Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep

Polysomnograms were obtained from 37 volunteers, before (baseline) and after (two consecutive recovery nights) a 64-h sleep deprivation, with (d-amphetamine or modafinil) or without (placebo) alerting substances. The drugs were administered at 23.00 hours during the first sleep deprivation night (after 17.5 h of wakefulness), to determine whether decrements in cognitive performance would be prevented; at 05.30 hours during the second night of sleep deprivation (after 47.5 h of wakefulness), to see whether performance would be restored; and at 15.30 hours during the third day of continuous work, to study effects on recovery sleep. The second recovery night served to verify whether drug-induced sleep disturbances on the first recovery night would carry over to a second night of sleep. Recovery sleep for the placebo group was as expected: the debt in slow-wave sleep (SWS) and REM sleep was paid back during the first recovery night, the rebound in SWS occurring mainly during the first half of the night, and that of REM sleep being distributed evenly across REM sleep episodes. Recovery sleep for the amphetamine group was also consistent with previously published work: increased sleep latency and intrasleep wakefulness, decreased total sleep time and sleep efficiency, alterations in stage shifts, Stage 1, Stage 2 and SWS, and decreased REM sleep with a longer REM sleep latency. For this group, REM sleep rebound was observed only during the second recovery night. Results for the modafinil group exhibited decreased time in bed and sleep period time, suggesting a reduced requirement for recovery sleep than for the other two groups. This group showed fewer disturbances during the first recovery night than the amphetamine group. In particular, there was no REM sleep deficit, with longer REM sleep episodes and a shorter REM latency, and the REM sleep rebound was limited to the first REM sleep episode. The difference with the amphetamine group was also marked by less NREM sleep and Stage 2 and more SWS episodes. No REM sleep rebound occurred during the second recovery night, which barely differed from placebo. Hence, modafinil allowed for sleep to occur, displayed sleep patterns close to that of the placebo group, and decreased the need for a long recovery sleep usually taken to compensate for the lost sleep due to total sleep deprivation.     

Heart Rhythm Control During Sleep in Ischemic Heart Disease

This paper deals with a computer-aided study of heart rate (HR) control during different sleep stages in 20 healthy volunteers and 75 ischemic heart disease (IHD) patients. In healthy subjects, the parasympathetic HR control was increased and the sympathetic control decreased during stages 1, 2, 3, and 4. REM sleep was characterized by a marked decrease in parasympathetic and a slight elevation in sympathetic contribution. Typical, “reduced” and “paradoxical” HP sleep patterns (HRSPs) were observed in IHD patients. The typical HRSP was similar to that observed in healthy subjects; the reduced HRSP was characterized by HR constancy, and the paradoxical HRSP by an HR increase in stages 3 and 4, and a decrease in REM sleep. The reduced HRSP was associated with the more frequent occurrence of cardiac abnormalities during REM sleep. HR oscillations during stage 2 depended on periodic apnoea episodes and were associated with cardiac abnormalities such as more frequent heart failure and cerebral blood flow disturbances, and overweight.     

Respiratory and body movements as indicators of sleep stage and wakefulness in infants and young children

Conventional polysomnographic (PSG) sleep staging to sleep staging based on a static-charge-sensitive bed (SCSB) recording in infants and young children was compared. The study consisted of whole-night clinical sleep studies in 22 children at 24 weeks (SD 24, range 1–79 weeks) of age. Most of the children presented with respiratory disturbances during sleep. From the SCSB record, sleep stages were differentiated according to regularity of breathing, presence of body movements, and most important, presence of high-frequency components of breathing (SCSB spikes). With both methods, three sleep/wake stages were distinguished: rapid eye movement (REM) sleep, non-rapid eye movement (NREM) sleep and wakefulness. The average inter-scorer reliability of the PSG sleep staging controlled in nine subjects was 88%. The average concordance between the two methods ranged from 82 to 85%, depending on the criteria used for scoring the SCSB. The mean sensitivity of the SCSB to detect NREM sleep ranged from 77 to 90% and the mean sensitivity to detect REM sleep ranged from 61 to 86%. The mean positive predictive value was 89–96% for NREM sleep and 54–67% for REM sleep. In conclusion, REM sleep is characterized by irregular breathing with superimposed fast respiratory movements. These changes are specific enough to allow distinction between episodes of NREM sleep, REM sleep and wakefulness with the non-invasive SCSB method in infants and young children. Incomplete concordance between PSG and SCSB score was most frequently observed during sleep stage transition periods, where the behavioural state and electrophysiological criteria disagreed. When combined with the PSG, the SCSB provides complementary information about the behavioural state of child.     

