A review of REM sleep deprivation.

Studies on the behavioral consequences of rapid eye movement (REM) sleep deprivation in animals and humans are critically reviewed. In animals, converging evidence--some reasonably well controlled--indicates that REM sleep deprivation probably heightens central neural excitability and increased motivational behavior, but has nuclear or inconclusive effects on learning. In humans, evidence indicates that REM sleep deprivation is not dream deprivation and is not harmful to schizophrenic, depressed, or healthy subjects. Controversy continues about whether or not (some) schizophrenic patients respond abnormally to REM sleep deprivation by having no REM rebound. Controlled but unconfirmed work indicates that that endogenous, but not reactive, depressive patients are improved by REM sleep deprivation, a finding consistent with the animal behavioral consequences of the procedure and with the unique REM-depriving properties of efficacious antidepressant drugs.

Improvement of depression by REM sleep deprivation. New findings and a theory.

We compared sleep variables in 14 drug-free endogenous depressives and in 14 age- and insomnia-matched, nondepressed controls before and after brief rapid eye movement (REM) sleep deprivation by awakenings. Before REM sleep deprivation, compared with controls, depressives had lower REM latency, higher REM frequency, and--a new finding--an abnormal temporal distribution of REM sleep. Depression improvement by REM sleep deprivation correlated with the ameliorative effect of brief REM sleep deprivation on on indicator of the abnormal temporal distribution of REM sleep. Several findings suggest that the depressive abnormalities represent a "damaged," weakened sleep cycle "oscillator" and its correlate, a circadian rhythm disturbance, and that REM sleep deprivation improved depression to the extent that it stimulated the oscillator and corrected one manifestation of the circadian rhythm disturbance.

REM sleep reduction effects on depression syndromes.

Thirty-four endogenous and 18 reactive, depressed patients (hospitalized and nonschizophrenic) were treated in a double-blind, crossover study of the hypothesis that rapid eye movement (REM) sleep reduction (by awakenings) relieves depression. In the endogenous group-but not in the reactive group-subjects deprived of REM sleep for three weeks improved significantly more than control subjects awakened from non-REM sleep. Therapeutic efficacy of REM sleep reduction appeared similar to reported efficacy of imipramine hydrochloride treatment of depression. Eight of nine endogenous patients, unimproved by REM sleep deprivation, did not improve with imipramine. Results suggested (1) that substantial REM sleep reduction has antidepressant activity, and (2) since imipramine and other drug antidepressants reduce REM sleep much more so than nonantidepressant drugs, that an antidepressant "mechanism" of drugs resides in their capacity to substantially reduce REM sleep.

Endogenous depression improvement and REM pressure.

In the treatment of endogenous depression by rapid eye movement (REM) sleep deprivation, depression improvement, measured on Hamilton and Global scales, correlated positively and significantly (P less than .05) with REM pressure (increase of REM sleep stimulated by REM sleep deprivation). This dose-response relationship suggests that (1) REM pressure was an indicator of a process that mediated the antidepressant effects of REM sleep deprivation, and (2) since improvement varied with stimulation of REM sleep, an unknown stimulus of REM sleep is a naturally occurring, endogenous antidepressant.

Drug effects on REM sleep and on endogenous depression.

In earlier work REM sleep deprivation (RSD) by arousals improved endogenous depression. This suggested that drugs producing a similar RSD would have antidepressant activity. The arousal RSD was large, persisted for weeks, and was followed by a REM rebound. We call RSD with these properties arousal-type RSD. The present study reviewed literature from 1962 to 1989 on drug REM sleep effects to examine the hypothesis that drugs producing arousal-type RSD improve endogenous depression. The literature reviewed concerned the REM sleep effects of amine precursors, antidepressants, antihistamines, antipsychotics, barbiturates, benzodiazepines, other hypnotics, drugs affecting cholinergic and noradrenergic neurotransmission, ethanol, lithium and narcotics. Four hundred and sixty-eight relevant papers were read and 215 contributed information that could be used in the review. The findings indicated that all drugs producing arousal-type RSD improved endogenous depression. Four drugs that improved endogenous depression did not produce arousal-type RSD.

Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder.

BACKGROUND: Sleep disturbances are common in major depressive disorder. In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency: in contrast, fluoxetine suppressed REM sleep. This study compared the objective and subjective effects of nefazodone and fluoxetine on sleep. METHODS: This paper reports combined results of three identical, multisite, randomized, double-blind, 8-week, acute-phase trials comparing nefazodone (n = 64) with fluoxetine (n = 61) in outpatients with nonpsychotic major depressive disorder and insomnia. Sleep electroencephalographic (EEG) recordings were gathered at baseline and weeks 2, 4, and 8. Clinical ratings were obtained at weeks 1-4, 6, and 8. RESULTS: Nefazodone and fluoxetine were equally effective in reducing depressive symptoms; however, nefazodone differentially and progressively increased (while fluoxetine reduced) sleep efficiency and reduced (while fluoxetine increased) the number of awakenings in a linear fashion over the 8-week trial. Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep. Nefazodone significantly increased total REM sleep time. Clinical evaluations of sleep quality were significantly improved with nefazodone compared with fluoxetine. CONCLUSIONS: Nefazodone and fluoxetine were equally effective antidepressants. Nefazodone was associated with normal objective, and clinician- and patient-rated assessments of sleep when compared with fluoxetine. These differential sleep EEG effects are consistent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action.

An alternative view of the neurobiology of dreaming.

The author critiques the recently proposed activation-synthesis hypothesis about the origin and formation of dreams. Many findings do not support the new hypothesis that specific pontine physiological processes, rather than mental processes, instigate dreams and produce their distortion. First, dreaming often occurs in the absence of the pontine processes. Second, forebrain activity (which can have mental correlates) is crucial to the instigation and maintenance of dreaming sleep. Finally, activity of the proposed pontine dream generator, which is claimed to cause dream distortion, is not reliably accompanied by dream distortion.

The effects of a 3-day increase of ambient temperature on body temperature and REM sleep in an animal model of depression.

This study examined the effects of elevated ambient temperature (Ta) on body temperature (Tb) and rapid eye movement (REM) sleep in depressed and control rats. Previous studies have shown that elevations of Ta to the rat's thermoneutral zone of 29 degrees C produced an increase of REM sleep in control rats. In this study, 15 male Sprague-Dawley rats, seven saline control rats (SAL) and eight rats that were classified as depressed according to the chlorimipramine model of depression (CLI rats), were implanted for continuous Tb and polysomnographic recording and were exposed to two Ta's, 22 degrees C and 29 degrees C. CLI and SAL rats had significantly more REM sleep and a lower body temperature at 29 degrees C than at 22 degrees C. At 22 degrees C, CLI rats had significantly more REM sleep during the light period and a higher Tb in the light and dark periods than SAL control rats. At 29 degrees C, there were no significant differences in REM sleep or in Tb between CLI and SAL rats. Because human endogenous depression is associated with abnormal REM sleep and an elevated nocturnal Tb, these results give further support for the validity of the CLI model of depression and provide insight into the relationships among Tb, Ta, REM sleep and depression.

The effect of a 3-day increase of ambient temperature toward the thermoneutral zone on rapid eye movement sleep in the rat.

This study examined the effect of a 3-day increase of ambient temperature (Ta) from the usual room temperature of 22 degrees C to the rat's thermoneutral zone (TNZ) of 29 degrees C on rapid eye movement (REM) sleep. Other laboratories have reported that brief increases of Ta to the TNZ increased REM sleep and that long-term increases of Ta produced long-term increases of REM sleep. However, these studies were limited by the lack of controls for order effects or by restricted recording times. In the present study, which controlled for order effects, polysomnographic recordings for 12 male Sprague-Dawley rats were obtained 24 hours a day for 3 days at an ambient temperature of 22 degrees C and for 3 days at the TNZ of 29 degrees C. In all rats, REM sleep minutes and REM sleep percentage of total sleep time were significantly greater at the higher temperature than at the lower temperature. The increase in REM sleep at 29 degrees C was stable over the 3-day recording period. Prolonged increase of ambient temperature towards the TNZ is a simple, nonpharmacological method of producing a sustained, significant increase of REM sleep in the rat.

