Challenging sleep homeostasis in narcolepsy-cataplexy: implications for non-REM and REM sleep regulation

STUDY OBJECTIVES: We recently proposed insufficient non-rapid eye movement sleep (NREMS) intensity to contribute to disturbed nocturnal sleep in patients with narcolepsy-cataplexy (NC). To test this hypothesis, we investigated the effect of physiologically intensified NREMS in recovery sleep following sleep deprivation. DESIGN: Nocturnal baseline and recovery sleep architecture, and the sleep electroencephalogram (EEG) before and after 40 hours of sustained wakefulness were compared between 6 drug-free patients with NC (age range: 19-37 years) and 6 individually matched, healthy control subjects (18-43 years). MEASUREMENTS: Sleep and sleep EEG power spectra (C3A2 derivation). The dynamics of the homeostatic Process S were estimated from the time course of slow-wave activity (SWA, spectral power within 0.75-4.5 Hz) across consecutive NREMS episodes. SETTINGS: Sleep research laboratory. RESULTS: In baseline, SWA decreased across consecutive NREMS episodes in patients with NC and control subjects. The build-up of SWA, however, was attenuated in NC in the second episode (P = 0.01) due to a higher number of short wake periods (P = 0.02). Prolonged wakefulness increased initial SWA in both groups (P = 0.003) and normalized the baseline differences between patients and control subjects in the time course of SWA in NREMS. The changed dynamics of SWA in the patients in recovery sleep when compared with baseline were associated with reduced numbers of intermittent wake periods in the first (P = 0.01) and second (P = 0.04) NREMS episodes. All patients, but no control subjects, showed a sleep-onset rapid eye movement period (SOREMP) in both baseline and recovery sleep. Sleep deprivation increased SOREMP duration (P = 0.03). CONCLUSIONS: Increased SWA after sleep deprivation indicates that sleep homeostasis is functional in NC. Increased NREMS intensity in recovery sleep postpones sleep fragmentation, supporting our concept that sleep fragmentation is directly related to insufficient NREMS intensity in NC. The persistence of SOREMP despite enhanced NREMS pressure suggests an abnormal interaction between NREMS and REMS regulatory processes.     

Effects of physostigmine infusion on healthy volunteers deprived of rapid eye movement sleep

Rapid eye movement sleep (REMS) deprivation is believed to alter the sensitivity of various neurotransmitter systems. In the present article, we studied 20 healthy volunteers divided into three groups. Group A attended the sleep laboratory for three nights: acclimatization, a baseline night, and one night of physostigmine infusion. Group B attended for eight nights; acclimatization, baseline, four nights of REMS deprivation, and two recovery nights. With the exception of the first recovery night, when group C volunteers were administered physostigmine, group C's schedule was identical to group B's. The infusions received by group A and C were composed of 1.0 mg of physostigmine, dissolved in 100 ml of saline solution. These were administered 5 min after sleep onset and thereafter every hour, except when the subjects were either awake or in REMS. All of the subjects receiving the cholinomimetic infusion were given a peripheral anticholinergic. Group A experienced a great number of awakenings with a decrease in REMS percentage. Group B recovery occurred over two nights, with an increase in the average length of REMS. Group C exhibited maximum REMS rebound on the first recovery night with an increased number of REMS episodes, as well as significant reductions in the first REMS latency. Our findings suggest that physostigmine alters REMS rebound following REMS deprivation.     

