Sleep: suppression of rapid eye movement phase in the cat after electroconvulsive shock.

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.

Insomnia with sleep apnea: a new syndrome.

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.

Apneas during sleep in infants: possible relationship with sudden infant death 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.

Sleep: the effect of electroconvulsive shock in cats deprived of REM sleep.

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.

Sexual behavior of male cats after administration of parachlorophenylalanine.

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.

Treatment of a 12-hour shift of sleep schedule with benzodiazepines.

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.

Rapid eye movement sleep deprivation: a central-neural change during wakefulness.

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.

"Hypersexuality" and behavioral changes in cats caused by administration of p-chlorophenylalanine.

The behavior of 26 male cats was systematically observed before, during, and after daily administration of the tryptophan hydroxylase inhibitor, p-chlorophenylalanine. These observations established that "hypersexuality," increased aggression, and perceptual disorientation are sequelae of the chronic administration of the drug in cats.

Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla.

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.

Narcolepsy: biogenic amine deficits in an animal model.

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.

Role of central alpha-1 adrenoceptors in canine narcolepsy.

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.

Two occult causes of insomnia and their therapeutic problems.

Insomnia may be associated with a sleep-induced apnea syndrome in nonobese patients who snore. The "central" type of apnea appears to be predominant in this population, in opposition to Pickwickian and nonobese hypersomniacs. An abnormal "swallowing reflex syndrome," also induced by sleep, may be a differential diagnosis. Sleeping pills that are central nervous system depressants should be cautiously prescribed for patients with such syndromes.

REM phase deprivation and schizophrenia II.

Nine schizophrenic patients with active symptomatology were compared with seven patient controls in their response to two nights of rapid eye movement (REM) sleep deprivation. The control subjects demonstrate "normal" increases in total REM and percentage REM time increase on recovery nights compared to base line nights. The schizophrenic subjects differ substantially from the control subjects in both these measurements and show no perceptible change from base line nights on recovery nights. The effects of medication, anxiety, sleep loss, ceiling effects, and intensity change were not considered adequate to account for the above results. However, many questions, such as the specificity of this rebound failure to the schizophrenic patients and the possibility of a sleep disturbance factor operating independently of psychiatric diagnosis, remain to be answered.

Delayed sleep phase syndrome. A chronobiological disorder with sleep-onset insomnia.

We describe a new syndrome called "delayed sleep phase insomnia." Thirty of 450 patients seen for a primary insomniac complaint had the following characteristics: (1) chronic inability to fall asleep at a desired clock time; (2) when not on a strict schedule, the patients have a normal sleep pattern and after a sleep of normal length awaken spontaneously and feel refreshed; and (3) a long history of unsuccessful attempts to treat the problem. These patients were younger than the general insomniac population and as a group did not have a specific psychiatric disorder. Six patients' histories are described in detail, including the successful nonpharmacological chronotherapy regimen (resetting the patients' biological clock by progressive phase delay). Delayed sleep phase insomnia is proposed to be a disorder of the circadian sleep-wake rhythm in which the "advance" portion of the phase response curve is small.

Sleep apnea syndrome due to upper airway obstruction: a review of 25 cases.

A sleep apnea syndrome due to upper airway obstruction was diagnosed in 25 adult men (25 to 65 years of age) using nocturnal polygraphic monitoring. Excessive daytime somnolence, hypnagogic hallucinations, and automatic behavior, personality changes with abnormal behavioral outbursts, impotence, morning headaches, abnormal motor activity during sleep, nocturnal enuresis, and high blood pressure should suggest this diagnosis when any of the symptoms are associated with loud snoring. Respiratory monitoring during sleep and nocturnal cardiovascular evaluation bring prognostic information and indications for therapy. Three types of therapeutic trials, namely, diet, medications with or without diet, and surgery have been performed. Only surgery has been beneficial in these cases.

Obstructive sleep apnea syndrome and tracheostomy. Long-term follow-up experience.

Obstructive sleep apnea syndrome (OSAS), a disabling disorder that leads to life-threatening cardiorespiratory events during sleep, has been treated by tracheostomy. This article reports long-term follow-up data of 50 patients who have undergone this procedure, and the indications for surgery are summarized. Surgery may result in secondary local and general acute and subacute complications, but, on a long-term basis, patients were completely relieved of clinical symptoms, returned to full activity, and adapted normally to social and familial life. Temporary closure of the tracheostomy during sleep led to recurrence of obstructive sleep apnea.

Diagnosis and treatment of sleep apnea within the community. The Walla Walla Project.

