Irene Tobler

A single dose of ethanol (0.60 g/kg of body weight) was administered to eight young healthy male subjects 35 minutes before bedtime. Compared to the average value of two baseline nights, subjective sleep and polysomnographically determined sleep parameters were not significantly affected. In the first 2 hours of sleep after ethanol intake, the combined value of wakefulness, stage 1, and movement time was reduced. In this interval, visually scored stage 4 sleep was increased, and electroencephalographic (EEG) power density in nonrapid-eye-movement (nonREM) sleep was enhanced in the lowest delta frequencies and reduced in the beta range. Computed for the entire sleep episode, power density in REM sleep was enhanced in some theta frequencies. In the sleep episode initiated 24 hours after ethanol intake, power density in nonREM and REM sleep was enhanced in delta and theta frequencies, and the subjectively perceived number of awakenings was reduced. The effects of ethanol on EEG power spectra during sleep differ from those published for benzodiazepine and nonbenzodiazepine hypnotics. This indicates that the effects of ethanol on the human sleep EEG are not mediated by the benzodiazepine receptor.

The objective of this study was to investigate the entrainment of melatonin rhythms in rams using symmetrical light-dark cycles of different period length. Five groups of six Ile de France rams were kept in 12L:12D for 7 weeks and then (i) 12L:12D, (ii) 11L:11D, (iii) 10L:10D, (iv) 13L:13D and (v) 14L:14D for a further 3 weeks. Environmental factors other than the light dark cycle were not controlled. The onset and offset of the plasma melatonin rhythm in DD after 3 weeks of the respective light treatments was assessed for 48 hr, immediately after transferring to DD. The duration of secretion in DD was positively related to the length of the previous dark phase. The phase of the melatonin rhythm with respect to the anticipated dark phase suggested entrainment with no change in phase-relationship to the zeitgeber by 12L:12D and 13L:13D. Entrainment with a phase-delay or a phase-advance was apparent after 11L:11D and 14L:14D, but the individual rhythms were not all synchronized with respect to each other after 10L:10D. Activity recordings for 2-3-week periods during 12L:12D, 10L:10D and 14L:14D all showed a major 24-hr component at all times, with activity during the light phase in 12L:12D. It appears that melatonin may be readily desynchronized from overt activity-rest cycles in sheep. The upper and lower entrainment limits are probably greater than 28 hr and close to 20 hr cycles, respectively.

Sleep states, the power spectra of the cortical electroencephalogram (EEG) and cortical temperature (Tcrt) were determined in young rats (age 23-24 days). Recordings were made for 1 day under habitual 12 h light: 12 h dark (LD 12:12) conditions and on the subsequent day under continuous darkness (DD). The amount and distribution of the vigilance states differed little between experimental conditions. Sleep occurred predominantly during the actual (LD) or habitual (DD) 12-h light period. The EEG power density in the actual light period was lower than in the habitual light period. These differences were largest in the delta range for the EEG of non-rapid eye movement of sleep (NREMS) and in the theta range for the EEG of REM sleep (REMS) and waking. EEG power density in NREMS was somewhat lower in the LD dark period than in the corresponding DD period. The typical 24-h pattern of EEG power density in NREMS, which reflects processes underlying sleep regulation, was little affected by the experimental conditions. It is concluded that the light during an LD 12:12 schedule suppresses the EEG but has little effect on the vigilance states.

