Effects of growth hormone on sleep-waking patterns in cats.

Cats given growth hormone in doses from 50–1000 μg, i.p., showed a selective elevation of REM sleep in the first 3 hr postinjection. Bovine thyrotropin control injections did not alter sleep patterns. When the effect of growth hormone on sleep was blocked by REM deprivation for the first 3 hr, the REM elevating effect of growth hormone still occurred in the subsequent sleep period. These results suggest that growth hormone affects the central nervous system, either directly or indirectly. Also, the greatly increased secretion of growth hormone, which has been reported during slow-wave sleep in man, may play a role in the occurrence of REM sleep.     

The effect of memorization processes on the structural organization of natural human sleep

The effect of sleep on learning was investigated, comparing results of memorizing and reproduction of an unknown text before and after subsequent sleep, with a detailed analysis of sleep patterns. Psychological tests excluded the possibility of emotional and stress factors. Presleep learning did not influence mean values of such sleep parameters as total sleep time or duration of different sleep stages. The main finding ot the present experiment was a redistribution of stage REM during nocturnal sleep following learning--its increase in the second sleep cycle with a corresponding decrease toward the end of night. Also, individual difficulties in learning were inversely related to REM latency. Changes in sleep patterns after learning didn't influence the total number of sleep cycles. It is suggested that the REM phase of sleep might be involved in the processing of information acquired during wakefulness.     

Temporally structured replay of awake hippocampal ensemble activity during rapid eye movement sleep

Human dreaming occurs during rapid eye movement (REM) sleep. To investigate the structure of neural activity during REM sleep, we simultaneously recorded the activity of multiple neurons in the rat hippocampus during both sleep and awake behavior. We show that temporally sequenced ensemble firing rate patterns reflecting tens of seconds to minutes of behavioral experience are reproduced during REM episodes at an equivalent timescale. Furthermore, within such REM episodes behavior-dependent modulation of the subcortically driven theta rhythm is also reproduced. These results demonstrate that long temporal sequences of patterned multineuronal activity suggestive of episodic memory traces are reactivated during REM sleep. Such reactivation may be important for memory processing and provides a basis for the electrophysiological examination of the content of dream states.     

A probabilistic model for the ultradian timing of REM sleep in mice

A salient feature of mammalian sleep is the alternation between rapid eye movement (REM) and non-REM (NREM) sleep. However, how these two sleep stages influence each other and thereby regulate the timing of REM sleep episodes is still largely unresolved. Here, we developed a statistical model that specifies the relationship between REM and subsequent NREM sleep to quantify how REM sleep affects the following NREM sleep duration and its electrophysiological features in mice. We show that a lognormal mixture model well describes how the preceding REM sleep duration influences the amount of NREM sleep till the next REM sleep episode. The model supports the existence of two different types of sleep cycles: Short cycles form closely interspaced sequences of REM sleep episodes, whereas during long cycles, REM sleep is first followed by an interval of NREM sleep during which transitions to REM sleep are extremely unlikely. This refractory period is characterized by low power in the theta and sigma range of the electroencephalogram (EEG), low spindle rate and frequent microarousals, and its duration proportionally increases with the preceding REM sleep duration. Using our model, we estimated the propensity for REM sleep at the transition from NREM to REM sleep and found that entering REM sleep with higher propensity resulted in longer REM sleep episodes with reduced EEG power. Compared with the light phase, the buildup of REM sleep propensity was slower during the dark phase. Our data-driven modeling approach uncovered basic principles underlying the timing and duration of REM sleep episodes in mice and provides a flexible framework to describe the ultradian regulation of REM sleep in health and disease.     

Evidence for the re-enactment of a recently learned behavior during sleepwalking

Animal studies have shown that sequenced patterns of neuronal activity may be replayed during sleep. However, the existence of such replay in humans has not yet been directly demonstrated. Here we studied patients who exhibit overt behaviors during sleep to test whether sequences of movements trained during the day may be spontaneously reenacted by the patients during sleep. We recruited 19 sleepwalkers (who displayed complex and purposeful behaviors emerging from non REM sleep), 20 patients with REM sleep behavior disorder (who enacted their dreams in REM sleep) and 18 healthy controls. Continuous video sleep recordings were performed during sleep following intensive training on a sequence of large movements (learned during a variant of the serial reaction time task). Both patient groups showed learning of the intensively trained motor sequence after sleep. We report the re-enactment of a fragment of the recently trained motor behavior during one sleepwalking episode. This study provides, to our knowledge, the first evidence of a temporally-structured replay of a learned behavior during sleep in humans. Our observation also suggests that the study of such sleep disorders may provide unique and critical information about cognitive functions operating during sleep.     

