artery disease-including stable and unstable angina,

- myocardial infarction,

- history of congestive heart failure,

- stroke, who have excessive daytime sleepiness with Epworth Sleepiness Scale of >15
will not be included in the study

- patient with OSA who

- depression,

- schizophrenia,

- untreated hypothyroidism,

- diabetes on insulin,

- seizure disorder,

- intrinsic renal and liver disorders,

- failure to give informed consent,

- patients with evidence of pulmonary diseases based on history and abnormal pulmonary
function testing, including obstructive (ratio of predicted forced expiratory volume
to forced vital capacity, <80% predicted) or restrictive lung disorders (total lung
capacity <80% predicted) with resting oxygen saturation of <96% and kyphoscoliosis
(chest wall deformities) will be excluded,

- patients on certain medications including, opiates derivatives, stimulants,
antidepressants, tranquilizers, anti-psychotic agents, theophylline and other central
nervous system altering medications will be ineligible,

- history of alcohol or recreational drug use will also serve as grounds for exclusion,

- patients with body mass index (BMI) >34kg/m2 will be excluded,

- subjects with sleep apnea are already using continuous positive airway pressure for
more than 7 days as therapy will not be eligible.