Several recent results show that sleep and sleep regulation are not only global phenomena encompassing the entire brain, but have local features. It is well established that slow-wave activity [SWA; mean electroencephalographic (EEG) power density in the 0.75-4.0 Hz band] in non-rapid eye movement (NREM) sleep is a function of the prior history of sleep and wakefulness. SWA is thought to reflect the homeostatic component of the two-process model of sleep regulation. According to this model, originally formulated for the rat and later extended to human sleep, the timing and structure of sleep are determined by the interaction of a homeostatic Process S and a circadian process. Our aim was to investigate the dynamics of SWA in the EEG of two brain regions (frontal and occipital cortex) after sleep deprivation (SD) in two of the mice strains most often used in gene targeting. C57BL/6J (n = 9) and 129/Ola (n = 8) were recorded during a 24-h baseline day, 6-h SD, and 18-h recovery. Both derivations showed a significant increase in SWA in NREM sleep after SD in both strains. In the first hour of recovery, SWA was enhanced more in the frontal derivation than in the occipital derivation and showed a faster decline. This difference resulted in a lower value for the time constant for the decrease of SWA in the frontal derivation (frontal: 10.9 +/- 2.1 and 6.8 +/- 0.9 h in Ola and C57, respectively; occipital: 16.6 +/- 2.1 and 14.1 +/- 1.5 h; P < 0.02; for each of the strains; paired t-test). Neither time constant differed significantly between the strains. The subdivision of SWA into a slower and faster band (0.75-2.5 Hz and 2.75-4.0 Hz) further highlighted regional differences in the effect of SD. The lower frequency band had a higher initial value in the frontal derivation than in the occipital derivation in both strains. Moreover, in the higher frequency band a prominent reversal took place so that power in the frontal derivation fell below the occipital values in both strains. Thus our results indicate that there may be differences in the brain in the effects of SD on SWA in mice, suggesting regional differences in the dynamics of the homeostatic component of sleep regulation. The data support the hypothesis that sleep has local, use- or waking-dependent features that are reflected in the EEG, as has been shown for humans and the laboratory rat.

The purpose of this study in the ISEMSI project was to record continuously the rest-activity cycle of the six subjects by ambulatory monitoring. It was planned to record the subjects during approximately 10 days of the pre-isolation period, the 28 days of isolation, and the 6-day post-isolation period. The three following major aims were envisaged: (1) to evaluate the possibility of monitoring the rest-activity cycle and sleep over prolonged time periods under conditions of confinement; (2) to examine the sleep period under the experimental condition in comparison to the pre- and post-experimental periods; and (3) to compare objective and subjective measures of sleep. The activity monitor is enclosed in a small metal case (68 g; 51 x 36.5 x 21 mm), which is worn on the wrist. The monitor is started via an interface; the recording interval was 1 minute. The subjects were instructed to read out their own data into a PC, and to obtain a graphic display within the confinement chambers to supervise the proper functioning of the activity monitors. Subjective data on sleep quality were obtained on a daily basis by means of a morning questionnaire. Once per week, the daytime vigilance states were assessed at 2-hour intervals on visual analogue scales. The activity recordings reflected the tightly controlled sleep-wake cycle during weekdays, and the permissive schedule on weekends. The data revealed no major sleep disturbances, which was in accordance with the subjective data. Most sleep complaints were due to the noise caused by snoring of other subjects. Self-rated tiredness tended to increase during confinement, whereas self-rated tenseness showed no trend. Due to organizational limitations, the data collected in the pre- and post-experimental periods were insufficient for an analysis. Summarizing, motor activity recorded by means of an ambulatory activity monitor proved to be a valuable non-electroencephalographic measure of sleep quality and rest-activity pattern of humans under conditions of long-term confinement. The activity monitor was found to be unobtrusive and reliable. The data read-out by the subjects during the experiment was feasible and contributed to the reduction of data loss. When the objective measures of sleep quality thus obtained were compared with subjective measures of this parameter, a good correspondence was found. Hence it can be said that activity monitoring represents a simple and reliable method for the long-term monitoring of sleep and wakefulness, which is well suited for application under space conditions.

In four experiments, performed at different months throughout the year, a significant daily rhythm in dopamine receptor binding has been observed. This rhythm is endogenous, as it persists in the absence of time cues. Striking differences in wave form, amplitudes, and timing of peaks during the year suggest that the endogenous rhythm undergoes seasonal variations.

Sleep was recorded in the rat after combined treatment with p-chlorophenylalanine (PCPA; 300 mg/kg) and 24-h sleep deprivation (SD) and then compared with sleep recorded after either treatment alone. PCPA alone reduced total sleep (TS), rapid eye movement sleep (REMS) per TS, as well as the power density of the EEG delta band (1.25-4.00 Hz) of non-REM sleep (NREMS). SD enhanced these sleep parameters and reduced the frequency of wake episodes. The combined treatment with PCPA and SD reduced TS and REMS/TS to a level similar to that induced by PCPA alone, and it increased delta activity to a level similar to that induced by SD alone. The frequency of wake episodes was reduced. It is concluded that essential aspects of sleep regulation are still functional during PCPA-induced insomnia. The sleep-inhibiting action of PCPA may be related to the hyperresponsiveness to stimuli rather than to the impairment of sleep regulation itself.

