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Study Objective: To assess the size, time course, and durability of the effects of long-term continuous positive airway pressure (CPAP) therapy on neurocognitive function, mood, sleepiness, and quality of life in patients with obstructive sleep apnea., Design: Randomized, double-blinded, 2-arm, sham-controlled, multicenter, long-term, intention-to-treat trial of CPAP therapy., Setting: Sleep clinics and laboratories at 5 university medical centers and community-based hospitals., Patients or Participants: Target enrollment is 1100 randomly assigned subjects across 5 clinical centers., Interventions: Active versus sham (subtherapeutic) CPAP., Measurements and Results: A battery of conventional and novel tests designed to evaluate neurocognitive function, mood, sleepiness, and quality of life., Conclusions: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) is designed to study obstructive sleep apnea and test the effects of CPAP through a comprehensive, controlled, and long-term trial in a large sample of subjects with obstructive sleep apnea.

Sleep Medicine has only recently been recognized as a specialty of medicine. Its development is based on an increasing amount of knowledge concerning the physiology of sleep, circadian biology and the pathophysiology of sleep disorders. This review chronicles the major advances in sleep science over the past 70 years and the development of the primary organizations responsible for the emergence of Sleep Medicine as a specialty, sleep disorders as a public health concern and sleep science as an important area of research.

The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 microg/kg, i.v.) and TA0910 (100 and 400 microg/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 microg/kg, i.v.) had no significant effect. TRH (25-1600 microg/kg, i.v.) and all three TRH analogs, CG3703 (6. 25-400 microg/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 microg/kg, i.v.), and TA0910 (25-1600 microg/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T3 and T4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.

Human narcolepsy is a neurological disorder known to be closely associated with HLA-DR2 and DQB1*0602. Because most autoimmune diseases are HLA-associated, a similar mechanism has been proposed for narcolepsy. However, neither systemic nor CNS evidence of an autoimmune abnormality has ever been reported. In this study, major histocompatibility (MHC) class I and class II expression was studied in the CNS of human and canine narcoleptics using immunohistochemistry and Northern analysis. Results indicated that canine narcolepsy is associated with a significant increase of MHC class II expression by the microglia. Moreover, the highest values were found between 3 and 8 months of age, strikingly concomitant to the development of narcolepsy in the canine model. In humans, class II expression was not found significantly different between control and narcoleptic subjects. This result could be explained by the old age of the subjects (69.86 +/- 5.31 and 68.36 +/- 4.74 years in narcoleptics and controls, respectively), because class II expression is significantly correlated with age in both humans and dogs. For the first time, this study demonstrated that the expression of MHC class II molecules in the CNS is age-dependent and that a consistent increase of their expression by the microglia might be critically involved in the development of narcolepsy.

Narcolepsy is a neurological disorder characterized by sleepiness and episodes of cataplexy. Cataplexy is an abrupt loss of muscle tone, most often triggered by sudden, strong emotions. A subset of cells in the medial medulla of the narcoleptic dog discharged at high rates only in cataplexy and rapid eye movement (REM) sleep. These cells were noncholinergic and were localized to ventromedial and caudal portions of the nucleus magnocellularis. The localization and discharge pattern of these cells indicate that cataplexy results from a triggering in waking of the neurons responsible for the suppression of muscle tone in REM sleep. However, most medullary cells were inactive during cataplexy but were active during REM sleep. These data demonstrate that cataplexy is a distinct behavioral state, differing from other sleep and waking states in its pattern of brainstem neuronal activity.

Identification of genes determining narcolepsy susceptibility is important not only for understanding that disorder but also for possible clues to general sleep-control mechanisms. Studies in humans reveal at least one such gene related to the major histocompatibility complex and in dog an as-yet-unmapped single, autosomal recessive gene canarc-1. Gene markers for canarc-1 were therefore sought by DNA restriction fragment length polymorphisms in our colony of narcoleptic dogs. A human mu-switch immunoglobulin probe and the enzyme Hae III identified a gene cosegregating with canarc-1 in backcrossed animals (logarithm of odds scores: m = 24, Z max = 7.2 at theta = 0%). canarc-1 was also shown not to be tightly linked with the dog major histocompatibility complex (m = 40, Z less than -2 at theta less than 4.8%). These results represent the mapping of a non-major histocompatibility complex narcolepsy gene and strongly suggest involvement of the immune system in the pathophysiology of that disease.

