Sleep-wake state and memory function

Facility of memory formation and retrieval is affected by sleep-wake state. This paper discusses memory function while individuals are awake, but sleepy, at the transitions in state (i.e., wake to sleep and sleep to wake), and in REM and NREM sleep. The basal state of arousal at the time of memory function seems to be critical and the sleepy state, state transitions, and NREM sleep seem to define a continuum of arousal with respect to memory function. While different memory systems have been described, the effect of sleep-wake state on memory systems appears to be non-specific. Finally there is a shift in neurobiology from the NREM to REM state and memory function also appears to change in REM sleep.     

Binocular Depth Perception Following REM Deprivation or Awake State Visual Deprivation

Based upon the demonstration by Wallach and Karsh (1963) that stereoacuity is easily disruptable in the awake state, we postulated that central visual excitation, which is a feature of rapid eye movement sleep, operates to prevent deterioration of depth perception capacity nightly during sleep. Three awake state and four REM sleep conditions, each consisting of an 8-hr period, were tested as follows: Awake: 1) baseline testing, 2) monocular patching, 3) binocular patching; Sleeping: 4) REM sleep deprivation, 5) NREM control (Stage 2 awakenings), 6) eye movement control (Condition 4 with substitution of awake eye movements), 7) uninterrupted sleep. A new device was developed and is described which measures stereoacuity as free as possible from other binocular or monocular cues in an actual depth situation. We replicated Wallach and Karsh's (1963) finding of awake state disruption of stereopsis following monocular patching. However, our results indicate that REM sleep deprivation by awakenings is not detrimental to binocular depth perception the next morning. In a second experiment, we found that binocular depth perception at the end of REM periods is not significantly different from depth perception at the beginning of REM periods. We have concluded that REM sleep does not have the function of enhancement of stereoacuity processing.     

Systematic Trends Across the Night in Human Sleep Cycles

The durations of successive sleep cycles, defined according to NREM (stage 2) or REM onsets, were objected to trend analysis in three groups of normal subjects and in a group of elderly patients with chronic brain syndrome (CBS). NREM sleep cycles showed consistent curvilinear trends for all groups except that the trend in children was distinguished by a lengthy first NREM cycle. REM steep cycles showed quite similar curvilinear trends for the three normal age groups with the middle two cycles being longer than the first and fourth. In the CBS patients, REM sleep cycles did not show a significant trend across the night. Real-time cycles (i.e., with time awake included) manifested trends quite similar to those excluding waking. The trends in sleep cycle durations are normative characteristics of sleep which may not be apparent on a single night. A more constant cycle was found in the CBS elderly and may indicate brain pathology. Sleep cycle trends, along with such other temporal characteristics as the decline in stage 4, may provide clues to the metabolic processes which underlie the sleep EEG. They also provide a more exact basis for investigation of hypothesized biorhythm correlates of NREM-REM cycles.     

Dreaming during non-rapid eye movement sleep in the absence of prior rapid eye movement sleep

STUDY OBJECTIVES: There is a long-standing controversy surrounding the existence of dream experiences during non-rapid eye movement (NREM) sleep. Previous studies have not answered the question whether this "NREM dream" originates from the NREM sleep mechanism because the subject might simply be recalling experiences from the preceding rapid eye movement (REM) sleep. METHODS: We scheduled 11 healthy men to repeat 20-minute nap trials separated by 40-minute periods of enforced wakefulness across a period of 3 days. At the end of the nap trial, each participant answered questions regarding the formal aspects of his dream experiences during the nap trial, using the structured interviews. RESULTS: We obtained a total of 172 dream reports after naps containing REM sleep (REM naps) and 563 after naps consisting of only NREM sleep (NREM naps). Dream reports from NREM naps were less remarkable in quantity, vividness, and emotion than those from REM naps and were obtained more frequently during the morning hours when the occurrences of REM sleep were highest. CONCLUSIONS: These results suggest that the polysomnographic manifestations of REM sleep are not required for dream experiences but that the mechanisms driving REM sleep alter experiences during NREM sleep in the morning. A subcortical activation similar to REM sleep may occur in human NREM sleep during the morning when REM sleep is most likely to occur, resulting in dream experiences during NREM sleep.     

The effects of selective interruption and deprivation of sleep in the human newborn

In two separate studies, newborn infants' responses to sleep stage deprivation were investigated. In the first study, neonates were selectively awakened from either REM or NREM sleep during 1 interfeeding sleep period and allowed to recover in an undistrubed second. In the 2nd study, infants were kept totally awake for 1 interfeeding period and allowed to sleep undisturbed during the next. The results indicate that selective sleep stage deprivation by manual awakenings was impossible to achieve during the newborn period. Rather, the infants were partially sleep deprived (both stages of sleep were reduced) with increased amounts of wakefulness. During the disturbance the interrupted sleep stage demonstrated considerable “tenacity.” During undisturbed recovery sleep, in both studies, total sleep time was markedly increased. NREM sleep demonstrated a greater tendency for preferential recovery than REM sleep.     