The hypnotic action and residual effects of a single bedtime dose of 8-chloro-6(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) (7.5 or 15 mg) or 8-chloro-6(o-chlorophenyl)-1-methyl-4H-S-triazolo[4,3-a] [1,4]benzodiazepine (triazolam) (0.25 or 0.5 mg) were investigated in young, healthy adults. Motor activity was continuously recorded by a wrist-worn activity monitor. In comparison to placebo, all compounds reduced night-time motor activity in the first half, but not in the second half of the night. Subjects rated their sleep as more quiet. Neither the spontaneous daytime motor activity nor the self-rated state in the morning and at noon was affected by drug intake in the preceding night. Performance in the morning as measured by a psychomotor test was significantly impaired only after triazolam 0.5 mg. There was no evidence for rebound insomnia in the 3 nights following drug intake. The results indicate that midazolam 15 mg and triazolam 0.25 mg have a reliable hypnotic action without significant residual sequelae.

The combined effect of midazolam (Ro 21-3981, Dormicum) and sleep deprivation on day-time sleep propensity was investigated in young, healthy adults. The oral administration of midazolam (15 mg) or placebo at bedtime was followed either by a sleep period of 7 or 4 h, or by no sleep at all. Sleep propensity was recorded at 2-h intervals throughout the following day by the multiple sleep latency test and self-ratings of tiredness. Performance was assessed in the morning and afternoon by a psychomotor test. Partial and total sleep deprivation caused a marked and significant increase of day-time sleep propensity. However, there was no significant difference between the midazolam and placebo condition after 7 or 4 h of sleep. After total sleep deprivation, sleep propensity was higher after placebo than after midazolam. Neither the treatment nor sleep duration had a significant effect on performance. The results show that a bedtime dose of 15 mg midazolam followed by normal or restricted sleep does not significantly affect day-time alertness.

Sleep states and power spectra of the electroencephalogram were determined for consecutive 4-s epochs during 24 h in rats that had been implanted with electrodes under deep pentobarbital anesthesia. The power spectra in non-rapid eye movement sleep (NREMS) showed marked trends: low-frequency activity (0.75-7.0 Hz) declined progressively throughout the 12-h light period (L) and remained low during most of the 12-h dark period (D); high-frequency activity (10.25-25.0 Hz) rose toward the end of L and reached a maximum at the beginning of D. Within a single NREMS episode (duration 0.5-5.0 min), slow-wave activity (0.75-4.0 Hz) increased progressively to a plateau level. The rise was approximated by a saturating exponential function: although the asymptote level of the function showed a prominent 24-h rhythm, the time constant remained relatively stable (approximately 40 s). After short interruptions of NREMS episodes, slow-wave activity rose more steeply than after long interruptions. The marked 24-h variation of maximum slow-wave activity within NREMS episodes may reflect the level of a homeostatic sleep process.

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The 24-hr sleep-wake distribution and power spectra of the electroencephalogram were determined in rabbits that had been implanted with cortical and hippocampal electrodes. A diurnal preference for sleep was observed. The spectral power density in nonrapid eye movement sleep (NREM sleep) of the cortex showed a decreasing trend in most frequencies within the 12-hr light period. In the 12-hr dim period no clear trend was present. Most hippocampal EEG frequencies decreased in NREM sleep in the first two hours of the light period, and thereafter stayed on a constant level. Sleep deprivation elicited the following changes: a prolonged increase of NREM sleep and a short increase of REM sleep; in the cortex, an increase of slow-wave activity (SWA; power density in the 0.25-2.0 Hz frequency band) in NREM sleep, which declined in the course of recovery; an enhancement of slow-wave (1.25-3 Hz) and theta (6.25-7 Hz) activity in REM sleep. The hippocampus showed an increase in NREM sleep power density in almost all frequencies. In REM sleep the hippocampus exhibited an increase in power density in the 6.25-7 Hz and 12.25-13 Hz bands, whereas in the 7.25-8 Hz band the values were below baseline. The results show that SWA in NREM sleep and theta activity in REM sleep are enhanced by sleep deprivation, as has been observed in other mammalian species. The EEG changes in the hippocampus resembled those in the cortex.

