Sleep and EEG power spectrum effects of the 5-HT1A antagonist NAN-190 alone and in combination with citalopram

The sleep and waking and EEG power spectrum effects of the putative 5-HT1A antagonist NAN-190 (0.5 mg/kg, i.p.) were studied alone and in co-administration with the selective serotonin re-uptake inhibitor citalopram (5.0 mg/kg, i.p.) in the rat. Citalopram, as in a prior dose-response study, reduced REM sleep. In addition, a slight increase in NREM sleep was observed. Citalopram reduced NREM fronto-parietal (FP) EEG power density in the 5-20 Hz range. When administered alone, NAN-190 suppressed REM sleep in the first 2 h, and reduced SWS-2 in the first 4 after administration. NAN-190 also suppressed selectively NREM sleep slow-wave activity in both fronto-frontal (FF) and FP EEG power spectrum. When administered in combination with citalopram, an attenuation of the power density reduction in the 7-15 Hz range in the FF EEG of citalopram alone, was observed. However, the EEG power spectral density and REM sleep suppressive effects of NAN-190 were both augmented. The results are compatible with the notion that serotonin is involved in the modulation of the slow wave activity in the EEG during NREM sleep. The results are cordant with other data suggesting that postsynaptic 5-HT1A stimulation might increase slow wave activity in the NREM EEG, and that serotonergic stimulation of other receptor subtypes (possibly 5-HT2) may decrease slow wave activity in the NREM EEG.     

Citalopram: differential sleep/wake and EEG power spectrum effects after single dose and chronic administration

The sleep/wake effects of the selective serotonin re-uptake inhibitor citalopram were studied in both a single-dose study with three dose levels (0.5, 2.0 and 5.0 mg/kg), and a 5-week chronic administration study (15 mg/kg/24 h). Single doses of citalopram resulted in a dose-dependent inhibition of rapid eye movement (REM) sleep. After chronic citalopram treatment there was a sustained REM sleep inhibition. Single doses of citalopram resulted in only minor changes in non-REM (NREM) sleep as well as in NREM EEG power spectral density. Chronic administration resulted in a major shift from SWS-2 to SWS-1. The observed corresponding changes in EEG power density were regional. A 30 to 40 percent reduction of power density in the 0.5-15 Hz range in the fronto-parietal EEG derivation was seen for the whole 8-h registration period. In the fronto-frontal EEG derivation only minor changes were seen. A decreasing trend in NREM sleep power density between 0.5 and 7 Hz, usually seen during the course of the light period, was not observed in the chronic condition, but was seen in control and single-dose condition, suggesting altered diurnal distribution of slow wave activity in the chronic condition. The data indicate that acute and chronic administration of citalopram shows clear differences in sleep effect, which may be caused by alteration of serotonergic transmission, and may be related to the antidepressant effect.     

Luxury perfusion following anterior ischemic optic neuropathy

To study the role of adenosine in sleep regulation, the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the antagonist caffeine were administered to rats. Intraperitoneal (i.p.) CPA 1 mg/kg but not 0.1 mg/kg, suppressed rapid-eye-movement (REM) sleep and enhanced electroencephalographic (EEG) slow-wave activity (power density 0.75-4.0 Hz) in non-REM sleep. The latter effect was remarkably similar to the response to 6-h sleep deprivation. The effects persisted when CPA-induced hypothermia was prevented. Caffeine (10 and 15 mg/kg i.p.) elicited a dose-dependent increase in waking followed by a prolonged increase of slow-wave activity in non-REM sleep. The combination of caffeine (15 mg/kg) and sleep deprivation caused less increase in slow-wave activity than sleep deprivation alone, indicating that caffeine may reduce the buildup of sleep pressure during waking. The results are consistent with the involvement of adenosine in the regulation of non-REM sleep.     

Behaviour-related effects of nicotine on slow EEG waves in basal nucleus-lesioned rats

The basal magnocellular nucleus is assumed to play a crucial role in cholinergic activation of the cortical EEG. The aim of this study was to establish whether intraperitoneally applied nicotine may counteract the power asymmetry of the slow waves in the cortical EEG of both hemispheres after an unilateral lesion in the basal nucleus. In 17 rats the basal nucleus (substantia innominata/ventral pallidum) was unilaterally lesioned by ibotenic acid. The lesion produced unilateral power increases of all frequencies up to 20 Hz in the frontal EEG that increased with higher arousal level. Additionally, synchronized spike and wave discharges appeared in the frontal EEG. The results indicate that the basal nucleus suppresses especially the delta EEG waves in the frontal motor cortex during motor active behaviour. Nicotine (0.1 and 1 mg/kg) partially counteracts the power asymmetry of frontal slow waves (2-6 Hz) only during exploratory sniffing but not during grooming and waking immobility. Physostigmine (1 mg/kg) was also effective during exploratory sniffing. The results may indicate a role of nicotinic mechanisms in the information input component of exploratory behaviour.     