All-night dynamics of the human sleep EEG

The dynamics of the sleep EEG were investigated by all-night spectral analysis of 51 sleep records. Power density was calculated for 1-Hz bins in the 0.25-25.0 Hz range. Values in non-rapid-eye-movement sleep (NREMS) were higher than in REMS in the 0.25-16.0 Hz range, and lower in the 18.25-22.0 Hz range. Power density in the 0.25-12.0 Hz range showed a declining trend over the first four NREMS episodes, which, depending on the frequency bin, could be approximated by non-linear or linear decay functions. In the frequency range of sleep spindles (12.25-15.0 Hz), power density in the 13.25-15.0 Hz band showed an increasing trend between NREMS episode 2 and NREMS episode 4. A correlation matrix of 25 1-Hz bins revealed for NREMS a negative correlation between slow-wave activity (SWA; 0.25-4.0 Hz) and activity in the spindle frequency range. This negative correlation was highest in the first NREMS episode and diminished progressively over the subsequent NREMS episodes. Within NREMS episodes, the values in the spindle frequency range showed a U-shaped time course, the trough coinciding with a high level of SWA. By contrast, in both the early and late part of the episode the two types of activity changed in the same direction. The results are consistent with recent electrophysiological studies indicating that the establishment of NREMS is associated with a progressive hyperpolarization of thalamocortical neurons during which the membrane potential exhibits oscillations first in the spindle frequency range and then in the range of SWA.     

Sleep structure and EEG power density in morning types and evening types during a simulated day and night shift

The objective of this study was to examine circadian and homeostatic regulation of sleep in humans. In 8 morning types (M-types) and in 8 evening types (E-types), sleep was recorded during 3 successive nights and, after shifting sleep to the daytime, during 3 consecutive days. Night sleep was highly similar in the M-types and E-types. Day sleep clearly differed from night sleep in both types: Day sleep was shorter and had a longer first REMS episode. Furthermore, EEG power density recorded during non-REMS in the delta and theta frequency bands was higher during all day-sleep periods. Remarkably, the enhancements did not occur in non-REMS episode 1 but were delayed. This was interpreted as an inhibition of EEG power density at the beginning of sleep, possibly caused by the time course of body temperature and/or by the higher REMS propensity. Also, clear differences between the types became apparent: Only in the E-types, the non-REMS episodes shortened in response to the shift in bedtime, and probably related to this, the time course of EEG power density over consecutive non-REMS episodes became almost flat. It was concluded that the circadian system exerts not only an influence on sleep duration and REMS propensity, but also affects the time course of the non-REMS process.     

Short nights reduce light-induced circadian phase delays in humans

STUDY OBJECTIVE: Short sleep episodes are common in modern society. We recently demonstrated that short nights reduce phase advances to light. Here we show that short nights also reduce phase delays to light. DESIGN: Two weeks of 6-hour sleep episodes in the dark (short nights) and 2 weeks of long 9-hour sleep episodes (long nights) in counterbalanced order, separated by 7 days. Following each series of nights, there was a dim-light phase assessment to assess baseline phase. Three days later, subjects were exposed to a phase-delaying light stimulus for 2 days, followed by a final phase assessment. SETTING: Subjects slept at home in dark bedrooms but came to the laboratory for the phase assessments and light stimulus. PARTICIPANTS: Seven young healthy subjects. INTERVENTIONS: The 3.5-hour light stimulus was four 30-minute pulses of bright light (-5000 lux) separated by 30-minute intervals of room light. The stimulus began 2.5 hours after each subject's dim-light melatonin onset, followed by a 6- or 9-hour sleep episode. On the second night, the bright light and sleep episode began 1 hour later. MEASUREMENTS AND RESULTS: The dim-light melatonin onset and dimlight melatonin offset phase delayed 1.4 and 0.7 hours less in the short nights, respectively (both p < or = .015). CONCLUSIONS: These results indicate for the first time that short nights can reduce circadian phase delays, that long nights can increase phase delays to light, or both. People who curtail their sleep may inadvertently reduce their circadian responsiveness to evening light.     

Sleep regulation after reduction of brain serotonin: effect of p-chlorophenylalanine combined with sleep deprivation in the rat

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.     