The heterogeneity of neural gene expression and the spatially limited expression of many low-abundance messenger RNAs in the brain has made cloning and analysis of such messages difficult. To generate amounts of nucleic acids sufficient for use in standard cloning strategies, we have devised a method for producing amplified heterogeneous populations of RNA from limited quantities of cDNA. Whole cerebellar RNA was primed with a synthetic oligonucleotide containing the T7 RNA polymerase promoter sequence 5' to a polythymidylate region. After second-strand cDNA synthesis, T7 RNA polymerase was used to generate amplified antisense RNA (aRNA). Up to 80-fold molar amplification has been achieved from nanogram quantities of cDNA. The amplified material is similar in size distribution to the parent cDNA and shows sequence heterogeneity as assessed by Southern and Northern blot analysis. Specific messages for moderate-abundance mRNAs for actin and guanine nucleotide-binding protein (G-protein) alpha subunits have been detected in the amplified material. By using in situ transcription to generate cDNA, sequences for cyclophilin have been detected in aRNA derived from single cerebellar tissue sections. cDNA derived from a single cerebellar Purkinje cell also has been amplified and yields material that hybridizes to cognate whole RNA and mRNA but not to Escherichia coli RNA.

Eleven patients with upper airway apnoea during sleep (one with SHY-Drager syndrome) were monitored polygraphically for wakefulness, sleep, and cardiovascular variables. Systemic hypertension and most of the severe arrhythmias recorded during sleep were secondary to repetitive obstructive apnonea and were mediated through the autonomic nervous system. Sleep related elevations of pulmonary arterial pressure were not influenced by atropine or impaired autonomic functions. Upper airway sleep apnoea is sleep related; the type of sleep (REM or NREM) is critical in the appearance of abnormalities. The distinction between two patient subgroups (total sleep dependent and NREM sleep dependent) has haemodynamic, and possibly long-term, implications. Sleep apnoea syndrome should be looked for in pateints with the Shy-Drager syndrome.

Several types of apnea are described in premature infants and in infants who have survived breathing-stoppage episodes which may be related to the sudden infant death syndrome. Upper airway apnea appears to induce the greatest changes: oxygen desaturation is more pronounced than in a central apnea of similar duration, and secondary cardiac changes are observed earlier and are more severe.

The role of central alpha-1 adrenergic receptors in cataplexy was investigated in genetically narcoleptic Doberman pinschers. Treatment of narcoleptic dogs with 25-600 micrograms/kg prazosin, a selective alpha-1 adrenergic receptor blocker, exacerbated cataplexy, whereas treatment with the alpha-1 agonist, methoxamine, ameliorated it. Subsequent studies showed that the beneficial effects of classical treatments of human narcolepsy (amphetamines and tricyclic antidepressants) are antagonized by prazosin, suggesting that these drugs are active through an indirect alpha-1 stimulation (via an increase of norepinephrine in the synaptic cleft). Other studies confirmed that the observed effects were not due to peripheral alpha-1 cardiovascular involvement. Atropine, a central anticholinergic agent, but not methylatropine, a peripheral one, completely suppressed the prazosin effect, which suggests that adrenergic and cholinergic systems act sequentially and not independently to generate cataplexy. Little is known about the physiological role of central alpha-1 adrenoceptors. This series of experiments implicates these receptors in narcolepsy-cataplexy.

1 Temazepam was evaluated in a strictly defined insomniac patient population under sleep laboratory conditions. Two protocols were used: a short-term (26-night) and a long-term (54-night) protocol evaluated the efficacy of the drug administered at night at 15 mg (short-term study) and 30 mg (long-term study), respectively. 2 Temazepam seemed to be both safe and effective at doses of 15 and 30 mg with up to 5 weeks of ingestion. 3 Suppression of slow wave sleep was observed at the high dose, but no suppression of REM sleep, found in studies with other benzodiazepines, was noted. 4 No evidence was found for development of tolerance or rebound effects.