Frontal Electroencephalogram Alpha Asymmetry During Sleep: Stability and Its Relation to Affective Style.

Electroencephalogram (EEG) alpha (8-12 Hz) asymmetries were collected from the mid-frontal and central regions during presleep wakefulness and Stage 1, Stage 2, and rapid eye movement (REM) sleep in 11 healthy right-handed participants who were free of psychiatric, neurological, and sleep problems. The authors found significant correlations between presleep wakefulness and different stages of sleep in the frontal, but not central, EEG alpha asymmetry measure. The strongest correlation was between presleep waking and REM sleep, replicating and extending relation earlier work to a normal population. The high degree of association between presleep waking and REM sleep may be a result of high cortical activation common to these states and may reflect a predisposition to different styles of emotional reactivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Compensatory sleep responses to wakefulness induced by the dopamine autoreceptor antagonist (-)DS121

The effect of the dopamine autoreceptor antagonist (-)DS121 on wakefulness, locomotor activity, body temperature and subsequent compensatory sleep responses was examined in the rat. Animals entrained to a light-dark cycle were treated at 5 h after lights-on (CT-5) with 0.5, 1, 5 or 10 mg/kg i.p. (-)DS121 or methylcellulose vehicle. An additional group received 5 mg/kg i.p. (-)DS121 or vehicle 6 h after lights-off (CT-18). At CT-5, (-)DS121 dose-dependently increased wakefulness, locomotor activity and body temperature, and decreased both non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM) during the first 4 h post-treatment relative to vehicle controls. REM interference lasted up to 3 h longer than NREM. Low doses of (-)DS121 (0.5 and 1 mg/kg) produced relatively little waking that was not followed by significant compensatory sleep responses. In contrast, higher doses (5 and 10 mg/kg) produced compensatory hypersomnolence (robust increases in NREM immediately after the primary waking effect) that was proportional to the duration of drug-induced wakefulness. NREM recovery 24 h post-treatment was the same for the 5 mg/kg (65.4 +/- 9.9 min) and 10 mg/kg (64.8 +/- 9.3 min) doses, but was not proportional to prior wake duration. NREM displaced by drug-induced wakefulness was recovered completely by 24 h post-treatment at the 5 mg/kg dose, but only 63.5% recovered at 10 mg/kg. In contrast, equivalent wakefulness produced by sleep deprivation yielded 100% NREM recovery. At CT-18, (-)DS121 (5 mg/kg) increased wakefulness without disproportionately increasing locomotor activity, and was compensated fully by 24 h post-treatment. These data show that (-)DS121 dose-dependently increases wakefulness, which is followed by hypersomnolence that is proportional to drug-induced wake-promoting efficacy.     

Genetics of aging and immunity

The influence of alcohol (ethanol) on sleep was investigated in 10 men. Polysomnography (PS) was recorded on a baseline night (BL-N) and an ethanol (0.8 g/kg) night (Et-N). On visual score rapid eye movement (REM) sleep was reduced, REM latency was prolonged on Et-N as compared to BL-N. Using the fast Fourier transformation method, electroencephalographic power density of REM sleep in delta frequencies band and in the 10-12 Hz range of non-REM sleep were enhanced. REM sleep and non-REM sleep changes were prominent in the second-half and first-half of the night, respectively.     

Dynamics of EEG spindle frequency activity during extended sleep in humans: relationship to slow-wave activity and time of day

The dynamics of EEG spindle frequency activity (SFA; spectral power density in the 12.25-15.0 Hz range) and its relationship to slow-wave activity (SWA; 0.75-4.5 Hz) were investigated in long sleep episodes (> 12 h). Young healthy men went to bed at either 19:00 h (early sleep; prior waking 36 h, n = 9) or 24:00 h (late sleep; prior waking 17 h, n = 8). In both nights, SWA in non-rapid-eye-movement sleep (NREMS) decreased over the first three to four 1.5-h intervals and remained at a low level in the subsequent five to six 1.5-h intervals. In contrast, the changes of SFA were more variable and differed between the lower (12.25-13.0 Hz), middle (13.25-14.0 Hz) and higher frequency bin (14.25-15.0 Hz). A pronounced influence of time of day was present in the lower and higher SFA bin, when the dynamics were analyzed with respect to clock time. In both the early and late sleep condition, power density in the lower bin was highest between 2:00 and 5:00 h in the morning and decreased thereafter. In the higher bin, power density was low in the early morning hours and increased as sleep was extended into the daytime hours. The results provide further evidence for a frequency-specific circadian modulation of SFA which becomes more evident at a time when SWA is low.     