Cortical temperature and EEG slow-wave activity in the rat: analysis of vigilance state related changes

Vigilance states, cortical temperature (T _CRT), and electroencephalograph (EEG) slow-wave-activity (SWA, mean power density in the 0.75–4.0 Hz range) of ten rats were recorded continuously during a baseline day, and two recovery days (Recovery 1 and 2) after 24 h of sleep deprivation (SD). The short term changes of T _CRT were analysed within episodes of nonrapid eye movement sleep (NREMS), REM sleep (REMS) and waking (W), and at transitions between vigilance states. SWA was analysed within NREMS episodes and at W to NREMS (WN) transitions. T _CRT increased during episodes of W and REMS, and decreased during NREMS episodes. These changes were a function of episode duration, and, for W and NREMS, of T _CRT at episode onset. In Recovery 1 the increase in T _CRT at NREMS to REMS (NR) and NREMS to W (NW) transitions tended to be attenuated. SWA within NREMS episodes was enhanced after SD. Over all experimental days, the increase of SWA and the decrease of T _CRT in NREMS episodes were not correlated.It is concluded that during recovery from SD the changes in T _CRT at state transitions were little affected. The lack of a relationship between changes in T _CRT and SWA indicates that separate mechanisms underlie the regulation of brain temperature and sleep intensity.     

Distribution of period-analyzed delta activity during sleep.

The distribution of delta EEG activity was evaluated during sleep in eight healthy adults. Digital period analysis, including an amplitude measurement, was used to quantify delta activity. The average percentages of delta half- and full-wave zero-crosses, mean delta power, and mean total power were computed for each nonrapid eye movement (NREM) period. The distribution of these delta measures was examined across NREM periods (NREMPs). No significant linear trends were evident in the zero-cross or power measures. Four subjects showed the highest delta power and greatest incidence of delta in the second rather than first NREMP. Regression analyses of individual delta incidence data revealed that only 62.5% of recording nights could be described with an exponential equation. Exponential regressions described 81% of delta amplitude cases. Further, delta activity in some subjects could be described by either linear or exponential regression. The findings suggest that the temporal changes of delta activity may not be entirely systematic across NREMPs and are variable across subjects.     

Sex differences in delta and alpha EEG activities in healthy older adults

STUDY OBJECTIVES: To examine sex effects on sleep stages and electroencephalogram (EEG) spectral power in older adults. DESIGN: Sleep was polygraphically recorded for 2 consecutive nights, and blood was sampled during the last 24 hours. SETTING: The University of Chicago Clinical Research Center. PARTICIPANTS: Two groups of healthy nonobese older subjects: 10 men (59 +/- 2 years), and 10 postmenopausal women (63 +/- 2 years). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A spectral analysis of the EEG was performed in the delta and alpha bands. There were no sex differences in sleep stages. Blood sampling resulted in reductions of total sleep time, sleep maintenance, slow-wave sleep, and absolute delta activity that were all larger in women than in men. In absolute values, delta and alpha activities in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep were higher in women than in men, but, for delta activity, the sex differences were larger in REM than in NREM sleep. In women, but not in men, absolute delta activity in REM was decreased during blood sampling and was strongly correlated with absolute delta activity in NREM. Delta activity in REM did not dissipate across the night in either group. When normalized for the activity in REM sleep, the sex difference in delta activity in NREM sleep was reversed, with lower activity in women. CONCLUSIONS: Sex differences in sleep EEG variables are present in older adults. When normalized, delta activity in older women is lower than in older men, which may be more consistent with sex differences in subjective complaints, in fragility of sleep in the presence of environmental disturbances, and in the relationship to growth-hormone release.     

Changes in EEG activity and hypothalamic temperature as indices for non-REM sleep to REM sleep transitions

A shift of physiological regulations from a homeostatic to a non-homeostatic modality characterizes the passage from non-NREM sleep (NREMS) to REM sleep (REMS). In the rat, an EEG index which allows the automatic scoring of transitions from NREMS to REMS has been proposed: the NREMS to REMS transition indicator value, NIV [J.H. Benington et al., Sleep 17 (1994) 28-36]. However, such transitions are not always followed by a REMS episode, but are often followed by an awakening. In the present study, the relationship between changes in EEG activity and hypothalamic temperature (Thy), taken as an index of autonomic activity, was studied within a window consisting of the 60s which precedes a state change from a consolidated NREMS episode. Furthermore, the probability that a transition would lead to REMS or wake was analysed. The results showed that, within this time window, both a modified NIV (NIV(60)) and the difference between Thy at the limits of the window (Thy(D)) were related to the probability of REMS onset. Both the relationship between the indices and the probability of REMS onset was sigmoid, the latter of which saturated at a probability level around 50-60%. The efficacy for the prediction of successful transitions from NREMS to REMS found using Thy(D) as an index supports the view that such a transition is a dynamic process where the physiological risk to enter REMS is weighted at a central level.     