Isolated REM Sleep Facilitates Recall of Complex Associative Information

This study directly tested the beneficial effect of isolated REM and isolated NREM sleep on the recall of narcoleptics. In a within subject design, 10 narcoleptics were instructed to sleep for a certain optimal duration and at a certain optimal time before each session, and were given 12–14 sessions, one a day, on different lists of a complex associative memory task and a minimally associative memory task. Following the 10-min task, the subject either had 20 min of polygraphically recorded napping or card playing, followed by a free recall test. The results for the complex associative task indicated significant differences between the three conditions for free recall. Recall was significantly better after isolated REM than after isolated NREM sleep or wakefulness and was significantly better after NREM than after wakefulness. The results from the minimally associative task were inconclusive. The results are consistent with the proposed neuronal activity correlates (NAC) theory that REM sleep actively consolidates and/or integrates complex associative information and that NREM sleep passively prevents retroactive interference of recently acquired complex associative information.     

Sleep state distribution of obstructive events in children: is obstructive sleep apnoea really a rapid eye movement sleep‐related condition?

Obstructive sleep apnoea (OSA) in children is commonly considered to occur predominantly in rapid eye movement (REM) sleep, but clinical experience suggests that this is not universally the case. We hypothesized that there would be a subgroup of children with OSA who have non‐REM (NREM) predominance of obstructive events and that these children share certain clinical characteristics. Thus, we aimed to compare the obstructive apnoea–hypopnoea index (OAHI) in REM versus NREM sleep and to assess factors influencing the distribution of events by sleep state. Polysomnography (PSG) recordings of 102 children aged 0–18 years with moderate to severe OSA (OAHI ≥5 h^?1) were reviewed. OAHI was calculated separately for REM and NREM sleep. A REM predominance index (RPI) was determined using log transformation [RPI = log (REM OAHI + 0.5) ? log (NREM OAHI + 0.5)] and compared with possible influencing factors using multiple linear regression. Analysis showed that obstructive events were more common in REM sleep (median REM OAHI 21.4 h^?1, median NREM OAHI 8.3 h^?1, P < 0.001). Mean RPI was significantly greater than zero (P = 0.003). However, a substantial minority of children (30.4%) had a higher NREM than REM OAHI. The factors that were related significantly to NREM predominance were older age (P = 0.02), higher arousal index (P < 0.001) and higher SpO₂ nadir (P < 0.001). Our findings demonstrate that while OSA is a REM sleep‐related problem in the majority of children, there is a significant subset of children with NREM predominance of obstructive events. This finding highlights the importance of considering sleep state distribution of events in studies of the pathophysiology and outcomes of OSA in childhood.     

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.     

Developmental changes in the sleep electroencephalogram of adolescent boys and girls

The sleep electroencephalogram (EEG) changes across adolescence; however, there are conflicting data as to whether EEG changes are regionally specific, are evident in non‐rapid eye movement (NREM) and rapid eye movement (REM) sleep, and whether there are sex differences. The present study seeks to resolve some of these issues in a combined cross‐sectional and longitudinal analysis of sleep EEG in adolescents. Thirty‐three healthy adolescents (18 boys, 15 girls; 11–14 years) were studied on two occasions 6–8 months apart. Cross‐sectional analysis of data from the initial visit revealed significantly less slow‐wave sleep, delta (0.3 to <4 Hz) and theta (4 to <8 Hz) power in both NREM and REM sleep with advancing age. The age–delta power relationship was significant at the occipital site, with age accounting for 26% of the variance. Longitudinal analysis revealed that NREM delta power declined significantly from the initial to follow‐up visit, in association with declining delta amplitude and incidence (P < 0.01), with the effect being greatest at the occipital site. REM delta power also declined over time in association with reduced amplitude (P < 0.01). There were longitudinal reductions in theta, alpha and sigma power in NREM and REM sleep evident at the occipital site at follow‐up (P < 0.01). No sex differences were apparent in the pattern of change with age for NREM or REM sleep. Declines in sleep EEG spectral power occur across adolescence in both boys and girls, particularly in the occipital derivation, and are not state‐specific, occurring in both NREM and REM sleep.     

Excitation of medullary respiratory neurons in REM sleep

STUDY OBJECTIVE: To study tonic inputs to medullary respiratory neurons during rapid eye movement (REM) sleep. DESIGN: Single medullary-respiratory-neuron recordings during sleep with spontaneous breathing and during apnea caused by mechanical hyperventilation. SETTING: Academic laboratory. SUBJECTS: Three tracheostomized adult cats implanted for polysomnography and extracellular microelectrode recordings. Intervention: Single medullary-respiratory-neuron recordings during spontaneous breathing and mechanical hyperventilation to apnea during non-REM (NREM) and REM sleep. RESULTS: Most but not all respiratory cells of all types (pre-inspiratory, decrementing, augmenting and late inspiratory, phase-spanning, and expiratory) were more active in REM sleep than in NREM sleep during both spontaneous breathing and apnea induced by mechanical hyperventilation. The mean discharge rate of the cells during spontaneous breathing in NREM sleep was 16.7 impulses per second and in REM sleep was 26.5 impulses per second. During ventilator-induced apnea, the mean rates were 10 impulses per second in NREM sleep and 17.5 per second during REM sleep. The increase in activity in REM sleep occurred after a delay of several seconds from the onset of REM sleep. Respiratory cells were excited at times individually and at other times simultaneously in either a reciprocal or nonreciprocal pattern. The degree of excitation of a neuron in REM sleep during ventilator-induced apnea was proportional to the degree of excitation of the neuron in REM sleep during spontaneous breathing. CONCLUSION: Medullary respiratory neurons are excited individually and collectively in REM sleep. The excitation occurs with a delay after the onset of the state and can stimulate and/or disorganize breathing.     