Monotremes and the evolution of rapid eye movement sleep

Early studies of the echidna led to the conclusion that this monotreme did not have rapid eye movement (REM) sleep. Because the monotremes had diverged from the placental and marsupial lines very early in mammalian evolution, this finding was used to support the hypothesis that REM sleep evolved after the start of the mammalian line. The current paper summarizes our recent work on sleep in the echidna and platypus and leads to a very different interpretation. By using neuronal recording from mesopontine regions in the echidna, we found that despite the presence of a high-voltage cortical electroencephalogram (EEG), brainstem units fire in irregular bursts intermediate in intensity between the regular non-REM sleep pattern and the highly irregular REM sleep pattern seen in placentals. Thus the echidna displays brainstem activation during sleep with high-voltage cortical EEG. This work encouraged us to do the first study of sleep, to our knowledge, in the platypus. In the platypus we saw sleep with vigorous rapid eye, bill and head twitching, identical in behaviour to that which defines REM sleep in placental mammals. Recording of the EEG in the platypus during natural sleep and waking states revealed that it had moderate and high-voltage cortical EEGs during this REM sleep state. The platypus not only has REM sleep, but it had more of it than any other animal. The lack of EEG voltage reduction during REM sleep in the platypus, and during the REM sleep-like state of the echidna, has some similarity to the sleep seen in neonatal sleep in placentals. The very high amounts of REM sleep seen in the platypus also fit with the increased REM sleep duration seen in altricial mammals. Our findings suggest that REM sleep originated earlier in mammalian evolution than had previously been thought and is consistent with the hypothesis that REM sleep, or a precursor state with aspects of REM sleep, may have had its origin in reptilian species.     

Interhemispheric asymmetry of human sleep EEG in response to selective slow-wave sleep deprivation.

Recent evidence suggests that the human sleep electroencephalogram (EEG) shows regional differences over both the sagittal and coronal planes. In the present study, in a group of 10 right-handers, the authors investigated the presence of hemispheric asymmetries in the homeostatic regulation of human sleep EEG power during and after selective slow-wave sleep (SWS) deprivation. The SWS deprivation was slightly more effective over the right hemisphere, but the left hemisphere showed a markedly larger increase of EEG power in the 1.00-24.75 Hz range during recovery-night non-REM sleep, and a larger increase of EEG power during both deprivation-night and recovery-night REM sleep. These results support the greater need for sleep recuperative processes of the left hemisphere, suggesting that local sleep regulation processes may also act during REM sleep. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spectral power and coherence analysis of sleep EEG in AIDS patients: decrease in interhemispheric coherence

Fifteen patients aged between 26 and 55 years with the acquired immunodeficiency syndrome (AIDS) and various cerebral manifestations of the disease underwent an all-night sleep electroencephalogram (EEG) registration. The recordings of 15 age-matched volunteers were examined as controls. Sleep stages were determined visually and the following spectral analysis was based on corresponding artifact-free 40-second periods. The sampling rate was 64 second-1, the spectral resolution was 0.25 Hz and the frequency ranged from 0.25-24 Hz. The power density spectra of eight EEG derivations (left and right frontopolar, frontal, central and occipital; reference montage to the ipsilateral Cb electrodes) and the coherence spectra of interhemispheric (interfrontal, interoccipital) and intrahemispheric (frontooccipital, left and right) channel pairs were computed. The power density of the patients in the 11.5-13-Hz frequency range of nonrapid eye movement (NREM) sleep was considerably lower than that of the controls (p < 0.05 and p < 0.01 at left and right frontal derivations, two-tailed Mann-Whitney U test). The power density of rapid eye movement (REM) sleep showed no consistent differences between the two groups. The interfrontal coherence of the whole frequency range below 12 Hz was markedly lower in the patient group. This applied to NREM sleep and also to REM sleep (p < 0.01 and p < 0.001 for different frequency bands between 1 and 12 Hz in NREM and REM sleep). Possible relations to clinical features are discussed.     

