Section of Psychopharmacology and Sleep Research
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University of Zürich - Institute of Pharmacology and Toxicology Section of Psychopharmacology and Sleep Research |
The development of nocturnal sleep and the sleep EEG was investigated in a longitudinal study during infancy. All-night polysomnographic recordings were obtained at home at 2 weeks, and at 2, 4, 6 and 9 months after birth (analysis of 7 infants). Total sleep time and the percentage of quiet sleep or non rapid eye movement sleep (QS/NREMS) increased with age, while the percentage of active sleep or rapid eye movement sleep (AS/REMS) decreased. Spectral power of the sleep EEG was higher in QS/NREMS than in AS/REMS over a large part of the 0.75-25 Hz frequency range. In both QS/NREMS and AS/REMS, EEG power increased with age in the frequency range below 10 Hz and above 17 Hz. The largest rise occurred between 2 and 6 months. A salient feature of the QS/NREMS spectrum was the emergence of a peak in the sigma band (12-14 Hz) at 2 months, which corresponded to the appearance of sleep spindles. Between 2 and 9 months, low-frequency delta activity (0.75-1.75 Hz) showed an alternating pattern with a high level occurring in every other QS/NREMS episode. At 6 months, sigma activity showed a similar pattern. In contrast, theta activity (6.5-9 Hz) exhibited a monotonic decline over consecutive QS/NREMS episodes, a trend that at 9 months could be closely approximated by an exponential function. The results suggest that (a) EEG markers of sleep homeostasis appear in the first postnatal months, and (b) sleep homeostasis goes through a period of maturation. Theta activity and not delta activity seems to reflect the dissipation of sleep propensity during infancy.
Am J Physiol Regel Integr Comp Physiol, 2004. 286: p. R528-R538
We investigated learning-related changes in amplitude, scalp topography, and source localization of the mismatch negativity (MMN), a neurophysiological response correlated with auditory discrimination ability. Participants (n = 32) underwent two EEG recordings while they watched silent films and ignored auditory stimuli. Stimuli were a standard (probability = 85%) and two deviant (probability = 7.5% each for high [HD] and low [LD]) eight-tone sequences that differed in the frequency of one tone. Between recordings, subjects practiced discriminating the HD or LD from the standard for 6 min. The amplitude of the LD MMN increased significantly across recordings in both groups, whereas the amplitude of the HD MMN did not. The LD was easier to discriminate than was the HD. Thus, practicing either discrimination increased the MMN for the easier discrimination. Learning and changes in the LD MMN amplitude were highly correlated. Source localizations of event-related potentials (ERPs) to all stimuli revealed bilateral sources in superior temporal regions. Compared with the standard ERP, the LD ERP revealed a stronger source in the left superior temporal region in both recordings, whereas the right-sided source became stronger after learning. Consistent with prior studies of auditory plasticity in animals and humans, tone sequence learning induced rapid neurophysiological plasticity in the human central auditory system. The results also suggest that there is asymmetric hemispheric involvement in tone sequence discrimination learning and that discrimination difficulty influences the time course of learning-related neurophysiological changes.
Learning & Memory 11:162–171 (2004)
A new algorithm for the detection of oscillatory events in the EEG is presented. By estimating autoregressive models on short segments the sleep EEG is described as a superposition of stochastically driven harmonic oscillators with damping and frequencies varying in time. Oscillatory events are detected, whenever the damping of one or more frequencies is smaller than a predefined threshold. The algorithm works well for the detection of sleep spindles as well as for delta and alpha waves. The distribution of the time intervals between the detected sleep spindles shows maxima around 3–4 s. It is discussed whether this maximum originates from slow oscillations or from stochasticity.
Neurocomputing 58-60:129--135 (2004)
The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is involved in the generation of various brain rhythmic activities that can be modulated by benzodiazepines. Here, we assessed the contribution of alpha2GABA type A (GABAA) receptors to the effects of benzodiazepines on sleep and waking oscillatory patterns by combining pharmacological and genetic tools. The effects of diazepam on the electroencephalogram were compared between alpha2(H101R) knock-in mice in which the alpha2GABAA receptor was rendered diazepam-insensitive, and their wild-type controls. The suppression of delta activity typically induced by diazepam in non-rapid eye movement (REM) sleep was significantly stronger in wild-type control mice than in alpha2(H101R) mice. Moreover, electroencephalogram frequency activity above 16-18 Hz was enhanced in wild-type mice both in non-REM sleep and waking. This effect was absent in alpha2(H101R) mice. Theta activity was enhanced after diazepam both in REM sleep and in waking in wild-type mice. In alpha2(H101R) mice, this effect was markedly reduced in REM sleep whereas it persisted in waking. These findings suggest that alpha2GABAA receptors, which are expressed in hypothalamic and pontine nuclei and in the hippocampus, are localized in distinct neural circuits relevant for the modulation of rhythmic brain activities by benzodiazepines.