Long-term effect of cued fear conditioning on REM sleep microarchitecture in rats

STUDY OBJECTIVES: To study long-term effects of conditioned fear on REM sleep (REMS) parameters in albino rats. DESIGN: We have investigated disturbances in sleep architecture, including muscle twitch density as REMS phasic activity, and freezing behavior in wakefulness, upon reexposure to a conditioned stimulus (CS) on Day 1 and Day 14 postconditioning. SUBJECTS: Male Sprague-Dawley rats prepared for polysomnographic recordings. INTERVENTIONS: After baseline sleep recording, the animals in the experimental group received five pairings of a 5-sec tone, co-terminating with a 1-sec, 1 mAfootshock. The control rats received similar numbers of tones and shocks, but explicitly unpaired. On postconditioning days, after reexposure to tones alone, sleep and freezing behavior were recorded. MEASUREMENTS AND RESULTS: Conditioned fear significantly altered REMS microarchitecture (characterized as sequential-REMS [seq-REMS: < or =3 min episode separation] and single-REMS [sin-REMS: >3 min episode separation]) on Day 14. The total amount and number of seq-REMS episodes decreased, while the total amount and number of sin-REMS episodes increased. Further, the CS induced significant increases in freezing and REMS myoclonic twitch density in the experimental group. Reexposure to the CS produced no alterations in controls. CONCLUSIONS: The results suggest that conditioned fear causes REMS alterations, including difficulty in initiating a REMS episode as indicated by the diminution in the number of seq-REMS episodes. Another finding, the increase in phasic activity, agrees with the inference from clinical investigations that retrieval of fearful memories can be associated with the long-term REMS disturbances characteristic of posttraumatic stress disorder.     

Long-term vs. short-term processes regulating REM sleep

In cats, rats, and mice, the amount of rapid eye movement sleep (REMS) lost during a sleep deprivation (SD) predicts the subsequent REMS rebound during recovery sleep. This suggests that REMS is homeostatically regulated and that a need or pressure for REMS accumulates in its absence, i.e. during both wakefulness and non-rapid eye movement sleep (NREMS). Conversely, it has been proposed that REMS pressure accumulates exclusively during NREMS [Benington and Heller, Am. J. Physiol. 266 (1994) R1992; Prog. Neurobiol. 44 (1994b) 433]. This hypothesis is based on the analysis of the duration of successive NREMS and REMS episodes and of electroencephalogram (EEG) events preceding REMS. Pre-REMS events (PREs) do not always result in sustained REMS and can thus be regarded as REMS attempts that increase as NREMS progresses. It is assumed that two processes regulating REMS can resolve the apparent contradiction between these two concepts: a 'long-term' process that homeostatically regulates the daily REMS amount and a 'short-term' process that regulates the NREM--REMS cycle. These issues were addressed in two SD experiments in rats. The two SDs varied in length (12 and 24 h) and resulted in very similar compensatory changes in NREMS but evoked very different changes for all REMS parameters studied. The large REMS increase observed after 24-h SD was accompanied by a reduction in unsuccessful PREs and an increase in sustained REMS episodes, together resulting in a threefold increase in the success-rate to enter REMS. Changes in success-rate matched those of a theoretically derived long-term REMS pressure. The SD induced changes in sleep architecture could be reproduced by assuming that the increased long-term REMS pressure interacts with the short-term process by increasing the probability to enter and remain in REMS.     

