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SLEEP DISORDERS AND
THEIR BIOBEHAVIORAL CONSEQUENCES

Pupillometric Sleepiness in Treated Sleep Disorders
Joan Shaver, Principal Investigator (5R01NR004959)
Abstract

Neurobiology of Sleep Apnea in Aging
David W. Carley, Principal Investigator (1R01AG016303)
Abstract

Absolute Near-Infrared Oximeter
Antonios Michalos, Principal Investigator (5R44NS040597)
C'Sola Olopade, Sub-Contract Principal Investigator
Abstract

Pupillometric Sleepiness in Treated Sleep Disorders
Patients with obstructive sleep apnea and narcolepsy can experience a diminished quality of life, decreased productivity, and workplace and traffic accidents due to the pathologic excessive daytime sleepiness (EDS) associated with these disorders. Currently, the extent of EDS is determined by polysomnography and the Multiple-Sleep Latency Test (MSLT), two EEG-based physiologic sleepiness measures that are labor intensive, time-consuming, expensive and receive limited health insurance coverage. As people become sleepy, their pupils oscillate widely and decrease in size. In this study, the Pupil Unrest Index (PUI) will be calculated to estimate sleepiness using desk top pupillometry, an efficient, convenient, non-invasive and easily repeatable technique. The PUI quantitatively describes the extent of pupillary oscillation during 15 minutes of alertness testing. Quantitative data comparing the PUI to other physiologic sleepiness measures are not available. The subject cohorts for this repeated measures, known groups methodologic study will consist of normal controls, and obstructive sleep apnea and narcolepsy subjects before and after usual treatment. The specific aims are to (1) correlate the PUI with MSLT sleep latencies among the subject groups; 92) compare the PUI to the MSLT in detecting sleepiness among the three subject groups; and (3) compare the PUI and the MSLT to other objective and subjective sleepiness measures between subject groups, and before and after usual treatment among the OSA and narcolepsy subjects. MANOVA will be used to examine the linear relationship between the PUI and the MSLT among the subject groups, and the differences in measures of perceived sleepiness, sleep quantity, sleep quality and continuity, mood and functional status between the subject groups, and pre-post-treatment fore subjects with OSA and narcolepsy. The sensitivity and specificity of the PUI in detecting sleepiness will be estimated using the MSLT results as the "gold standard" for classifying subjects. MLR will be used to estimate the relationship between the PUI or the MSLT, and other objective and subjective sleepiness measures. Results will provide evidence about the PUI as a reliable and valid objective outcome measure of waking tendency among controls, and pre-post-treatment for OSA and narcolepsy subjects.

Watch a Video Clip of Pupil Oscillations

Neurobiology of Sleep Apnea in Aging
Sleep apnea syndrome affects at least 3 percent - 5 percent of the adult population in this country and available data suggest that significant morbidity and mortality result from this disorder. It is now well established that the prevalence of sleep-related apnea is dramatically elevated in the elderly with recent estimates ranging from 28 percent - 67 percent for elderly males and from 20 percent - 54 percent for elderly females. However, the mechanisms underlying the age related increase in apnea genesis remain poorly understood. This uncertainly stems in part from a paucity of appropriate animal models to study spontaneous apneas in all stages of sleep. Rapid eye movement (REM) sleep is associated with apneas, reductions in respiratory and upper airway motor outputs, and increased variability of respiration, heart rate and blood pressure. We present novel preliminary evidence suggesting that increased apnea expression with aging results from dysregulation of brainstem respiratory control systems by brainstem phasic events (BPE) in the elderly. Ponto-geniculo-occipital (PGO) waves are a close marker of BPE and are closely associated with cardio- respiratory changes, including apnea. The overall goals of this proposal are to (i) investigate the neural mechanisms by which BPE influence apnea genesis, and (ii) establish the importance of these mechanisms to the age-related increase in apnea. To achieve these goals, we will combine descriptive and interventional human studies with invasive central nervous system measurements and manipulations in rats using a model of sleep-related respiratory instability which we have characterized. We will focus our attention on the pedunculopontine tegmental nucleus (PPT), the putative site of the burst generator responsible brainstem phasic events detectable as PGO waves. We will manipulate BPE expression in two directions: 1) we will augment expression by acoustic stimulation and sleep deprivation in man and rat and by microinjection of cholinergic agonists into PPT in the rat; and 2) we will reduce expression by electrolytic lesions of the PPT in the rat. These manipulations in old and young patients, controls, and rats will provide a comprehensive approach to define the mechanisms and importance of brainstem phasic event-induced respiratory instability in aging.

Absolute Near-Infrared Oximeter
Our goals in Phase I have been completed and showed the feasibility of our approach. We applied Near-Infrared Spectroscopy (NIRS), a non-invasive method and an affordable, portable, bedside technique for the diagnosis of the degree of the hypoxic insult in the brain, in sleep apnea, during daytime napping. It has been suggested that chronic, recurrent hypoxia during sleep leads to brain injury, which causes neuropsychological deficits and decline of cognitive function. Cerebrovascular accidents, including fatal strokes are not uncommon. Conventional polysomnography, a relatively expensive test, detects sleep apnea at various sleep stages and determines arterial oxygen saturation. However, current clinical methods do not provide information on brain oxygenation, which is important especially in subjects with preexisting anatomical or functional vascular pathology. NIRS enables continuous real-time measurements of changes in the hemoglobin oxygenation and blood volume, thus providing information on tissue oxygenation and hemodynamics. In Phase II we propose the development of a tool and the application of NIRS to determine cerebral hemodynamics during sleep, in association to overnight polysomnographic sleep studies. Our goal is the development of reliable, cost efficient instrumentation for early detection of cerebral hemodynamic abnormalities in sleep apnea, for the prevention of hypoxic cerebral morbidity and mortality.