12-hour pattern of the waking state in the normal infant and in the infant who has survived the 'syndrome of sudden infant death' (author's transl)

The authors report the results of 16 sleep EEGs carried out on 5 infants said to have survived the syndrome of sudden infant death (near-miss group) and 5 controls. The recordings were performed at 1.5 months, 3 months and 4.5 months, times when the risk of sudden death is maximum. The EEG appearance and the organization of sleep patterns have been studied in both groups. The various states of wakefulness, and the modalities of sleep and waking were subjected to statistical analysis with respect to age. The study showed no significant difference between the percentages of different states of wakefulness in the control and 'near-miss' group, but there were more sleep onsets in active sleep (REM) in this group compared with the controls and there were fewer waking periods, although when they occurred these were more prolonged.     

Effects of accumbens m-chlorophenylbiguanide microinjections on sleep and waking in intact and 6-hydroxydopamine-treated rats

Effects of the 5-HT3 receptor agonist, m-chlorophenylbiguanide (10.0-40.0 microg), on sleep and waking were studied in control, vehicle-treated and 6-hydroxydopamine-injected rats. Bilateral injections of m-chlorophenylbiguanide into the nucleus accumbens of the control and the vehicle-infused animals significantly increased waking and reduced slow wave sleep. Rapid eye movement sleep (REM sleep) remained unchanged. Pretreatment with the selective 5-HT3 receptor antagonist, MDL 72222 (1aH,3a,5a, H-tropan-3-yl-3,5-dichloro-benzoate) (0.5 mg/kg, s.c.), reversed the effects of m-chlorophenylbiguanide (10.0-20.0 microg) on sleep and waking in the control group. Administration of the 5-HT3 receptor agonist to the 6-hydroxydopamine-treated animals modified only slightly the time spent in wakefulness and slow wave sleep, while REM sleep was significantly and dose dependently reduced. Our findings further support the proposal that increase of wakefulness and reduction of slow wave sleep after activation of 5-HT3 receptors, is partly related to the release of endogenous dopamine.     

Power spectral analysis of electroencephalographic desynchronization induced by cocaine in the rat

Whereas it is well-known that cocaine induces EEG desynchronization and behavioral excitation in animals and human subjects, the detailed effect of cocaine on EEG activity remains to be fully elucidated. This communication reports our attempts in quantifying the effect of cocaine on EEG signals recorded from the somatosensory cortex of adult male Sprague-Dawley rats under chloral hydrate anesthesia (400 mg/kg i.p.). Continuous, on-line and real-time power spectral analysis revealed that i.v. administration of two doses of cocaine (1.5 or 3.0 mg/kg) dose-dependently induced EEG desynchronization, as indicated by a decrease in the root mean square and an increase in the mean power frequency values. More interestingly, whereas both doses of cocaine promoted a reduction in the alpha (8-13 Hz), theta (4-8 Hz) and delta (1-4 Hz) spectral components, the beta band (13-32 Hz) underwent differential alterations. The lower dose of cocaine elicited a transient increase, followed by a decrease in the power of the beta band. A prolonged increase in the power of the beta band, on the other hand, was observed after the higher dose of cocaine. These results suggest that subtle changes in the individual EEG spectral components, which are dose-dependent, may underlie the EEG desynchronization induced by cocaine.     

The development of falling asleep during the first months of life in man (author's transl)

Ten normal infants were studied at 2, 6, 12 and 20 weeks of age. EEG, respiratory rhythm, eye movements and chin EMG were recorded after the evening meal. Recording was continued during the stages of sleep. During the period of falling asleep the periods of REM sleep have been analyzed and compared with the periods of REM sleep occurring after non-REM sleep. REM sleep occurring on falling asleep and that occurring after non-REM sleep differed. Some of the following criteria were different at the earliest time of examination; absence of chin EMG activity, number of apnoeic episodes; other criteria (eye movements, respiration) differed during the first 5 months. The large number of eye movements at 2 and 6 weeks and the high respiratory rate, corresponding to that occurring during waking, could indicate that during REM sleep occurring on falling asleep, one is observing manifestations connected with the waking state.     

Dream reports from different stages of sleep.