The effects of intravenous administration of prostaglandins (PGs) were investigated in genetically narcoleptic Doberman pinschers. The treatment of narcoleptic dogs with PGE2 and PGE2 methyl ester, but not PGD2 and PGD2 methyl ester, induced a dose-dependent reduction of canine cataplexy, a dissociated manifestation of rapid-eye-movement sleep. The effect was specific and not associated with any change in other behavior. Furthermore, the effect was long-lasting (up to 2 hr) and could not be explained by the acute cardiovascular changes seen after intravenous PG administration. PGE2 methyl ester, a lipophilic derivative of PGE2 with more central penetration than PGE2, was 4 times more potent than PGE2. These results indicate that PGE2 modifies cataplexy through a central effect and suggest that this prostaglandin may play a role in rapid-eye-movement sleep regulation.

Concentrations of biogenic amine metabolites in discrete brain areas differed significantly between dogs with genetically transmitted narcolepsy and age- and breed-matched controls. Dopamine and 3,4-dihydroxyphenylacetic acid were consistently elevated in the brains of narcoleptic animals, while homovanillic acid was not. Narcoleptic animals consistently exhibited lower utilization of dopamine and higher intraneuronal degradation of dopamine but no uniform decrease in serotonin utilization. Hence neuropathology appears to be associated with genetically transmitted canine narcolepsy. The data indicate a nonglobal depression of dopamine utilization or turnover or both.

Normal sleepers underwent sleep recordings and daytime tests of sleep tendency, performance, and mood while being shifted 180 degrees in their sleep-wake schedule. After two baseline 24-hour periods, subjects postponed sleep until noon. For the next three 24-hour periods, they were in bed from 1200 to 2000 and received triazolam, flurazepam, or placebo at bedtime in parallel groups. Placebo subjects showed significant sleep loss after the shift. Active medication reversed this sleep loss. Despite good sleep, flurazepam subjects appeared most impaired of the three groups on objective assessments of waking function; triazolam subjects were least impaired.

Nasal continuous positive airway pressure (CPAP) is an effective therapy for sleep apnea. We treated 144 patients with nasal CPAP and observed them for periods of as long as 25 months. No pneumothoraces occurred in any patient. Compliance rates were between 65% (90/139) and 83% (90/108), depending on the patient population considered. Demographic factors unrelated to discontinuing using CPAP included age, sex, and the presence of a housemate. Better-educated patients were less able to tolerate the equipment. Dry throat and nose and sore eyes were the most common side effects, but only sore eyes related to the amount of pressure. Side effects were unrelated to the number of months on the treatment, and obesity was related to higher pressures. Our study provides optimistic intermediate-term follow-up observations of patients on nasal CPAP therapy for sleep apnea. Whether adverse consequences occur over longer periods of time remains to be seen.

In 22 children (11 boys and 11 girls), aged 9 to 13 years, respiration was monitored during one night of sleep. No child had a significant history of breathing problems during sleep. Sleep was recorded using standard techniques (electroencephalography, electrooculography, electromyography), and respiration was measured with nasal thermistors and abdominal or thoracic strain gauges. Respiratory pauses (five seconds or longer) were determined for all sleep stages. Respiratory rate was scored only in the first and last sleep cycles and during ten waking minutes before sleep onset. Respiratory rate was significantly affected by wakefulness or stage of sleep: highest in wakefulness and stage 1, lowest in stage 2 of the last sleep cycle. Regularity of respiratory rate showed a similar effect. Variance of respiratory rate was significantly lower in girls than boys. Respiratory pauses during sleep were seen in every child, ranging from 3 to 40 pauses per night (average, 17.2 for boys and 18.0 for girls). Significantly greater numbers of pauses per minute were seen in stage 1 and rapid eye movement (REM) sleep than in stages 2, 3 and 4. The longest respiratory pause was 25 seconds. The conclusion is made that a small number of respiratory pauses during sleep are normal in children of this age.