A new method for continuous, long-term polysomnographic recording of neonatal rats.

STUDY OBJECTIVES: Many findings suggest that in altricial mammals neonatal REM sleep has developmental functions. However, investigations of these developmental functions has been hampered by technical limitations of the conventional polysomnographic (PSG) recording technique. One limitation is that continuous (24 hour/day), long-term (weeks) PSG recordings have not been achieved. A second limitation is that the metal screw electrodes and head plugs cemented to the skull cannot be removed to allow the neonate to mature into adulthood. As a result of these limitations, the relationship between neonatal sleep/wake variables and adult variables has not been studied. Also the effects of polysomnographically controlled neonatal REM sleep deprivation on adult variables have not been studied. The present work describes a new technique called the soft head plug (SH) method for continuous, long-term PSG recording. DESIGN: In the new technique, electrodes are thin, strong, Teflon wires that are led by a suturing needle through the soft skull to the epidural space, then with a U-turn exited from the skull and tied to the entry wire. Thus, in contrast to the conventional technique, the soft head plug technique does not use screws as electrodes and does not cement a hard, relatively large electrode plug to the skull, removal of which is fatal or very traumatic. The SH recording electrodes can be removed without damage to neonates. SETTING: NA. PATIENTS: NA. INTERVENTIONS: NA. RESULTS: In the present study sleep/wake results with the soft head plug technique were reliable (replicated) and, compared with results of the conventional method, valid. CONCLUSIONS: The results indicate that the soft head plug technique can be used to study relationships between neonatal sleep/wake variables and adult variables.

Ontogeny of REM rebound in postnatal rats.

STUDY OBJECTIVES: The aim of this study was to determine developmental changes (ontogeny) of REM rebound in postnatal rats. DESIGN: Different groups of 2, 3, and 4-week-old experimental rats were instrumentally REM sleep deprived (RSD rats) for 33-48 hours and their sleep was monitored polysomnographically for 48 hours after the REM sleep deprivation (RSD). Age-matched control (RSC) rats also had polysomnographic recordings. SETTINGS: N/A. PARTICIPANTS: Subjects were 18 male Long-Evans RSD rats (5 age 2 weeks, 5 age 3 weeks, and 8 age 4 weeks); and 17 age-matched male Long Evans RSC rats (5 age 2 weeks, 5 age 3 weeks, and 7 age 4 weeks). INTERVENTIONS: Implants for the polysomnographic recordings of the RSD and RSC rats were made by the soft head plug method which permitted continuous, 24 hour/day records during the REM deprivation and post deprivation periods. RSD rats had instrumental RSD by the shaking platform method. RSC rats remained in stationary cages. MEASUREMENTS AND RESULTS: At age 2 weeks, compared with age-matched RSC rats, RSD rats had no REM rebound. At age 3 weeks, compared with age-matched RSC rats, RSD rats had a small but significant REM rebound limited to the first 6 hours after RSD. At age 4 weeks, compared with RSC rats, RSD rats had a larger REM rebound that extended for 18 hours after RSD. The size and duration of REM rebound at the different ages was significantly different. Total sleep lost during the RSD process at each age was made up. CONCLUSIONS: The findings possibly indicate that in rats a REM sleep homeostatic process develops between ages 2 and 4 weeks and that a total sleep homeostatic process is already developed by age 2 weeks.

An instrumental method for long-term continuous REM sleep deprivation of neonatal rats.

