Section of Psychopharmacology and Sleep Research
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University of Zürich - Institute of Pharmacology and Toxicology Section of Psychopharmacology and Sleep Research |
Animals emerging from hibernation or daily torpor show an initial increase in electroencephalogram slow-wave activity (SWA, power density between 0.75 and 4.0 Hz) in non-REM sleep, which subsequently declines. These typical features of sleep following prolonged waking led to the interpretation that the animals incur a sleep deprivation (SD) during torpor. This hypothesis has recently been questioned because the increase in SWA disappears in ground squirrels when sleep deprived immediately following hibernation. Here we show that in Djungarian hamsters subjected to SD immediately after daily torpor a predictable increase in SWA occurs during recovery. This supports the notion that the hamsters must sleep to dissipate the pressure for SWA incurred during torpor. The similarity between sleep after waking and torpor may provide a key for understanding sleep regulation.
Neuroreport, 11, 881-885 (2000).
Gene targeted mice can be used as models to investigate the mechanisms underlying sleep regulation. Three commonly used background strains for gene targeting (129/Ola, 129/SvJ and C57BL/6J) were subjected to 4-h and 6-h sleep deprivation (SD), and their sleep and sleep EEG were continuously recorded. The two-process model of sleep regulation has predicted the time course of slow-wave activity (SWA) in nonREM sleep after several sleep-wake manipulations in humans and the rat [3] [9]. We tested the capacity of the model to predict SWA in nonREM sleep on the basis of the temporal organization of sleep in mice. The strains differed in the amount and distribution of sleep and the time course of SWA. After spontaneous waking episodes of 10-30 min as well as after SD, SWA was invariably increased. Simulations of the time course of SWA were successful for 129/SvJ and C57BL/6J, but were not satisfactory for 129/Ola. Since the time constants are assumed to reflect the dynamics of the physiological processes involved in sleep regulation, the results provide a basis for the use of gene targeted mice to investigate the underlying mechanisms.
Brain Res, 857, 8-19 (2000).
Changes in the functional organization of the brain in the course of sleep and waking are reflected by different patterns of regional cerebral blood flow (rCBF). To investigate the effect of the hypnotic zolpidem, a benzodiazepine receptor agonist, drug or placebo were administered to eight young healthy men prior to bedtime. The subjects were sleep-deprived to promote sleep during the 4-h recording period in the positron emission tomography (PET) scanner. Intravenous injections of labeled water were administered during pre-drug wakefulness, and during stage 2, stage 4 and REM sleep, each injection being followed by an emission scan. Statistical parametric mapping was used to investigate effects of treatment and sleep states. During sleep (combined stages 2 and 4, and REM sleep) relative rCBF was lower after zolpidem than after placebo in the basal ganglia and insula, and higher in the parietal cortex. A 'multiple study' analysis of REM sleep revealed that rCBF in the anterior cingulum was lower after zolpidem than after placebo, whereas rCBF in occipital and parietal cortex, parahippocampal gyrus and cerebellum was higher. When the pooled data (drug and placebo) of stage 2 and stage 4 were compared to wakefulness, rCBF was lower in prefrontal cortex and insula, and higher in occipital and parietal cortex. The results indicate that some differences in rCBF from wakefulness to nonREM sleep are further augmented by zolpidem.
J. Sleep Res., 9, 161-173 (2000).
To study the role of GABA-ergic mechanisms in sleep regulation, the combined action of 40-h sleep deprivation and either 20 mg zolpidem or placebo on the sleep EEG were investigated by quantitative EEG analysis in eight young men who participated in a positron emission tomography (PET) study. Compared to baseline, sleep deprivation increased low-frequency (1.25-7.0 Hz) EEG power in nonREM (NREM) sleep in the placebo night. After administration of zolpidem, power in the 3.75-10.0 Hz range and in the 14.25-16.0 Hz bin was reduced. The largest decrease was observed in the theta band. Comparison with placebo revealed that zolpidem attenuated power in the entire 1.75-11.0 Hz range. Plasma concentration of zolpidem at 4.5 hours after intake showed a positive correlation with the drug-induced difference in power from placebo in the 14.25-16.0 Hz band. Regional EEG analysis based on bipolar derivations along the antero-posterior axis disclosed for NREM sleep a drug-induced posterior shift of power in the frequency range of 7.75-9.75 Hz. Zolpidem did not affect REM sleep spectra. It is concluded that sleep deprivation and agonistic modulation of GABAA receptors have separate and additive effects on power spectra and that their effects are mediated by different neurophysiological mechanisms.