Proceedings of the National Academy of Sciences of the United States of America 101:3674-3679 (2004).
Regional differences in the effect of sleep deprivation on the sleep electroencephalogram (EEG) may be related to interhemispheric synchronization. To investigate the role of the corpus callosum in interhemispheric EEG synchronization, coherence spectra were computed in mice with congenital callosal dysgenesis (131) under baseline conditions and after 6-h sleep deprivation, and compared with the spectra of a control strain (C57BL/6). In B1 mice coherence was lower than in controls in all vigilance states. The level of coherence in each of the three totally acallosal mice was lower than in the mice with only partial callosal dysgenesis. The difference between 131 and control mice was present over the entire 0.5-25 Hz frequency range in non-rapid eye movement sleep (NREM sleep), and in all frequencies except for the high d and low q band (3-7 Hz) in rapid eye movement (REM) sleep and waking. In control mice, sleep deprivation induced a rise of coherence in the Dband of NREM sleep in the first 2 h of recovery. This effect was absent in Ell mice with total callosal dysgenesis and attenuated in mice with partial callosal dysgenesis. In both strains the effect of sleep deprivation dissipated within 4 h. The results show that EEG synchronization between the hemispheres in sleep and waking is mediated to a large part by the corpus callosum. This applies also to the functional changes induced by sleep deprivation in NREM sleep. In contrast, interhemispheric synchronisation of 0 oscillations in waking and REM sleep may be mediated by direct inter-hippocampal connections.
Neuroscience 124:481-488 (2004).
Rab proteins are small GTPases involved in intracellular trafficking. Among the 60 different Rab proteins described in mammals, Rab3a is the most abundant in brain, where it is involved in synaptic vesicle fusion and neurotransmitter release. Rab3a constitutive knockout mice (Rab3a-/-) are characterized by deficient short- and long-term synaptic plasticity in the mossy fiber pathway and altered circadian motor activity, while no effects on spatial learning have been reported so far for these mice. The goals of this study were to analyse possible behavioral consequences of the lack of synaptic plasticity in the mossy fiber pathway using a broad battery of sensitive behavioral measures that has been used previously to analyse the behavior of Gdi1 mice lacking a protein thought to regulate Rab3a. Rab3a-/- mice showed normal acquisition but moderately impaired platform reversal learning in the water maze including reference memory and episodic-like memory tasks. A mild deficit in spatial working memory was also observed when tested in the radial maze. Analysis of expolorative behavior revealed increased locomotor activity and enhanced exploratory activity in open field, O-maze, dark/light box and novel object tests. Spontaneous activity in normal home cage settings was unaffected but Rab3a-/- mice showed increased motor activity when the home cage was equipped with a wheel. No differences were found for delayed and trace fear conditioning or for conditioned taste aversion learning. Congruent with earlier data, these results suggest that Rab3a-dependent synaptic plasticity might play a specific role in the reactivity to novel stimuli and behavoral stability rather than being involved in memory processing. On the other hand, the phenotypic changes in the Rab3a-/- mice bore no relation to the behavioral changes observed in the Gdi1 mice. Such divergence in phenotypes implies that the putative synaptic interaction between Gdi1 and Rab3a should be reconsidered and re-analysed.
European Journal of Neuroscience, 19:1895-1905 (2004).
Narcolepsy with cataplexy is thought to be a hypocretin ligand or hypocretin receptor deficiency syndrome caused by genetic and environmental factors. We looked for an abnormality of the hypocretin pathway in HLA-DQB1*0602-positive monozygotic twins who were concordant for narcolepsy-cataplexy. They had normal cerebrospinal fluid concentrations of hypocretin-1, and we found no mutation in the prepro-hypocretin gene or either hypocretin receptor gene. Our finding points to the existence of presumably genetic forms of narcolepsy with cataplexy without any demonstrable defect in the hypocretin pathway.
Lancet 363:1199-1200 (2004).
Prolonged wakefulness increases electroencephalogram (EEG) low-frequency activity (<10 Hz) in waking and sleep, and reduces spindle frequency activity (approximately 12-16 Hz) in non-rapid-eye-movement (nonREM) sleep. These physiologic markers of enhanced sleep propensity reflect a sleep-wake-dependent process referred to as sleep homeostasis. We hypothesized that caffeine, an adenosine receptor antagonist, reduces the increase of sleep propensity during waking. To test this hypothesis, we compared the effects of caffeine and placebo on EEG power spectra during and after 40 h of wakefulness. A total of 12 young men underwent two periods of sleep deprivation. According to a randomized, double-blind, crossover design, they received two doses of caffeine (200 mg) or placebo after 11 and 23 h of wakefulness. Sleep propensity was estimated at 3-h intervals by measuring subjective sleepiness and EEG theta (5-8 Hz) activity, and polysomnographic recordings of baseline and recovery nights. Saliva caffeine concentration decreased from 15.7 micromol/l 16 h before the recovery night, to 1.8 micromol/l 1 h before the recovery night. Compared with placebo, caffeine reduced sleepiness and theta activity during wakefulness. Compared with sleep under baseline conditions, sleep deprivation increased 0.75-8.0 Hz activity and reduced spindle frequency activity in nonREM sleep of the recovery nights. Although caffeine approached undetectable saliva concentrations before recovery sleep, it significantly reduced EEG power in the 0.75-2.0 Hz band and enhanced power in the 11.25-20.0 Hz range relative to placebo. These findings suggest that caffeine attenuated the build-up of sleep propensity associated with wakefulness, and support an important role of adenosine and adenosine receptors in the homeostatic regulation of sleep.