STUDY OBJECTIVES: The present study describes a new method for instrumental REM sleep deprivation (RSD) of neonatal rats. DESIGN: In the new method, an experimental neonatal rat and a yoked control neonatal rat were singly housed in a small plexiglass chamber which was divided into two separate units by a vertical wall. The floor of the housing chamber was attached to the platform of a standard laboratory test tube shaker. EEG and EMG electrodes were implanted by the soft head plug method which permitted continuous, long-term polysomnography. EEG and EMG signals were sent to a computer that was programmed to turn on the shaker for 5 seconds whenever the experimental rat entered REM sleep. SETTING: NA PATIENTS: NA INTERVENTIONS: NA RESULTS: The shaking of the chamber usually terminated REM sleep by entry to slow-wave sleep or wake. Amount of RSD depended on the shaker's oscillation speed. At higher speed the method reduced REM sleep by more than 80%. CONCLUSIONS: Thus, the new instrumental method of RSD can be used to study developmental functions of neonatal REM sleep. In particular, the instrumental method can test the hypothesis that in rats neonatal RSD produces the adult depressogenic effect of neonatally administered clomipramine.

A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia.

BACKGROUND: Zolpidem is a short-acting, nonbenzodiazepine hypnotic with rapid onset of action. Even though it is not a benzodiazepine, it binds to one of three types of central benzodiazepine receptors, showing selective binding to the type 1 benzodiazepine receptor subtype. Therapeutic hypnotic dosages do not disturb normal sleep patterns (sleep architecture). METHOD: A randomized, double-blind, placebo-controlled, parallel group multicenter trial was conducted to determine the effectiveness of 10 mg and 15 mg of zolpidem in the long-term (35 nights) treatment of chronic insomnia in 75 patients. Sleep stage effects and motor and cognitive effects during the 35-night treatment period and the 3-night posttreatment period were also investigated. RESULTS: Within the first week of treatment, 10 mg of zolpidem had a significant effect on latency to persistent sleep and sleep efficiency. Efficacy was maintained throughout the 35 nights of drug administration. There was no evidence of residual effect with 10 mg of zolpidem. Stage 3-4 sleep was preserved at both the 10-mg and 15-mg zolpidem dosages. There was no evidence of tolerance at either dose and no significant treatment differences between the 10-mg zolpidem group and placebo in latency to persistent sleep or sleep efficiency during the posttreatment period. Also, the 10-mg zolpidem dosage was judged by the patients to have helped them fall asleep. Similar results were observed with the 15-mg zolpidem dosage. However, there were significant decreases in REM sleep at Weeks 3 and 4 with 15 mg of zolpidem compared with placebo. Overall, incidence rates of treatment-emergent adverse events in the zolpidem groups were similar to those in the placebo group. CONCLUSION: This is the first sleep laboratory study using a parallel placebo group to demonstrate efficacy for longer than 4 weeks with a hypnotic agent. In this study 10 mg of zolpidem was found to be safe and effective for the long-term treatment of chronic insomnia, demonstrating hypnotic efficacy without affecting sleep stages or producing tolerance effects, rebound effects, or detrimental effects on psychomotor performance. The 15-mg zolpidem dosage provided no clinical advantage over the 10-mg zolpidem dosage.

A comparison of the effects of flurazepam 30 mg and triazolam 0.5 mg on the sleep of insomniacs.

The effects of oral, bedtime triazolam 0.5 mg and flurazepam 30 mg, on the laboratory sleep of 12 insomniacs were compared in a double blind, crossover study. A 22 consecutive night schedule was used: Nts. 1--2 placebo; 3--6 first drug; 7--8 placebo; 9--14 no drugs; 15--16 placebo; 17--20 second drug; 21--22 placebo. In 6 Ss first drug was triazolam and second drug was flurazepam. In the other 6 Ss the drug order was reversed. Effects on sleep were assessed objectively by conventional EEG/EOG/EMG sleep recordings and subjectively by questionnaires administered each morning. Side or toxic effects were assessed by physical exams, clinical lab tests, and twice daily questionnaires. During their administration the two drugs were practically indistinguishable in their effects. Both significantly reduced objective and subjective measures of insomnia, such as total wake time and sleep latency. On discontinuation the drugs differentially affected sleep, e.g., on the first post flurazepam night total sleep time was significantly more than baseline whereas on first post triazolam night, total sleep time was significantly less than baseline. There were no remarkable side or toxic effects with either drug.