Evaluation of a filter/integrator system for quantifying delta activity in the sleep electroencephalogram

The integrated output of a delta bandpass filter was evaluated as a means of quantifying delta activity in the sleep electroencephalogram (EEG). Total integrated slow wave amplitude (ISWA) and a density measure (ISWA/20-s epoch) were determined from four complete NREM sleep periods (NREMPs) on each of 2 baseline nights from 15 subjects. Total ISWA displays a linear decline across NREMPs, whereas ISWA/20-s epoch shows a curvilinear decline. Both measures show highly significant correlations with manually staged slow wave sleep and a high degree of intra-individual consistency between nights, for both whole-night values and those of individual NREMPs. The slow-wave density index (ISWA/20-s epoch) demonstrated consistently higher between-night correlations across NREMPs than did the total ISWA index, particularly in the first NREMP, suggesting it may better characterize the nightly distribution of delta activity in an individual's sleep EEG.     

Increased homeostatic response to behavioral sleep fragmentation in morning types compared to evening types

STUDY OBJECTIVES: To evaluate the influence of chronotype on sleep stages and quantitative sleep EEG when sleep pressure is increased and sleep schedule remains constant. DESIGN: A 5-day session comprising an adaptation night, a baseline night, two nights of sleep fragmentation, and a recovery night. SETTING: Chronobiology laboratory. PARTICIPANTS: Twenty-four healthy subjects aged 19-34 years: 12 morning types and 12 evening types selected by questionnaire. Each group included 6 men and 6 women with a habitual sleep duration of 7 to 9 hours. Interventions: Two nights of behavioral sleep fragmentation induced by forced 5-min awakenings every half-hour. MEASUREMENTS AND RESULTS: Each night of polysomnography recording lasted 8 hours and was based on each subject's preferred sleep schedule. On both nights of sleep fragmentation, stage 1 sleep increased, while both total sleep time and minutes of slow wave sleep decreased. No difference was observed in sleep architecture between morning types and evening types during sleep fragmentation nights or during recovery night. Spectral analysis of all-night NREM sleep EEG showed that during the recovery night, morning types had a larger fronto-central increase in low frequency activities and a larger centro-parietal decrease in 14-15 Hz activity than evening types. The largest group difference was for slow wave activity in the fronto-central area during the first part of the sleep episode. CONCLUSIONS: These results add further support to a postulated difference in homeostatic sleep regulation between morning types and evening types, with morning types showing indications of a higher homeostatic response to sleep disruption.     

A quantitative analysis of phasic and tonic submental EMG activity in human sleep

Submental muscle activity and slow-wave activity in the EEG (mean power density in the 0.75-4.5-Hz band) were determined for consecutive 20-sec epochs in 34 all-night recordings of human sleep. Muscle activity was quantified by calculating the statistical variance of the digitized electromyogram (EMG). The tonic level of muscle activity was lower in REM sleep (REMS) than in nonREMS, and higher in the first nonREMS episode but an increasing trend within all subsequent nonREMS episodes. EEG slow-wave activity increased in the first part of all nonREMS episodes and decreased in the first part of all REMS episodes. The absolute or relative difference in muscle activity between two consecutive 20-sec intervals was used for defining EMG arousals. The density of arousals did not differ significantly among nonREMS episodes. Weak and moderate arousals showed an increasing density over consecutive REMS episodes. While arousals were uniformly distributed within REMS episodes, they were concentrated at the beginning and the end of nonREMS episodes.     

Patterns in the distribution of REM sleep in normal human sleep

Results are reported of four analyses of the distribution of REM sleep across nights of two subjects who slept for 50 consecutive nights on a regimented, but normal, sleep schedule. We found (a) a strong phase-setting effect of sleep onset on the distribution of REM sleep within nights, (b) no systematic change in the phase of the distribution of REM sleep across nights, and (c) a relationship between the nocturnal temperature minimum and the distribution of REM sleep within nights. Our results are consistent with the notion that the nightly distribution of REM sleep may be determined by an oscillatory process, the phase of which is reset at sleep onset, but which may be subject to other influences, such as the circadian temperature rhythm. These results are in general agreement with those found by investigators studying subjects on free-running or other abnormal sleep schedules.     

Estradiol and Progesterone Modulate Spontaneous Sleep Patterns and Recovery from Sleep Deprivation in Ovariectomized Rats

Study Objectives:

Women undergo hormonal changes both naturally during their lives and as a result of sex hormone treatments. The objective of this study was to gain more knowledge about how these hormones affect sleep and responses to sleep loss.