Eeg sleep and affective psychosis

EEG sleep changes in delusional depression have been reported previously but no attempt has been made to examine sleep profiles among specific delusional subtypes. In 29 psychotically depressed patients, those patients with delusions of guilt or sin demonstrated both increased sleep discontinuity and decreased REM sleep, especially during the first REM period, while patients with somatic delusions showed increased REM activity, especially in the first REM period. The implications of these findings are discussed.     

Sleep and depression--results from psychobiological studies: an overview.

Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity, in depression sleep is characterized by a reduction of slow wave sleep and a disinhibition of REM sleep, with a shortening of REM latency, a prolongation of the first REM period and increased REM density. These findings have stimulated many sleep studies in depressive patients and patients with other psychiatric disorders. In the meantime, several theoretical models, originating from basic research, have been developed to explain sleep abnormalities of depression, like the two-process-model of sleep and sleep regulation, the GRF/CRF imbalance model and the reciprocal interaction model of non-REM and REM sleep regulation. Interestingly, most of the effective antidepressant agents suppress REM sleep. Furthermore, manipulations of the sleep-wake cycle, like sleep deprivation or a phase advance of the sleep period, alleviate depressive symptoms. These data indicate a strong bi-directional relationship between sleep, sleep alterations and depression.     

Sleep microstructure around sleep onset differentiates major depressive insomnia from primary insomnia

In the present study we investigate whether alterations of sleep propensity or of wake propensity are implicated in sleep initiation disturbances encountered in major depressive insomnia and in primary insomnia. For this purpose, the time course of electroencephalogram (EEG) power density during the period preceding sleep onset and during the first non-rapid eye movement (REM) period was examined in three age and gender matched groups of 10 women and 11 men (healthy controls, primary insomniacs and depressive insomniacs). In contrast to healthy controls and depressive insomniacs, patients with primary insomnia did not experience a gradual decrease of their alpha and beta1 power during the sleep onset period and had a lower delta activity in the 5 min preceding sleep onset. Compared with the two other groups, depressive patients exhibit less dynamic changes in slow wave activity during the first non-REM period. The present results suggest that hyperarousal (high 'Process W') may mainly be implicated in the sleep initiation difficulties of primary insomniacs whereas the homeostatic sleep regulation process seems to be partially maintained. In our major depressed patients, the sleep initiation disturbances appeared to relate to a lower sleep pressure (low 'Process S') rather than to hyperarousal. This study supports the idea that different mechanisms are implicated in sleep disturbances experienced by primary insomniacs and major depressive insomniacs.     

The role of hippocampal theta activity in sensory gating in the rat.

Sensory gating is defined as a decreased reaction on the second click, measured as evoked potentials (EP) within a double click paradigm. Recently, it was established that gating in rats was decreased during REM sleep compared to wakefulness and non-REM sleep. REM sleep in the rat is characterized by hippocampal theta rhythm. Therefore, it was investigated whether sensory gating would also be diminished during other states with hippocampal theta. Twelve Wistar rats were implanted with hippocampal electrodes and exposed to double clicks during passive wakefulness, REM sleep, and activity (voluntary movements and walking on a moving belt). Gating was examined by use of the amplitudes of the EPs in reaction to the first conditioned amplitude (CAMP) and second click test amplitude (TAMP), as well as two gating parameters (C-T score and T/C ratio). Except passive wakefulness all behavioral conditions were accompanied by hippocampal theta. Normal gating was always found, except during REM sleep. The CAMP was than lower than during passive wakefulness. Gating was less disturbed during behavioral activity. Negative correlations were found between the percentage theta power on the one side and the CAMP, respectively, the C-T score, on the other. The correlation between the percentage theta power and the T/C ratio was also significant. It is concluded that the presence of hippocampal theta is not a sufficient condition to cause disturbances in auditory sensory gating. Behavioral states that accompany theta activity, however, tend to affect the CAMP. The decrease in gating found during REM sleep cannot be easily related to well-known neurochemical and pharmacological data.     