The effects of estazolam on sleep, performance, and memory: a long-term sleep laboratory study of elderly insomniacs.

Insomnia, a common complaint among the elderly, is generally treated with benzodiazepines. Long-acting benzodiazepines (e.g., flurazepam) often produce daytime somnolence and performance deficits, whereas short-acting drugs (e.g., triazolam) have been associated with marked rebound insomnia and anterograde memory loss. The authors designed a pilot study to evaluate the efficacy of an intermediate-acting benzodiazepine, estazolam (e.g., ProSom), as well as its side effects. The parameters studied were sleep, daytime performance, and memory. Ten geriatric patients (greater than 60 years of age) with insomnia participated in the study. They received placebo nightly for 2 weeks (baseline), estazolam 1 mg nightly for the next 4 weeks (treatment phase), and placebo again for 2 weeks (withdrawal period). Sleep was monitored by polysomnography the first two nights of each week in a sleep laboratory. Estazolam significantly decreased sleep latency, nocturnal awakenings, and wake time after sleep onset. Total sleep time increased an average of 63 minutes the first night of treatment. Significant improvements in wake time after sleep onset and total sleep time also were observed in the fourth week of estazolam treatment. Rebound insomnia occurred on the first withdrawal night only for wake time and total sleep time. By the next night, these sleep parameters returned to baseline. Neither day-time performance nor anterograde memory was adversely affected by estazolam treatment or its withdrawal. A 1-mg dose of estazolam appears to be a safe and effective hypnotic for elderly patients with insomnia.

Decreased dorsal raphe nucleus neuronal activity in adult chloral hydrate anesthetized rats following neonatal clomipramine treatment: implications for endogenous depression.

Although the biological cause of endogenous depression is unknown, one commonly held hypothesis proposes that depression results, in part, from decreased central serotonin (5-HT) neurotransmission. Previous research found that clomipramine (CLI) treatment of neonatal rats produced, in adult rats, a variety of behavioral and physiological dysfunctions resembling those found in human endogenous depression. It was later reported that adult CLI-treated rats exhibited a decreased discharge of 5-HT neurons in the dorsal raphe nucleus (DRN) compared with control rats. This finding, however, was not replicated in subsequent studies that detected differences in DRN receptor function. Several factors were identified that may have contributed to the inability of the latter studies to detect CLI vs. control differences in DRN firing rates and interspike interval histograms (ISIH). Among these were the anesthetic used, the age at which the adult rats were tested, and the location of the recording electrode. The present study controlled these variables by using chloral hydrate anesthesia, testing 'depressed' rats at both 2 and 3 months of age, and verifying electrode location using standard histological techniques. We found that DRN unit firing in 'depressed' rats (0.417 +/- 0.071 spikes/s) was less than half that of 'non-depressed' control rats (i.e. neonatal saline treatment 0.968 +/- 0.12 spikes/s). Additionally, ISIH's indicated that, in addition to the lower firing rate of 5-HT DRN neurons, adult CLI rats had an altered temporal discharge pattern of these neurons. Thus, the ISIH of 5-HT DRN neurons recorded from CLI rats was characterized by a flat distribution suggesting random temporal firing patterns. These results confirm previous findings of decreased DRN firing rates and flat ISIH's in 'depressed' rats and extend previous findings to younger rats of a different strain. The results thereby lend support to the hypothesis of a role for decreased central 5-HT as a substrate for the behavioral deficiencies observed in endogenous depression and suggest that these deficiencies may also result, in part, from a random, rather than orderly, temporal pattern of discharge in these neurons.

Brainstem carbachol injections in the urethane anesthetized rat produce hippocampal theta rhythm and cortical desynchronization: a comparison of pedunculopontine tegmental versus nucleus pontis oralis injections.