BACKGROUND: Patients with sleep disorders are common in primary care, yet most physicians lack training in the diagnosis and treatment of such patients. OBJECTIVES: To enhance recognition of sleep disorders by community physicians and transfer the diagnostic testing and care of such patients from tertiary care centers to the local community. To present our polysomnogram experience relevant to sleep apnea. METHODS: Sleep disorders specialists provided a community with education, diagnostic equipment, and ongoing support as sleep disorders expertise was established locally. Outcomes for a 2-year period were assessed by chart review, patient questionnaire, tabulation of polysomnographic data, and comparison with published reports from specialized centers. RESULTS: Referral for sleep testing increased by almost 8-fold in patients at the Walla Walla Clinic in Walla Walla, Wash, from 0.27% (2 of 752 cases reviewed) to 2.1% (294 of 14330 internal medicine patients). Data were collected from all community physicians for a 2-year period on 360 new patients who underwent polysomnogram testing. This resulted in the diagnosis of sleep-related breathing disorders in 81% and periodic leg movements of sleep in 18%. Nasal continuous positive airway pressure treatment was given to 228 patients (average baseline apnea index of 19.1), representing a higher volume of patients than at many traditional sleep centers, yet compliance with continuous positive airway pressure was comparable. CONCLUSIONS: Sleep apnea is significantly underrecognized by primary care physicians. As a result of the intervention, local sleep expertise was established and large numbers of patients were discovered and treated in the community. Thus, a significant public health problem is identified and a solution established.

Activity feedback to the mammalian circadian pacemaker: influence on observed measures of rhythm period length.

In the mouse, activity is precisely timed by the circadian clock and is normally most intense in the early subjective night. Since vigorous activity (e.g., wheel running) is thought to induce phase shifts in rodents, the temporal placement of daily exercise/activity could be a determinant of observed circadian rhythm period. The relationship between spontaneous running-wheel activity and the circadian period of free-running rhythms was studied to assess this possibility. With ad libitum access to a running wheel, mice exhibited a free-running period (tau) of 23.43 +/- 0.08 hr (mean +/- SEM). When running wheels were locked, tau increased (23.88 +/- 0.04 hr, p less than 0.03), and restoration of ad libitum wheel running again produced a shorter period (tau = 23.56 +/- 0.06 hr, p less than 0.05). A survey of free-running activity patterns in a population of 100 mice revealed a significant correlation between the observed circadian period and the time of day in which spontaneous wheel running occurred (r = 0.7314, p less than 0.0001). Significantly shorter periods were observed when running was concentrated at the beginning of the subjective night (tau = 23.23 +/- 0.04), and longer periods were observed if mice ran late in the subjective night (tau = 23.89 +/- 0.04), F (1, 99) = 34.96, p less than 0.0001. It was previously believed that the period of the circadian clock was primarily responsive to externally imposed tonic or phasic events. Systematic influences of spontaneous exercise on tau demonstrate that physiological and/or behavioral determinants of circadian timekeeping exist as well.

Serotonin and the mammalian circadian system: II. Phase-shifting rat behavioral rhythms with serotonergic agonists.

The suprachiasmatic nuclei (SCN) receive primary afferents from the median and dorsal raphe, but the role of these projections in circadian timekeeping is poorly understood. Studies of the SCN in vitro suggest that quipazine, a general serotonin (5-HT) receptor agonist, can produce circadian time-dependent phase advances and phase delays in circadian rhythms of neuronal activity. The present study addresses whether quipazine and the selective 5-HT1A receptor agonist 8-OH-DPAT are similarly effective in vivo. Drinking and wheel-running patterns of male Wistar rats individually housed in constant darkness were monitored before and after subcutaneous administration of quipazine (5-10 mg/kg) at either circadian time (CT) 6 or CT 18, with and without running wheels available. Dose-dependent phase advances (20-180 min) were produced at CT 6. Significant phase shifts were not observed at CT 18. CT 6 quipazine-treated animals also showed a sustained and significant shortening of rhythm period (tau) following treatment (-0.28 hr; p < 0.002). tau shortening was inconsistently observed in CT 18 quipazine-treated rats. Neither quipazine-induced phase shifts nor tau effects were dependent on wheel-running activity per se. 8-OH-DPAT delivered via intracerebral ventricular treatment into the third ventricle (5 microliters at 100 microM in saline) produced slightly smaller phase advances (20-90 min) at CT 6, but did not produce phase delays at CT 18 or changes in tau. These findings support in vitro evidence that 5-HT-ergic agonists can phase-shift the circadian pacemaker.

Daytime sleepiness: quantification of a behavioral state.

A neurophysiological technique that quantifies drowsiness as the speed of falling asleep at intervals across a day is used to identify patterns of sleepiness/alertness. The Multiple Sleep Latency Test (MSLT) reveals a daily biphasic organization of sleepiness that is affected in predictable ways by the length and continuity of nocturnal sleep on one or several nights, and by maturation, aging, sleep pathology, and drug ingestion. The systematic nature of these relationships provides impetus to efforts examining the neurobiological mechanisms subserving the delicate balance of sleep and wakefulness.