Early pathology in sleep studies of patients with familial Creutzfeldt–Jakob disease

In this study, we aimed to assess sleep function in patients with recent‐onset familial Creutzfeldt–Jakob disease (fCJD). The largest cluster of fCJD patients is found in Jews of Libyan origin, linked to the prion protein gene (PRNP) E200K mutation. The high index of suspicion in these patients often leads to early diagnosis, with complaints of insomnia being a very common presenting symptom of the disease. The study included 10 fCJD patients diagnosed by clinical manifestations, magnetic resonance imaging (MRI) scan of the brain, elevated tau protein in the cerebrospinal fluid (CSF) and positive PRNP E200K mutation. Standard polysomnography was performed after a brief interview confirming the presence of sleep disturbances. All patients showed a pathological sleep pattern according to all scoring evaluation settings. The sleep stages were characterized by (i) disappearance of sleep spindles; (ii) outbursts of periodic sharp waves and shallowing of sleep consisting in increased Stage 2 and wake periods during the night, as well as decrease of slow‐wave sleep and rapid eye movement (REM) sleep. Recordings of respiratory functions reported irregular breathing with central and obstructive apnea and hypopnea. The typical hypotonia occurring during the night and atonia during REM sleep were replaced by hyperactive sleep consisting of multiple jerks, movements and parasomnia (mainly talking) throughout the night. In conclusion, we report unique pathological sleep patterns in early fCJD associated with the E200K mutation. Specific respiratory disturbances and lack of atonia could possibly serve as new, early diagnostic tools in the disease.     

Nonrandom variability of respiration during sleep in healthy humans

STUDY OBJECTIVES: Breath-to-breath variability is not purely random but is, instead, characterized by correlations on short- and long-term scales. Short-term correlations might reflect intact metabolic-control mechanisms. To investigate whether the higher variability of breathing during rapid eye movement (REM) compared to non-REM (NREM) sleep is of random or nonrandom nature--reflecting an altered respiratory control--short-term and long-term correlations of respiratory drive and timing were determined. DESIGN: A full-night polysomnogram with a pneumotachograph attached to a full-face mask was performed. For each breath during NREM and REM sleep, respiratory components were analyzed based on the quantitative airflow. SETTING: Data collection took place in the sleep laboratory. PARTICIPANTS: Twenty-nine healthy subjects (age, 25.8 +/- 3.1 years). MEASUREMENTS AND RESULTS: Long-term correlations are practically absent in respiratory timing and drive components during NREM sleep, whereas they are present during REM sleep. Short-term correlations are present in respiratory drive, tidal volume, and minute ventilation during both NREM and REM sleep. In all timing components, additional short-term correlations are absent. CONCLUSION: We conclude that from NREM to REM sleep, short-term regulation of respiratory drive remains strongly metabolically controlled and clearly different from the short-term regulation of the rhythm-generating function. Regulation of respiratory timing and drive during REM sleep is characterized by additional long-term correlations. We speculate that this is the result of cortical influences during phasic REM sleep. Thus, the variability of breathing during REM sleep contains a nonrandom component, such that breathing components remain dependent upon each other even with large time lags between components.     