Of 250 patients referred to the Stanford Sleep Disorders Clinic, 35 were diagnosed for a sleep induced apnea syndrome. Thirty of them (27 adults and 3 children) were nonobese and complained of a sleep disorder. In 12 patients (9 adults and 3 children) extensive cardiorespiratory workups were done during sleep and wakefulness. Three types of sleep induced apnea syndrome were identified: diaphragmatic (or central), obstructive and mixed. The diaphragmatic type was predominant in sleep apnea insomnia; obstructive was predominant in sleep apnea hypersomnia. Hemodynamic changes were documented during sleep. Tracheostomy, done in two cases, improved the sleep induced symptomatology.

In the aged, sleep may be a vulnerable period for death from cardiovascular causes. Because of its high prevalence in the elderly, sleep apnea has been suggested to be one mechanism contributing to such sleep-related mortality. In this study, a cohort of 198 non-institutionalized elderly individuals (mean age at entry = 66) were followed for periods up to 12 years after initial polysomnography. The mortality ratio for sleep apnea (defined as a Respiratory Disturbance Index of over 10 events per sleep hour) was estimated to be 2.7 (95% CI = .95, 7.47). Multiple regression with the Cox proportional hazards model suggested that cardiovascular death was most clearly associated with age in this cohort. These results raise the possibility that "natural" death during sleep in the elderly may be associated with specific pathophysiological events during sleep.

Rats were deprived of paradoxical (radid eye movement or REM) sleep for a 6-day period but were allowed substantial non-REM (slow wave) sleep. Thresholds for electroconvulsive shock dropped significantly after deprivation in all these animals, but thresholds in control animals treated in a similar manner, but allowed REM sleep exhibited no change. Deprivation seems to heighten neural excitability.

Three adult cats were deprived of rapid eye movement sleep for six separate periods of up to 32 days. Animals were allowed normal amouints of sleeping time during which rapid eye movement sleep was interrupted, whenever it occurred, by human observers who continually monitored the animals and their electrocortical activity. Cortical responses evoked by pairs of acoustic clicks were recorded during wakefulness. Recovery functions derived from these data were facilitated during periods of deprivation of rapid eye movement sleep and returned to base-line values when animals were allowed normal amounts of this sleep phase. This change was noted repeatedly within, as well as between, subjects. It did not occur during control periods when non-rapid eye movement sleep was interrupted on identical schedules, nor did it occur when the cats were deprived of all sleep for 22 hours a day for 5 days.

Three cats were deprived of rapid-eye-movement (REM) sleep for 10 days, and three were deprived for 12 days. All cats received an electrically induced convulsion on each of the last 3 days of deprivation, as well as on the 1st recovery day just prior to sleep onset. As controls, four cats were deprived of REM sleep for 12 days and one was deprived for 10 days; the controls received no convulsions. Compensatory increases in REM sleep during recovery days were present in the convulsed animals, but were substantially lower than the recovery increases of control animals. During recovery REM sleep, convulsed cats did not display the exaggerated bursts of eye movements and body twitches seen in the nonconvulsed controls.

The behavior of 12 male cats was observed before and after six or eight daily injections of parachlorophenylalanine. Sexual performance was either unchanged or diminished; aggressive behavior was not seen. Serotonin concentrations in the brains were uniformly lowered.

A new clinical syndrome, sleep apnea associated with insomnia, has been characterized. Repeated episodes of apnea occur during sleep. Onset of respiration is associated with general arousal and often complete awakening, with a resultant loss of sleep. An important clinical implication is that patients complaining only of insomnia may be suffering from this syndrome.

Electroconvulsive shock, administered for 5 to 7 days, reduced the daily rapid eye movement sleep time of seven cats to as little as 28 percent of base line levels. After day 4, eye movements during periods of cortical activation without tonic electromyographic activity were greatlyreduced. Although partially deprived of rapid eye movements for as long as 7 days, the cats showed no compensatory rise in rapid eye movement time during the recovery period, but controls equally deprived gave significant rebounds. Rapid eye movement time of anesthetized cats was not affected by current that usually produces con vulsions; it was lowered in animals convulsed with metrazol, but the same dosage of this drug, administered so as to avoid convulsions, had little eflect. It appears that some aspect of the convulsion is responsible for lowering the rapid eye movement time.