The actometer is worn on the wrist and stores the sum of the signals induced by movements in a solid-state memory. If the data are collected at one-minute intervals for example, they are fed into a personal computer and printed graphically after at least 21 days. The method serves for long-term recording of the rest-activity rhythm and its disturbances, and the movements occurring during sleep under normal life conditions. Furthermore, sleep disturbances as well as the effect of drugs on sleep and the results of therapeutic interventions can be objectively determined. Research and clinical applications are described.

Sleep states and power spectra of the electroencephalogram (EEG) were determined in freely moving young rats. Recordings during 24 h were obtained from the same animals at three different ages. Already at the age of 23 days waking predominated in the 12-h dark period. Rapid-eye-movement sleep (REMS) declined between the age of 23 and 40 days. Its 24-h maximum was situated in the dark period at 23 and 29 days of age and in the light period at 40 days. Slow-wave activity (SWA; 0.75-4.0 Hz) of the non-REMS (NREMS) EEG showed marked age-related changes: a declining trend in the 12-h light period was absent at 23 days, moderate at 29 days, and prominent at 40 days. At 23 days, SWA progressively declined within ultradian sleep episodes and at 24 days was massively increased after 2-h sleep deprivation (SD). At the age of 30 days, 6-h SD induced much smaller changes. The distinct 24-h pattern of high-frequency activity (10.25-25.0 Hz) was present at all ages and may represent an EEG correlate of a circadian process. We conclude that homeostatic mechanisms regulating NREMS intensity are already operative a few days after weaning.

Vigilance states, electroencephalogram (EEG) power spectra (0.25-25.0 Hz), and cortical temperature (TCRT) of 10 rats were obtained during a baseline day, a 24-h sleep deprivation (SD) period, and 2 days of recovery (recoveries 1 and 2). EEG power density in waking gradually increased in most frequencies during the SD period. Non-rapid-eye-movement (NREM) sleep was enhanced on both recovery days, and rapid-eye-movement sleep was enhanced only on recovery 1. In the initial 4 h of recovery 1, EEG slow-wave activity (SWA; mean power density 0.75-4.0 Hz) in NREM sleep was elevated relative to baseline, and the number of brief awakenings (nBA) was reduced. In the dark period of recovery 1 and the light period of recovery 2, SWA was below baseline, and nBA was increased. During the entire recovery period, SWA and nBA, both expressed as deviation from baseline values, were negatively correlated. During the SD period, TCRT was above baseline, and in the initial 16 h of recovery 1 it was below baseline. Whereas TCRT was negatively correlated with NREM sleep, no significant correlation was found between TCRT and SWA within NREM sleep. It is concluded that SD causes a short-lasting intensification of sleep, as indicated by the enhanced SWA and the reduced nBA, and a long-lasting increase in sleep duration. The different time courses of SWA and TCRT suggest that variations in NREM sleep intensity are not directly related to changes in TCRT.

... However, no significant increase in SWS or SWA in the last 3 hr of the sleep episode over any of the preceding 3-hr intervals was present and SWA in this interval was significantly below the values observed at the beginning of sleep. ...

The hypnotic action and residual effects of a single night-time dose of midazolam (Ro 21-3981, Dormicum, 7.5 mg; CAS 59467-70-8) were investigated in young, healthy adults. The subjects went to bed at the habitual time and were awakened 3 h later for drug or placebo intake. Then they were allowed to continue their sleep. Motor activity was continuously recorded by a wrist-worn activity monitor. In comparison to placebo, prolonged night-time immobility periods were more frequent after midazolam. Sleep tended to be perceived as more quiet and as less interrupted by awakenings. 15 min after awakening in the morning, the subjects felt more relaxed after midazolam than after placebo. Performance assessed 2 h after awakening by a psychomotor test showed no decrement. The results show that a 7.5-mg dose of midazolam taken in the first half of the night has a significant hypnotic action without impairing psychomotor performance in the morning.