Neuropsychopharmacology 29:1-7 (2004).
Sleep is superior to waking for promoting performance improvements between sessions of visual perceptual (Stickgold et al., 2001) and motor (Smith and MacNeill, 1994; Fischer et al., 2002; Walker et al., 2002) learning tasks. Few studies have investigated possible effects of sleep on auditory learning (Fenn et al., 2003; Atienza et al., 2004). A key issue is whether sleep specifically promotes learning, or whether restful waking yields similar benefits (Tononi and Cirelli, 2001). According to the "interference hypothesis," sleep facilitates learning because it prevents interference from ongoing sensory input, learning (e.g., Walker et al., 2003a) and other cognitive activities that normally occur during waking. We tested this hypothesis by comparing effects of sleep, busy waking (watching a film) and restful waking (lying in the dark) on auditory tone sequence learning. Consistent with recent findings for human language learning (Fenn et al., 2003), we found that compared with busy waking, sleep between sessions of auditory tone sequence learning enhanced performance improvements. Restful waking provided similar benefits, as predicted based on the interference hypothesis. These findings indicate that physiological, behavioral and environmental conditions that accompany restful waking are sufficient to facilitate learning and may contribute to the facilitation of learning that occurs during sleep.
Neuroscience, 127: 557-561(2004).
The two-process model of sleep regulation posits that the interaction of its two constituent processes, a sleep/wake dependent homeostatic Process S and a circadian Process C, generates the timing of sleep and waking. The time course of Process S was derived from a physiological variable, EEG slow-wave activity. In addition to the timing of sleep, changes of daytime vigilance are accounted for by the interaction of the two processes. The attractiveness of the model derives from its physiological basis and its mathematical simplicity. The two-process model stimulated the establishment of other models of neurobehavioral functions. The background of the model is reviewed and simulations of alertness and sleepiness are discussed..
Aviation Space and Environmental Medicine, 75:A37-A43 (2004).
Zolpidem is a widely used hypnotic that binds preferentially to alpha1GABAA receptors. We determined the role of these receptors in the effects of zolpidem on sleep in mutant mice carrying zolpidem-insensitive alpha1GABAA receptors and wild-type controls. Sleep was promoted by zolpidem in both genotypes. In wild-type mice non-REM sleep EEG power was markedly reduced in a broad frequency band >5 or 9Hz after 5 and 10mg/kg zolpidem, respectively. In mutants a power reduction appeared at the highest dose only, and was restricted to some low frequencies and the 9-10Hz bin.We conclude that the effects of zolpidem on the sleep EEG in mice are distinct from the changes typically induced by benzodiazepines, and are primarily mediated by alpha1GABAA receptors.
Neuroreport, 15:2299-2302 (2004).
Regional differences in EEG slow wave activity (SWA) during sleep after sleep deprivation (SD) may be a consequence of differential metabolic activation of cortical areas. We investigated the relationship between the regional EEG dynamics and 2-deoxyglucose (DG) uptake after SD in mice. Six hours’ SD were combined with natural unilateral whisker stimulation in an enriched environment to selectively activate the barrel cortex and motor areas. As expected, an interhemispheric asymmetry of 2-DG uptake was found in the barrel cortex immediately after SD. To test whether sleep contributes to recovery of the asymmetry, the stimulation was followed by either undisturbed sleep or by an additional SD. The asymmetry vanished after recovery sleep but also after the additional period of wakefulness without stimulation. In addition, relative 2-DG uptake in the primary motor cortex and retrosplenial area was significantly higher immediately after the SD than after the additional sleep or wakefulness, whereas no other region differed between the groups. Whisker stimulation elicited a greater increase in EEG SWA during non rapid eye movement sleep in the stimulated hemisphere than in the control hemisphere; this increase lasted for 10 h. Within a hemisphere, the initial increase in SWA was higher in the frontal than in the parietal derivation. We conclude that the regional SWA differences during sleep are use-dependent and may be related to the regional pattern of metabolism during the previous waking episode. However, the regional metabolic recovery is not dependent on sleep, and is not directly reflected in changes in SWA during sleep.
European Journal of Neuroscience, 20:1363-1370 (2004).