Design:

Rats were ovariectomized and implanted subcutaneously with Silastic capsules containing oil vehicle, 17β-estradiol and/or progesterone. After 2 weeks, sleep/wake states were recorded during a 24-h baseline period, 6 h of total sleep deprivation induced by gentle handling during the light phase, and an 18-h recovery period.

Measurements and Results:

At baseline and particularly in the dark phase, ovariectomized rats treated with estradiol or estradiol plus progesterone spent more time awake at the expense of non-rapid eye movement sleep (NREMS) and/or REMS, whereas those given progesterone alone spent less time in REMS than ovariectomized rats receiving no hormones. Following sleep deprivation, all rats showed rebound increases in NREMS and REMS, but the relative increase in REMS was larger in females receiving hormones, especially high estradiol. In contrast, the normal increase in NREMS EEG delta power (an index of NREMS intensity) during recovery was attenuated by all hormone treatments.

Conclusions:

Estradiol promotes arousal in the active phase in sleep-satiated rats, but after sleep loss, both estradiol and progesterone selectively facilitate REMS rebound while reducing NREMS intensity. These results indicate that effects of ovarian hormones on recovery sleep differ from those on spontaneous sleep. The hormonal modulation of recovery sleep architecture may affect recovery of sleep related functions after sleep loss.

Citation:

Deurveilher S; Rusak B; Semba K. Estradiol and progesterone modulate spontaneous sleep patterns and recovery from sleep deprivation in ovariectomized rats. SLEEP 2009;32(7):865-877.     

THE FIRST NIGHT EFFECT: AN EEG STUDYOF SLEEP

The electroencephalographic records from 43 subjects who slept for four consecutive nights in a laboratory environment were studied in an effort to describe the First Night Effect. These records showed that the first night of laboratory sleep contains more awake periods and less Stage I-rapid eye movement sleep. There is a delay in the onset of Stages IV and I-REM and the sleep is more changeable. These effects rapidly adapt out by the second night of sleep.     

Temporal characteristics of delta activity during NREM sleep in depressed outpatients and healthy adults: group and sex effects

STUDY OBJECTIVES: The primary aim was to evaluate group and sex differences in delta activity across non-rapid eye movement (NREM) sleep in depressed patients and healthy controls. DESIGN: Repeated-measures ANOVA contrasted delta power, amplitude and incidence in the first three NREM periods (stages 2, 3, and 4) of sleep. The time course of delta activity was evaluated with exponential regressions. Age effects on delta were evaluated with linear regression analysis. SETTING: Two consecutive nights were spent in the laboratory, the first of which served as adaptation. PATIENTS OR PARTICIPANTS: Twenty-two (9 men, 13 women) symptomatic, but unmedicated, outpatients with major depressive disorder (MDD) and 23 healthy controls (15 men, 8 women) participated in the study. MEASUREMENTS AND RESULTS: Delta power and amplitude showed significant group by sex interactions. Men with MDD showed lower power and amplitude in NREM sleep compared to women with MDD, but did not differ significantly from controls. However, the time course of delta power and amplitude was significantly different in men with MDD, with lower accumulation and slower dissipation across NREM sleep than all other groups. Women with MDD showed no evidence of lower delta power and amplitude or an abnormal time course compared to control women or men. Age had a differential influence on delta activity between the groups, with little age-related change in delta activity in the depressed groups. CONCLUSIONS: It was concluded that slow-wave sleep deficiencies may be characteristic of men, but not women, with MDD. It was also concluded that the influence of age on delta activity varied as a function of both psychiatric status and sex.     

The Effect of Presleep Focal Attention Load on Subsequent Sleep Patterns

The hypothesis that a load on focal attention prior to sleep results in subsequent changes in sleep patterns was investigated. Eight females and 2 males slept in the laboratory for 4 nights: 2 adaptation nights, 1 experimental night preceded by a focal attention load, and 1 control night preceded by relaxed activity. On the experimental night, time in bed, total sleep time, and stage REM sleep were significantly longer than on the control night. The results support the hypothesis and suggest that attention during REM sleep has a unique character.