Prenatal morphine exposure and sleep-wake disturbances in the fetus

We have previously shown that acute exposure to low-dose morphine stimulates arousal and breathing movements in the fetal lamb. We now report on the effects of subacute low-dose morphine exposure on the regulation of fetal sleep-wake behavior and breathing patterns. Morphine was infused to 11 fetal lambs (121-129 days gestation) at a constant rate of 400 micrograms/h for 7 days via a mini osmotic pump implanted subcutaneously in the maternal flank and connected directly to an indwelling catheter in the fetal vena cava. On day 1, morphine resulted in a state of arousal in all fetuses, with loss of quiet sleep and rapid eye movement (REM) sleep. This response was greatly reduced by day 2 and was insignificant by day 3, despite continuous drug exposure. There was no decrease in plasma morphine levels. Two fetuses died during morphine exposure. Upon removal of the pump, all fetuses exhibited disturbances in their sleep cycles within 1-3 h, with an increase in arousal time and loss of REM sleep. The duration of the arousal and quiet sleep episodes was also greatly reduced. Such disturbances were noted for 3-4 days after termination of morphine infusion. Four fetuses were delivered prematurely (131-136 days) during this period. These results demonstrate the rapid onset of tolerance to low-dose morphine exposure in the fetus and the development of physical dependence, as manifested by a mild abstinence syndrome characterized by sleep-wake disturbances.     

Sleep stage 2: an electroencephalographic, autonomic, and hormonal duality

STUDY OBJECTIVES: It is generally thought that the electroencephalogram of sleep stage 2 is not uniform, depending on whether sleep stage 2 evolves toward slow-wave sleep (SWS) or toward rapid eye movement (REM) sleep. We provide here further evidence of the duality of sleep stage 2 on the basis of its autonomic and hormonal background. PARTICIPANTS: Fourteen healthy men (aged 21-29 years) underwent 1 experimental night. INTERVENTIONS: Sleep and cardiac recordings were taken from 11:00 PM to 7:00 AM. Blood was sampled continuously over 10-minute periods. MEASUREMENTS AND RESULTS: Autonomic activity, as inferred from heart rate variability analysis and hormone profiles, were examined with regard to the normalized hypnograms. We found a dual activity of the autonomic nervous system during sleep stage 2, with a progressive decrease in heart rate variability sympathetic indexes during the transition toward SWS contrasting with high and rather stable levels during sleep stage 2 that evolve toward REM sleep. Also, different profiles were observed in 2 major hormone systems, the activating adrenocorticotropic system and the renin-angiotensin system. Cortisol, in its active period of circadian secretion, was stable during sleep stage 2 preceding SWS and increased significantly when sleep stage 2 preceded REM sleep. For plasma renin activity, sleep stage 2 played a transitional role, initiating increasing levels that peaked during SWS and decreasing levels that reached a nadir during REM sleep. CONCLUSIONS: These results indicate an autonomic and hormonal duality of sleep stage 2 that is characterized by a "quiet" period preparing SWS and an "active" period preceding REM sleep. These differences may confer a fundamental role on this sleep stage in ultradian sleep regulation.     

Sleep and circadian rhythm during a short space mission

Summary An experiment was conducted to assess sleep and circadian regulation in an orbiting space-craft. In orbit the weakened influence of 24-h zeitgebers could result in delayed circadian phases with the possibility of a transition to free-running circadian rhythms. This and the specific stressors of a space mission may lead to changes in ultradian sleep regulation and in reduced sleep quantity and quality. During the mission sleep was recorded polygraphically on tape, as was body temperature. Daytime alertness was rated subjectively by a mood questionnaire. For comparison the same parameters were measured during a baseline period preceding the space mission. The circadian rhythms of body temperature and alertness were found to be delayed in space compared to baseline. This may mark a phase shift or the transition to a circadian state of free-run. Sleep was shorter and more disturbed. The structure of sleep was significantly altered. In space REM latency was shorter, there was less REM sleep in the second non-REM/REM cycle, and slow-wave sleep was redistributed from the first to the second cycle. The self-assessed mood resembled sleep disturbances and adaptation to the space environment. Reduced sleep quality and quantity are likely to result in fatigue and lower daytime performance. Countermeasures should be adopted to improve sleep of astronauts.Abbreviations EEG electroencephalogram - EMG electromyogram - EOG electro-oculogram     

Power spectrum analysis and heart rate variability in Stage 4 and REM sleep: evidence for state-specific changes in autonomic dominance

The present study investigated autonomic activity during NREM and REM sleep stages and wakefulness by spectral analysis of heart rate variability. The results demonstrated that NREM sleep in humans was characterized by a widely different autonomic activation pattern than REM sleep: high parasympathetic activity was found in NREM, while REM was characterized by attenuated vagal tone, and augmented sympathetic activity. The overall pattern during wakefulness showed an intermediate position between NREM and REM patterns; parasympathetic activity was lower than in NREM and higher than in REM, with an opposite trend for sympathetic activity.     