Previous research has demonstrated that brainstem injections of acetylcholine agonists (e.g., carbachol) produced electrophysiological indicators of rapid-eye-movement (REM) sleep in the cat. Recent reports now indicate that this phenomenon may hold true for rats as well. Relatively few reports, however, have examined the effect of these injections on REM indicators in the anesthetized rat, a preparation useful for elucidating underlying neurobiological mechanisms controlling REM sleep processes. The present study compared the effect of injections of carbachol (5 micrograms in 250 nl) into the pedunculopontine tegmental nucleus (PPTg) or the nucleus pontis oralis (NPO) on two tonic indicators of REM sleep in the urethane-anesthetized rat. Namely, changes in the hippocampal EEG and in the cortical EEG. Carbachol injections into either site produced a change in both the hippocampal EEG and cortical EEG to a REM-like state at short latencies. The length of these changes (duration of effect), however, was site-dependent. Thus, PPTg carbachol injections induced significantly longer lasting effects in both the hippocampal and cortical EEG than did NPO injections. The results that brainstem carbachol injections in rats, as in cats, may provide a useful model for investigating tonic REM sleep processes.

Decreased raphe unit activity in a rat model of endogenous depression.

One theory about the pathogenesis of endogenous depression is that decreased serotonergic (5-HT) neurotransmission is involved in producing the disorder. A key component of brain 5-HT neurotransmission is the discharge rate of 5-HT neurons in the dorsal raphe nucleus (DRN), a major aggregation of 5-HT neurons. We tested the hypothesis that the discharge rate of 5-HT neurons in the DRN was decreased in a new animal (rat) model of human endogenous depression. In this model, rats are treated neonatally with the antidepressant chlorimipramine. When adult, these animals exhibit several behavioral, REM sleep, and treatment response features of the human disorder. We found in a single unit measurements in adult, pentobarbital-anesthetized rats that, compared with 'non-depressed' control rats, the 'depressed' rats had a lower discharge rate of 5-HT neurons in the DRN. This correlation is consistent with the theory that 5-HT neurotransmission is diminished in endogenous depression.

The critical window of brain development from susceptive to insusceptive. Effects of clomipramine neonatal treatment on sexual behavior.

The immature brain is much more sensitive to abnormal experience, particularly sleep deprivation, drug exposure, and maternal separation. The critical time period during which features in the brain's susceptibility to such experience change, however, has not yet been determined. In previous studies on rats, we found that neonatal treatment with clomipramine (CLI) during postnatal days 8--21 (P8-21) produced behavioral and physiological abnormalities in adult rats that resembled the abnormalities found in human endogenous depression. The objective of the present study is to determine (1) the critical (more specifically, the latest) time frame in which CLI treatment will produce adult depression and (2) the shortest treatment window during which CLI can induce adult depression. Male rats were neonatally treated with CLI (20 mg/kg, sc) twice daily or with an equivolume of saline. The treatment windows were P12--17, P14--20, P16--22, and P12--15. Six variables, including number of mounts, intromission, ejaculation, mount latency, ejaculation latency, and post-ejaculation interval, were measured visually between the ages of 4 and 5 months. Rats treated with CLI showed significant sexual impairment in treatment windows P12--17 and P14--20 and slight sexual deficiency in the short window P12--15. No significant sexual impairment was found in window P16--22. We concluded that P14--20 was the latest window during which CLI treatment produces adult sexual deficiency and that 6 days might be the shortest treatment window to produce significant behavior abnormalities.

Evidence for REM sleep deprivation as the mechanism of action of antidepressant drugs.

In the treatment of endogenous depression REM sleep deprivation and imipramine have similar efficacy. Across drugs, efficacy of antidepressant activity is directly related to capacity of drugs to produce large and sustained reductions of REM sleep. Endogenous depression unimproved by REM sleep deprivation is unimproved by imipramine. Endogenous depression improvement by REM sleep deprivation and by amitriptyline have the same biological correlate, viz, REM rebound. In animals REM sleep deprivation produces several behavioral changes (e.g., increased motor, sexual, aggressive, pleasure seeking, feeding activities) which are the reverse of behavioral changes of human endogenous depression.