8 Ss (paid volunteer males, ages 17-27) were placed in the information-gathering sleep situation for 57 (nonconsecutive) nights. Ss were awakened during various stages of sleep (determined by EEG and eye movement activity), and the content of their dream or thoughts at the time of the awakening explored. Mental activity (dreaming, thinking) was reported at all levels of sleep. Reports during periods of rapid eye movement (REM) revealed more statements involving affective, visual, and muscular content with less correspondence to residue of S's waking life, than in non-REM periods. Results are related to Freudian theory of dreams. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The history of sleep research in the 20th century

Not until the 19th century theories on sleep were based upon experimental findings in animal and humans. The so-called 'hypnotoxin theory' culminated, when Legendre and Piéron successfully induced sleep in a dog by transmission of cerebrospinal fluid from a dog deprived of sleep. The main discussion concerning the origin of sleep has been the question if sleep is a passive or an active state. Similarities with coma, the positive Babinski sign and pathoanatomical findings in patients who died after encephalitis lethargica were the arguments for the 'deafferentiation hypothesis'. Bremer's classical brainstem-transsections in cats confirmed this idea. Pavlov was the major representative of the idea that sleep was due to a general inhibition of the brain. Hess induced physiological sleep in cats by electrical stimulation of the diencephalon, proving the active nature of sleep. The introduction of the EEG in animals by Caton and in humans by Berger allowed for the first time the measurement of sleep depth without waking the sleeper. After discovery of the REM sleep periods by Aserinsky and Kleitman in 1953 and the demonstration of periodical sleep cycles by Dement and Kleitman, polysomnography with simultaneous whole night recording of EEG, EMG, electrooculogram and other physiological parameters was established as the major diagnostic tool in sleep disorders. One of the most important questions about the function of sleep is still unresolved. NREM sleep is believed to have a restorative function, whereas REM sleep might be involved in learning processes. According to the sleep interpretation of Sigmund Freud, the dream content represents endogenous wishes which cannot be expressed during wakefulness because of an internal 'sensor'. A more recent theory by Hobson explains the dreams by a very unspecific brainstem activity occurring during REM sleep which projects to the frontal brain and activates stored memory. The most important sleep disease of the 20th century is certainly the sleep-apnea syndrome. Charles Dickens described in his 'Pickwick Papers' subjects with this illness already 150 years ago. The pathogenetic significance of the apneas during sleep, however, were recognized in 1965 only by Gastaut and at the same time by Jung and Kuhlo. Treatment for insomniacs was restricted for many years to alcohol, opium and barbiturates. Following the horrible sequelae of thalidomide therapy in 1956, a more efficient treatment was available through the introduction of benzodiazepines after 1960.     

Changes in EEG power density during sleep laboratory adaptation

First- and second-night effects on the electroencephalogram (EEG) were investigated by means of polygraphic sleep recordings and all-night spectral analysis. Eighteen normal subjects were studied for three consecutive nights in a hospital sleep laboratory. Visual sleep scoring showed that there was a first-night effect in normal subjects similar to that reported previously [increased wakefulness; decreased total sleep time, sleep efficiency, and rapid eye movement (REM) sleep]. Spectral analysis of the sleep EEG revealed important changes, most of which occurred in REM sleep. Increased delta, theta, and beta1 power densities accompanied by decreased mean frequency were seen in REM sleep in the second night. On the basis of REM sleep deprivation results previously published, our data suggest that the second night could be affected by partial REM sleep deprivation that occurred in the first night. Delta and theta power density values decreased in the first non-rapid eye movement episode of nights 1 and 2; this could result from increased REM sleep pressure. The overall consistency of spectral data in the first and second night with REM sleep findings derived from visual scoring in the first night lends further support to this hypothesis. The sleep disturbance experienced during the first night in a sleep laboratory may be a useful and valid model of transient insomnia. Therefore, we conclude that data from all nights recorded should be included in assessing a subject's sleep.     

Respiratory responses to tracheobronchial stimulation during sleep and wakefulness in the adult cat

The response to tracheal stimulation (50 microliters of tap water) during wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep was investigated in adult cats. In wakefulness, repetitive coughing occurred on 80% of the trials. In NREM and REM sleep, the most frequent response (approximately 69% and 58% of the trials, respectively) was arousal, followed by coughing. Apneas occurred following the stimulus and before arousal in 11% and 24% of the trials in NREM and REM sleep, respectively. In NREM sleep, the tracheal stimulus sometimes evoked expiratory efforts following a normal inspiratory effort (11% of the trials). These were much weaker than the expiratory efforts during coughing in wakefulness. In REM sleep, stimulation in 11% of the trials elicited increased inspiratory efforts. Although these may have been diminutive preparatory inspirations for coughing, they were much smaller than preparatory inspirations associated with coughing in wakefulness, and they were never followed by active expiratory efforts. Arousal from either NREM or REM sleep in response to tracheal stimulation was sometimes associated with an augmented breath. This response, which is common upon spontaneous arousal, may lead to deeper aspiration of the tracheal fluid. We conclude that in cats coughing requires wakefulness and that airway stimuli in sleep cause a variety of respiratory responses, some of which may be maladaptive.