Cav2.3 E-/R-type voltage-gated calcium channels modulate sleep in mice

Mammalian sleep is characterized by cycles of REM and non-REM (NREM), i.e. slow-wave sleep (SWS) phases. The major neuroanatomical basis of SWS is the thalamocortical circuitry, which operates in different functional modes to determine the state of vigilance. At high vigilance, the tonic mode predominates; stages of low vigilance and SWS are characterized by rebound burst firing. Electrophysiologically, rebound bursting depends on low-threshold Ca^2?+ spikes and T-type Ca^2?+ channels have been shown to modulate SWS. We recently demonstrated that Ca_v2.3 R-type Ca^2?+ channels are capable of modulating absence seizures, a pathophysiological aberration of the thalamocortical oscillations related to SWS. We thus analyzed sleep architecture in control and Ca_v2.3(?|?) mice using implantable electroencephalography (EEG)/electromyography (EMG) radiotelemetry during spontaneous and urethane-induced sleep. The results demonstrate significantly reduced total sleep time and impairment of SWS generation in Ca_v2.3(?|?) mice, which affects global sleep architecture (i.e. the ratio of REM to NREM). Furthermore, the relative δ power is significantly reduced in Ca_v2.3(?|?) mice during NREM sleep although these mice display longer prior wakefulness, possibly indicating disturbances in sleep homeostasis. This observation is supported by recordings following urethane administration. This is the first study to shed light on the fundamental role of Ca_v2.3 channels in rodent sleep physiology.     

Plasma renin activity and sleep-wake structure of narcoleptic patients and control subjects under continuous bedrest.

In order to determine if renin release would be affected by a dysfunction of the circadian and ultradian organization of sleep, 24-hour profiles of plasma renin activity (PRA) concomitant with sleep stages were established in 10 normal subjects and nine narcoleptic patients, with 10-minute blood sampling intervals. Mean PRA levels were similar in control subjects and narcoleptic patients. Individual 24-hour profiles revealed that the previously described association between renin oscillations and sleep stage alternations was preserved. Increased PRA release was observed during the transition from rapid eye movement (REM) sleep or waking periods to nonrapid eye movement (NREM) sleep, and REM sleep occurred as PRA levels were decreasing. Thus, PRA curves exactly reflected the irregularities and disturbances in the sleep structure of the narcoleptic patients. The 24-hour PRA profiles of the patients did not show the general upward trend during nighttime sleep, which is probably induced in the control subjects by the repetitive recurrence of longer episodes of undisturbed NREM sleep. Because of marked sleep fragmentation in the patients, the duration of NREM sleep was often insufficient to allow for the occurrence of a significant PRA increase. Because sleep onset REM (SOREM) episodes, characteristic of narcolepsy, are not preceded by NREM sleep and its associated increase in PRA, no relative PRA decline occurred during this type of REM sleep. In conclusion, the 24-hour PRA profiles of the narcoleptic patients reflected exactly their sleep stage distribution, confirming previous findings that PRA oscillations appear to be inseparable from the NREM-REM sleep cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ultradian and circadian modulation of dream recall: EEG correlates and age effects

Dreaming occurs during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, which both are regulated by homeostatic, ultradian, and circadian processes. However, the magnitude of how ultradian REM and NREM sleep and its EEG correlates impact onto dream recall remains fairly unknown. In this review, we address three questions: 1. Is there an ultradian NREM–REM sleep modulation in successful dream recall, which is gated by the circadian clock? 2. What are the key electrophysiological correlates that account for dream recall during NREM and REM sleep and 3. Are there age-related changes in the ultradian and circadian regulation in dream recall and its electrophysiological correlates? Knowledge on the specific frequency and topography NREM and REM sleep differences prior to dream recall may pinpoint to the cerebral correlates that account for this cognitive process, and hint to their possible physiological meaning.     