J. Sleep Res., 9, 175-183 (2000).
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 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. It is thought to reflect the homeostatic component of the two-process model of sleep regulation. Our aim was to investigate the dynamics of SWA in the EEG of two brain regions (frontal and occipital cortex) after sleep deprivation 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 sleep deprivation (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 significantly smaller 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). The subdivision of SWA into a slower and faster band (0.75-2.5 Hz and 2.75-4.0 Hz), showed that it is especially the lower frequency band which has higher initial values and decreases more quickly than the higher one. Thus, our results indicate regional brain differences 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 which are reflected in the EEG, as has been shown for humans and the laboratory rat.
J. Neurophysiology, 84, 1888-1893 (2000).
Despite an initial sedative effect, alcohol disrupts sleep persistently and should not be used as a sleeping aid. Nocturnal withdrawal symptoms may lead to an increased duration of wakefulness, and to tachycardia and sweating in the second half of the night. It is not known by which mechanism alcohol affects sleep; however, effects do not appear to depend on the stimulation of benzodiazepine receptors or the antagonism at adenosine receptors. Alcohol can exacerbate primary sleep disturbances such as sleep apnea and nocturnal myoclonus, and thereby contribute to excessive daytime sleepiness. The sleep of alcoholic patients is characterized by increased sleep latency, and reduced sleep efficiency, total sleep time, slow wave sleep and non-REM sleep. Even during abstinence, the changes in sleep architecture can persist for months or years, and might contribute to a relapse into alcoholism. The use of benzodiazepines or other hypnotics to treat alcohol-related sleep disturbances is not recommended.
Ther. Umsch., 57, 241-245 (2000).
OBJECTIVES: Investigation of sleep and sleep EEG before and after stereotactic neurosurgery. METHODS: All-night polysomnographic recordings were obtained in 3 neurogenic pain patients and 3 parkinsonian patients. One subject of each group was recorded in addition 3 months after surgery. Stereotactic operations were performed in the medial thalamus and on the pallido-thalamic tract to relieve neurogenic pain and parkinsonian symptoms, respectively. RESULTS: Sleep efficiency was little affected by the surgical intervention in neurogenic pain patients and a dramatic reduction in REM sleep occurred, which had recovered in the subject recorded after 3 months. After the surgery parkinsonian patients showed an increase in total sleep time and in sleep efficiency, and a decrease in REM sleep latency. Sleep efficiency remained elevated in the 3 months follow-up. Medial thalamotomy abolished spindle frequency activity (SFA) in the power and coherence spectra in non-REM sleep stage 2 systematically. Pallido-thalamic tractotomy attenuated SFA only to varying degrees. After 3 months SFA had reemerged. The alpha peak of the waking EEG was shifted to lower frequencies after surgery in 5 of 6 patients and had reverted to the original frequency 3 months later. CONCLUSIONS: Medial thalamotomy or pallido-thalamic tractotomy had acute and reversible effects on the EEG and long-term deleterious side effects of stereotactic surgery on sleep and sleep EEG are improbable. The results provide further evidence for the involvement of the human thalamus in the generation of sleep spindles.
Clin. Neurophysiol., 111, 1266-1275 (2000).
Despite the almost ubiquitous presence of sleep and the sleep stages nonREM and REM sleep in mammals and birds, the functions of sleep still remain elusive. Several promising approaches may shed light on this problem. Thus investigation of sleep-like states such as hibernation and torpor have shown that these states are more similar to sleep deprivation than to sleep. Furthermore, sleep-like states, which are homeostatically compensated for after rest deprivation have been found in Drosophila. These results allow to search for genes and gene products which change as a function of the vigilance states in these more simpler organisms. Thereafter, homologous genes can be investigated in mice.
Ther. Umsch., 57, 417-420 (2000).
The aim of the study was to investigate whether the electromagnetic field (EMF) emitted by digital radiotelephone handsets affects brain physiology. Healthy, young male subjects were exposed for 30 min to EMF (900 MHz; spatial peak specific absorption rate 1 W/kg) during the waking period preceding sleep. Compared to the control condition with sham exposure, spectral power of the electroencephalogram (EEG) in non-rapid-eye-movement sleep was increased. The maximum rise occurred in the 9.75-11.25 Hz and 12.5-13.25 Hz band during the initial part of sleep. These changes correspond to those obtained in a previous study where EMF was intermittently applied during sleep. Unilateral exposure induced no hemispheric asymmetry of EEG power. The present results demonstrate that exposure during waking modifies the EEG during subsequent sleep. Thus the changes of brain function induced by pulsed high-frequency EMF outlast the exposure period.