Selective REM sleep deprivation during daytime I. Time course of interventions and recovery sleep

Although repeated selective rapid eye movement (REM) sleep deprivation by awakenings during nighttime has shown that the number of sleep interruptions required to prevent REM sleep increases within and across consecutive nights, the underlying regulatory processes remained unspecified. To assess the role of circadian and homeostatic factors in REM sleep regulation, REM sleep was selectively deprived in healthy young adult males during a daytime sleep episode (7-15 h) after a night without sleep. Circadian REM sleep propensity is known to be high in the early morning. The number of interventions required to prevent REM sleep increased from the first to the third 2-h interval by a factor of two and then leveled off. Only a minor REM sleep rebound (11.6%) occurred in the following undisturbed recovery night. It is concluded that the limited rise of interventions during selective daytime REM sleep deprivation may be due to the declining circadian REM sleep propensity, which may partly offset the homeostatic drive and the sleep-dependent disinhibition of REM sleep.     

An ether stressor increases REM sleep in rats: possible role of prolactin

Sleep alterations after a 1-min exposure to ether vapor were studied in rats to determine if this stressor increases rapid eye-movement (REM) sleep as does an immobilization stressor. Ether exposure before light onset or dark onset was followed by significant increases in REM sleep starting approximately 3-4 h later and lasting for several hours. Non-REM (NREM) sleep and electroencephalographic slow-wave activity during NREM sleep were not altered. Exposure to ether vapor elicited prolactin (Prl) secretion. REM sleep was not promoted after ether exposure in hypophysectomized rats. If the hypophysectomy was partial and the rats secreted Prl after ether exposure, then increases in REM sleep were observed. Intracerebroventricular administration of an antiserum to Prl decreased spontaneous REM sleep and inhibited ether exposure-induced REM sleep. The results indicate that a brief exposure to ether vapor is followed by increases in REM sleep if the Prl response associated with stress is unimpaired. This suggests that Prl, which is a previously documented REM sleep-promoting hormone, may contribute to the stimulation of REM sleep after ether exposure.     

Restricted sleep regime in rhesus monkeys: differential effect of one night's sleep loss and selective REM deprivation.

The differential effect of either one night's total sleep deprivation (TSD) or of selective REM deprivation (REMD) was examined on post-deprivation daytime EEG patterns with respect to control, in the same group of rhesus monkeys. TSD resulted in significantly decreased wakefulness and increased amounts of NREM and REM on the first day following TSD. In contrast, highly significant REM elevation without alteration of other EEG states occurred for 3 days after REMD. Post-deprivation behavioural and photic-induced neural changes were minor. The results obtained after sleep deprivation in simians are comparable with similar findings in human subjects.     

Biphasic effects of pimozide on sleep-wakefulness in dogs

Sleep-wakefulness patterns in dogs were studied using computerized on-line power spectral analysis and off-line automatic stage-classification during control recordings and after oral treatment with three doses of the specific dopamine blocker pimozide. A biphasic effect on sleep-wakefulness patterns was found. At 0.016 mg/kg (the ED₅₀-value for the antagonism of apomorphine-induced vomiting in dogs), pimozide significantly increased the time spent awake, and significantly decreased slow wave sleep and REM sleep. No significant effects were obtained with a four times higher dose of pimozide. At 0.16 mg/kg, pimozide significantly decreased the time spent awake and significantly increased slow wave sleep and REM sleep. The effects appear the opposite of those described for apomorphine and suggest that dopamine plays a role in the physiology of sleep-wakefulness regulation.     

Effects of bromocriptine and alpha-flupenthixol on sleep in REM sleep deprived rats.

Administration of bromocriptine mesylate (5 mg/kg, i.p.), a dopamine receptor stimulant, to rats which were deprived of REM sleep for 24 hours resulted in a significant increase in wakefulness as well as significant reduction of REM sleep during the first 5 hours of EEG recording. These effects were completely abolished by pretreatment with α-flupenthixol (0.2 mg/kg, i.p.), a dopamine receptor blocker. The loss of REM sleep has not been regained during the next 25 hours of EEG recording suggesting that the stimulation of dopamine receptors reduced REM sleep without causing subsequent REM rebound. These data raise questions on the negative dopamine control of REM sleep and on the potential use of dopamine stimulants in clinical situations characterized by excessive REM or by REM sleep dysfunction (narcolepsy).     