Heart rate variability during sleep as a function of the sleep cycle

In this work, in order to evaluate whether autonomic differences distinguish REM sleep and NREM sleep through the whole sleeping period, statistical analysis on spectral power associated with low frequency and high frequency bands were performed on the whole polysomnographic recording, considering the sleep cycle as a unit of sleep. Our results from nine subjects show that power associated with low frequency is higher in REM sleep than in NREM sleep, while power associated with high frequency is significantly higher in NREM sleep than in REM sleep. Differences between REM sleep and NREM sleep are not of the same magnitude within the whole sleep episode and, independent of sleep stages, specific trends are observable in the autonomic control of heart rate during the night.     

Neurochemical perspectives on the control of breathing during sleep

A specific depression of minute ventilation occurs during sleep in normal subjects. This sleep-related ventilatory depression is partially related to mechanical events and upper airway atonia but some data also indicate that it is likely to be centrally mediated. This paper reviews the anatomical and neurochemical connections between sleep/wake- and respiratory-related areas in an attempt to identify the potential implication of sleep-related neurochemicals (serotonin, catecholamines, GABA, acetylcholine) in the sleep-related hypoventilation. The review of available data suggests that the sleep-related ventilatory depression depends upon the enhanced GABAergic activity together with a loss of suprapontine influence depending on the cessation of activity of the reticular formation. During REM sleep, an additional inhibitory activity emerges from the pontine cholinergic neurons, which contributes to the breathing irregularities and the associated depression of minute ventilation and ventilatory response to chemical stimuli. This model may contribute to a better understanding of the neurochemical environment of respiratory neurons during sleep, which remains a question of importance regarding the numerous pathological states that are linked to specific perturbations of breathing control during sleep.     

Neuroendocrine and metabolic aspects of narcolepsy

Summary Human narcolepsy is characterized by excessive daytime sleepiness and various pathological manifestations of REM sleep. The disorder has a strong HLA-associated genetic background. Against this background, unknown causes induce in the majority of cases an almost complete stop in the production of orexins (hypocretins) within the hypothalamus in early adulthood. These peptides interact with various neurotransmitter systems involved in the regulation of sleep; in addition, they are also linked to numerous networks regulating appetite, weight and metabolism. As a consequence, narcolepsy is not only characterized by ­typical disturbances of sleep and wakefulness, but also by endocrine and metabolic abnor­malities. These include obesity and reduced circulating leptin levels. The respective data are summarized in this paper and the underlying causes discussed.     

The effects of 1 week of REM sleep deprivation on parvalbumin and calbindin immunoreactive neurons in central visual pathways of kittens

Many maturational processes in the brain are at high levels prenatally as well as neonatally before eye-opening, when extrinsic sensory stimulation is limited. During these periods of rapid brain development, a large percentage of time is spent in rapid eye movement (REM) sleep, a state characterized by high levels of endogenously produced brain activity. The abundance of REM sleep in early life and its ensuing decline to lower levels in adulthood strongly suggest that REM sleep constitutes an integral part of the activity-dependent processes that enable normal physiological and structural brain development. We examined the effect of REM sleep deprivation during the critical period for visual development on the development of two calcium-binding proteins that are associated with developmental synaptic plasticity and are found in the lateral geniculate nucleus (LGN) and visual cortex. In this study, REM sleep deprivation was carried out utilizing a computer-controlled, cage-shaking apparatus that successfully suppressed REM sleep. Body weight data suggested that this method of REM sleep deprivation produced less stress than the classical multiple-platform-over-water method. In REM sleep-deprived animals with normal binocular vision, the number of parvalbumin-immunoreactive (PV) neurons in LGN was found to be lower compared with control animals but was not affected in visual cortex. The pattern of calbindin-immunoreactivity (CaB) was unchanged at either site after REM sleep deprivation. Parvalbumin-immunoreactivity develops later than calbindin-immunoreactivity in the LGN, and the REM sleep deprivation that we applied from postnatal day 42-49 delayed this essential step in the development of the kitten's visual system. These data suggest that in early postnatal brain development, REM sleep facilitates the usual time course of the expression of PV-immunoreactivity in LGN neurons.