Neuroreport, 11, 3321-3325 (2000).
Running wheels are widely used in studies on biological rhythms. In mice wheel diameters have ranged from 11 cm to 23 cm. We provided mice with running wheels of two different sizes: 15 cm diameter and 11 cm diameter. The amount of running in the 12-h light:12-h dark condition and the endogenous period of wheel running in constant darkness was determined over 40 days. On the 1st day in constant darkness all animals were exposed to a 15-min light pulse at circadian time 13. The animals in the small wheel ran significantly less both in 12 h light: 12 h dark and constant darkness, and showed a longer endogenous period in constant darkness compared to animals in the large wheel. Moreover, after the light pulse at circadian time 13, mice in the small wheel showed a significantly smaller phase delay in running wheel activity than mice in the larger wheels. The data suggest that the magnitude of a photic phase shift depends on the amount and timing of activity the animals display in relation to this stimulus. It can be concluded that technical features of the running wheel can influence the circadian period of wheel running.
J Comp Physiol [A], 186, 969-973 (2000).
Photoperiod influences the distribution of sleep and waking and electroencephalogram (EEG) power density in the Djungarian hamster. In an experimental procedure combining short photoperiod (SP) and low ambient temperature, the light-dark difference in the amount of sleep was decreased, and the changes in slow-wave activity (SWA) (mean EEG power density between 0.75 and 4.0 Hz) in nonrapid eye movement (NREM) sleep within 24 h were abolished. These findings, obtained in three different groups of animals, suggested that at the lower ambient temperature, the influence of the circadian clock on sleep-wake behavior was diminished. However, it remained unclear whether the changes were due to the photoperiod, ambient temperature, or both. Here, the authors show that EEG and electromyogram recordings in a single group of animals sequentially adapted to a short and long photoperiod (LP) at low ambient temperature (approximately15 degrees C) confirm that EEG power is reduced in SP. Moreover, the nocturnal sleep- wake behavior and the changes in SWA in NREM sleep over 24 h were restored by returning the animals to LP and retaining ambient temperature at 15 degrees C. Therefore, the effects cannot be attributed to ambient temperature alone but are due to a combined effect of temperature and photoperiod. When the Djungarian hamster adapts to winter conditions, it appears to uncouple sleep regulation from the circadian clock.
J Biol Rhythms, 15, 429-436 (2000).
To investigate the relationship between markers of sleep homeostasis during waking and sleep, the electroencephalogram of eight young males was recorded intermittently during a 40-h waking episode, as well as during baseline and recovery sleep. In the course of extended waking, spectral power of the electroencephalogram in the 5-8Hz band (theta activity) increased. In non-rapid eye movement sleep, power in the 0.75- 4.5Hz band (slow-wave activity) was enhanced in the recovery night relative to baseline. Comparison of individual records revealed a positive correlation between the rise rate of theta activity during waking and the increase in slow-wave activity in the first non-rapid eye movement sleep episode. A topographic analysis based on 27 derivations showed that both effects were largest in frontal areas.From these results, we suggest that theta activity in waking and slow-wave activity in sleep are markers of a common homeostatic sleep process.
Neuroscience, 101, 523-529 (2000).
To test the theory that sleep is a regional, use-dependent process, rats were subjected to unilateral sensory stimulation during waking. This was achieved by cutting the whiskers on one side, in order to reduce the sensory input to the contralateral cortex. The animals were kept awake for 6 h in an enriched environment to activate the cortex contralateral to the intact side. Whiskers are known to be represented in the barrel field of the contralateral somatosensory cortex and their stimulation during exploratory behavior results in a specific activation of the projection area. In the 6 h recovery period following sleep deprivation, spectral power of the nonrapid eye-movement (NREM) sleep EEG in the 0.75-6.0 Hz range exhibited an interhemispheric shift towards the cortex that was contralateral to the intact whiskers. The results support the theory that sleep has a regional, use-dependent facet.
J Sleep Res, 9, 367-371 (2000).