Differential activation within costal diaphragm during rapid-eye-movement sleep in cats

Simultaneous recordings of the diaphragmatic electromyogram (EMG) were made from two separate regions of the costal diaphragm in six normal cats. The diaphragmatic activities were always synchronous and the amplitudes and rates of rise were similar during slow-wave sleep. In contrast, during natural rapid-eye-movement (REM) sleep, different activity was often present in the two leads. These differences were in the time of onset and offset, as well as in the amplitude and spike patterns, and occurred in approximately 5-20% of the diaphragmatic bursts averaged over the entire REM sleep period. With respect to eye movement density, the rate of differential activation was higher during periods of high density (26%) than in the absence of eye movements (1%) in the four animals for which these data were available. Differential activation of portions of the costal diaphragm is apparently a normal event of REM sleep. This could result from descending state-specific phasic neuronal activity that bypasses the medullary respiratory generator. Differential activation of portions of the diaphragm could contribute to disordered ventilation during REM sleep.     

Effects of purified human interleukin-1 on sleep and febrile response of cats

From cats prepared for chronic polygraphic recordings sleep patterns were obtained for 8 hours after: 1) intracerebroventricular (icv) injection of artificial cerebrospinal fluid (aCSF), day 1; 2) icv injection of interleukin-1 (I1-1), day 2; 3) injection of aCSF, 24 h after injection of I1-1, day 3; 4) injection of aCSF, 48 after injection of I1-1, day 4. Three doses of I1-1 were tested. The dose of 10 nmol slightly prolonged sleep, whereas a dose of 40 nmol totally inhibited sleep. Twenty nmol of I1-1 elicited sleep and increased body temperature. Total sleep (TS) time was significantly increased due to the significant increase in non REM (NREM) sleep as compared to the control day 1. REM sleep was also increased, but this increase did not reach statistical significance. Wakefulness (W) was significantly reduced. At this time the cats were febrile. On day 3, a further significant increase in TS occurred. NREM was significantly increased when compared with day 1, whereas the increase in REM sleep was significant when compared to both day 1 and day 2. At this time body temperature was normal. The increase in REM sleep on days 2 and 3 resulted entirely from the significant increase in the number of REM periods. On day 4, W showed tendency to increase while sleeping time decreased; such tendency suggests that sleep increase caused by I1-1 slowly returns to the control levels. Our results, together with the earlier evidence on somnogenic and pyrogenic action of I1-1, suggest that these actions may be temporarily dissociated.     

Selective REM Sleep Deprivation Improves Expectation-Related Placebo Analgesia

The placebo effect is a neurobiological and psychophysiological process known to influence perceived pain relief. Optimization of placebo analgesia may contribute to the clinical efficacy and effectiveness of medication for acute and chronic pain management. We know that the placebo effect operates through two main mechanisms, expectations and learning, which is also influenced by sleep. Moreover, a recent study suggested that rapid eye movement (REM) sleep is associated with modulation of expectation-mediated placebo analgesia. We examined placebo analgesia following pharmacological REM sleep deprivation and we tested the hypothesis that relief expectations and placebo analgesia would be improved by experimental REM sleep deprivation in healthy volunteers. Following an adaptive night in a sleep laboratory, 26 healthy volunteers underwent classical experimental placebo analgesic conditioning in the evening combined with pharmacological REM sleep deprivation (clonidine: 13 volunteers or inert control pill: 13 volunteers). Medication was administered in a double-blind manner at bedtime, and placebo analgesia was tested in the morning. Results revealed that 1) placebo analgesia improved with REM sleep deprivation; 2) pain relief expectations did not differ between REM sleep deprivation and control groups; and 3) REM sleep moderated the relationship between pain relief expectations and placebo analgesia. These results support the putative role of REM sleep in modulating placebo analgesia. The mechanisms involved in these improvements in placebo analgesia and pain relief following selective REM sleep deprivation should be further investigated.     