Wrist motor activity was continuously monitored in 10 major unipolar depressed inpatients. Clinical state and motor activity parameters were studied. The data obtained at the beginning of the hospitalization, before the antidepressant treatment, were compared to chose found just before discharge. Time of day effect and subtypes of depression (endogenous versus non-endogenous) were considered. Motor retardation is related to both fluctuations of activity level and high number of 15 minute immobility epochs. Immobility parameters at night and during day were a good indicator of the severity of the depressive state. The temporal pattern of activity level was related to the subtype of depression.

... In: MH Kryger, T. Roth and WC Dement (Eds.), Principles and Practice of Sleep Medicine, 2nd edn., Saunders, Philadelphia, pp. 309-320. ... Neurosci Lett., 42: 49-54. Trachsel, L., Edgar, DM and Heller, HC (1991) Are ground squirrels sleep deprived during hibernation? Am. ...

The key clinical aspects of FFI, i.e. hypovigilance and attention deficit, inability to generate EEG sleep patterns, sympathetic hyperactivity and attenuation of vegetative and hormonal circadian oscillations, are related to selective atrophy of the anteroventral and mediodorsal thalamic nuclei. These nuclei constitute the limbic part of the thalamus interconnecting limbic and paralimbic regions of the cortex and other subcortical structures in the limbic system including the hypothalamus. The hypothalamus released from cortico-limbic control is shifted to a prevalence of activating, as opposed to deactivating, functions including loss of sleep, sympathetic hyperactivity and the attendant attenuation of autonomic circadian and endocrine oscillations. These findings document that the limbic thalamus has a strategic position in the central autonomic network running from the limbic cortical regions to the lower brain stem which regulates the body's homeostasis in an integrated fashion.

There is a wealth of data supporting a central role for the prion protein (PrP) in the neurodegenerative prion diseases of both humans and other species, yet the normal function of PrP, which is expressed at the cell surface of neurons and glial cells, is unknown. It has been speculated that neuropathology may be due to loss of normal function of PrP. Here we show that in mice devoid of PrP there is an alteration in both circadian activity rhythms and patterns. To our knowledge, this is the first null mutation that has been shown to affect sleep regulation and our results indicate that at least one of the inherited prion diseases, fatal familial insomnia, where there is a profound alteration in sleep and the daily rhythms of many hormones, may be related to the normal function of the prion protein.

Mice are the preferred mammalian species for genetic investigations of the role of proteins. The normal function of the prion protein (PrP) is unknown, although it plays a major role in the prion diseases, including fatal familial insomnia. We investigated its role in sleep and sleep regulation by comparing baseline recordings and the effects of sleep deprivation in PrP knockout mice (129/SV) and wild-type controls (129/SV x C57BL/6), which are the mice used for most gene targeting experiments and whose behavior is not well characterized. Although no difference was evident in the amount of vigilance states, the null mice exhibited a larger degree of sleep fragmentation than the wild-type with almost double the amount of short waking episodes. As in other rodents, cortical temperature closely reflected the time course of waking. The increase of slow-wave activity (SWA; mean EEG power density in the 0.25-4.0 Hz range) at waking to nonrapid eye movement (NREM) sleep transitions was fas...

It is now well known that daily torpor induces a sleep deficit. Djungarian hamsters emerging from this hypometabolic state spend most of the time in sleep. This sleep is characterized by high initial values of EEG slow-wave activity (SWA) that monotonically decline during recovery sleep. These features resemble the changes seen in numerous species during recovery after prolonged wakefulness or sleep deprivation (SD). When hamsters are totally or partially sleep deprived immediately after emerging from torpor, an additional increase in SWA can be induced. It has been therefore postulated, that these slow- waves are homeostatically regulated, as predicted by the two-process model of sleep regulation, and that during daily torpor a sleep deficit is accumulated as it is during prolonged waking. The predominance of SWA in the frontal EEG observed both after SD and daily torpor provides further evidence for the similarity of these conditions. It has been shown in several animal and human ...