Control of motoneuron function and muscle tone during REM sleep, REM sleep behavior disorder and cataplexy/narcolepsy

REM sleep triggers a potent suppression of postural muscle tone - i.e., REM atonia. However, motor control during REM sleep is paradoxical because overall brain activity is maximal, but motor output is minimal. The skeletal motor system remains quiescent during REM sleep because somatic motoneurons are powerfully inactivated. Determining the mechanisms triggering loss of motoneuron function during REM sleep is important because breakdown in REM sleep motor control underlies sleep disorders such as REM sleep behavior disorder (RBD) and cataplexy/narcolepsy. For example, RBD is characterized by dramatic REM motor activation resulting in dream enactment and subsequent patient injury. In contrast, cataplexy a pathognomonic symptom of narcolepsy - is caused by the involuntary onset of REM-like atonia during wakefulness. This review highlights recent work from my laboratory that examines how motoneuron function is lost during normal REM sleep and it also identifies potential biochemical mechanisms underlying abnormal motor control in both RBD and cataplexy. First, I show that both GABAB and GABAA/glycine mediated inhibition of motoneurons is required for generating REM atonia. Next, I show that impaired GABA and glycine neurotransmission triggers the cardinal features of RBD in a transgenic mouse model. Last, I show that loss of an excitatory noradrenergic drive onto motoneurons is, at least in part, responsible for the loss of postural muscle tone during cataplexy in narcoleptic mice. Together, this research indicates that multiple transmitters systems are responsible for regulating postural muscle tone during REM sleep, RBD and cataplexy.     

Vasotocin, melatonin and narcolepsy: Possible involvement of the pineal gland in its patho-physiological mechanism

Both the pineal nonapeptide hormone arginine vasotocin (AVT) (2.5 μg) administered intra-nasally and the pineal indole melatonin (50 mg) administered intravenously to three male narcoleptics (two with auxiliary symptoms and one with sleep attacks only), dramatically increased the amount of REM sleep and decreased REM sleep latency. The duration of the sleep onset REM periods in the two narcoleptics with auxiliary symptoms increased by more than 100 percent after AVT and melatonin administration. In the narcoleptic with sleep attacks only both AVT and melatonin induced REM periods at sleep onset. The hypothesis is advanced that narcolepsy represents an impairment of the melatonin-AVT control in the induction and circadian organization of REM sleep associated with an immaturity of REM triggering centers.     

The influence of prior wakefulness on REM sleep

Data from studies of naps and of shifted sleep were used to determine the relationship between two measures of rapid eye movement (REM) sleep (percentage of REM in the first 2 hr of sleep and REM latency) and prior wakefulness. For each sample, we calculated the difference between the observed value and that predicted by a cosine function that estimated the circadian rhythm of REM sleep propensity. The difference values were found to correlate reliably with hours and log hours of prior wakefulness. We conclude that while REM sleep is regulated in part by an endogenous circadian oscillator, it is also influenced by the duration of prior wakefulness.     

Vasotocin, melatonin and narcolepsy: Possible involvement of the pineal gland in its patho-physiological mechanism

Both the pineal nonapeptide hormone arginine vasotocin (AVT) (2.5 μg) administered intra-nasally and the pineal indole melatonin (50 mg) administered intravenously to three male narcoleptics (two with auxiliary symptoms and one with sleep attacks only), dramatically increased the amount of REM sleep and decreased REM sleep latency. The duration of the sleep onset REM periods in the two narcoleptics with auxiliary symptoms increased by more than 100 percent after AVT and melatonin administration. In the narcoleptic with sleep attacks only both AVT and melatonin induced REM periods at sleep onset. The hypothesis is advanced that narcolepsy represents an impairment of the melatonin-AVT control in the induction and circadian organization of REM sleep associated with an immaturity of REM triggering centers.     

A world record in marathon tennis: sleep deprivation and performance

We studied the effects of marked sleep deprivation on the EEG patterns and performance of a physically fit man (age 26) on the occasion of the world record continuous marathon tennis play (147 hours, 20 minutes). Before and immediately after the marathon, the sleep patterns of the player were recorded in our laboratory. After playing for 40 and 80 hours and within 24 hours, the performance changes were evaluated each hour. Amounts of the different sleep stages during the first recovery night compared with those of the baseline indicate an increase of 56% for total sleep time, 54% for stages 1 and 2, 154% for stages 3 and 4 and 20% for REM sleep. During the second recovery night, only REM sleep showed an increase. Activity index showed a marked decrease after 80 hours of sleep deprivation compared with that after 40 hours and was dramatically worsened during nighttime. The number of faults and pauses was also increased after 80 hours, suggesting a clear performance deterioration. Our results confirmed the effects of sleep deprivation on the recovery and performance deterioration.