Ultrashort sleep-wake cycle: timing of REM sleep. Evidence for sleep-dependent and sleep-independent components of the REM cycle

This study investigated the temporal structure of REM sleep in three experiments utilizing the ultrashort 7-min sleep, 13-min waking cycle. The experiments were carried out for 24 or 36 h, with and without previous sleep deprivation, under two experimental conditions of instructing subjects to fall asleep or to resist sleep. Multiple REM episodes occurred in all three experiments in the two experimental conditions, particularly during the night period. The first nocturnal REM period appeared 5 h after the nocturnal sleep gate, of which 80-100 min were accounted for by non-REM (NREM) sleep. Thereafter, REM episodes occurred periodically, with a mean inter-REM interval of 86 min. Only 14 min of this interval consisted of NREM sleep. We believe that these results suggest that although the activation of the REM oscillator is dependent on a critical accumulation of NREM sleep, once activated, it continues to function during brief periods of waking.     

Thinking and hallucinating: reciprocal changes in sleep

Internal deliberations (focused thoughts) and endogenous percepts (hallucinations) vary in a reciprocal manner across the states of waking and sleep, paralleling changes in regional brain activation. As subjects go from waking through sleep onset to NREM sleep and then to REM sleep, they report progressively more hallucinoid imagery and progressively less thinking. We have investigated whether this reciprocity in cognition between NREM and REM is maintained throughout the night. To do so, we analyzed 229 REM and 165 NREM reports collected with the Nightcap sleep monitoring system from 16 participants in their homes over 14 nights. The reports were scored for the presence of hallucinations and directed thinking by external judges. As predicted, hallucinations were more frequent in REM than in NREM for each segment of the night, and directed thinking was more frequent in NREM in the first 5 h of the night. Late in the night, directed thinking was equally infrequent in NREM and REM. At the same time, hallucinations increased within both NREM and REM as the night progressed, whereas directed thinking decreased in NREM and remained at a stable, low level in REM. These findings suggest that a reciprocal shift in focused thinking and hallucinating is a general property of cognitive activity across the wake-sleep cycle. Biological evidence supports the hypothesis that these cognitive changes are governed by specific state regulatory and neurocognitive processes at several levels of the brain.     

Do neurotoxic lesions in rostral medullary nuclei induce/accentuate hypoventilation during NREM sleep?

Experimentally induced neuronal dysfunction in respiratory regions of the rostral medulla decrease breathing more in anesthetized mammals than in awake mammals. Sleep is similar to anesthesia in that excitatory inputs to respiratory neurons are reduced compared to the awake state; thus, we hypothesized that neurotoxic lesions in rostral medullary nuclei would, relative to wakefulness (WK), induce and/or accentuate hypoventilation during non-rapid eye movement (NREM) sleep. To test the hypothesis, goats were studied between 21:00 h and 03:00 h: (1) before and 30 days after chronically implanting microtubules bilaterally into the rostral medulla and, (2) 9-15 h and 2-17 days after unilateral injections of 100 nl to 1 microl, 50 mM ibotenic acid into the vestibular, gigantocellularis reticularis, or facial nuclei, or the retrotrapezoid nucleus/parapyramidal region. Arterial blood was repeatedly sampled in all studies during WK, and NREM and rapid eye movement (REM) sleep states. There was no significant (P>0.10) change in Pa(CO(2)) between WK and NREM sleep (and REM sleep when sufficient data were obtained) before or after implantation of microtubules and in studies after creating the neurotoxic lesions. Breathing frequency also did not significantly (P>0.10) differ between states in any of the studies. The data thus did not support the hypothesis. We speculate that in goats efficient compensatory mechanisms maintain Pa(CO(2)) homeostasis during normal sleep and the same and/or other mechanisms maintain homeostasis when excitatory drive is further reduced by lesions in rostral medullary nuclei.     

Arousal thresholds during human tonic and phasic REM sleep

The goal of the present study was to investigate arousal thresholds (ATs) in tonic and phasic episodes of rapid eye movement (REM) sleep, and to compare the frequency spectrum of these sub‐states of REM to non‐REM (NREM) stages of sleep. We found the two REM stages to differ with regard to behavioural responses to external acoustic stimuli. The AT in tonic REM was indifferent from that in sleep stage 2, and ATs in phasic REM were similar to those in slow‐wave sleep (stage 4). NREM and REM stages of similar behavioural thresholds were distinctly different with regard to their frequency pattern. These data provide further evidence that REM sleep should not be regarded a uniform state. Regarding electroencephalogram frequency spectra, we found that the two REM stages were more similar to each other than to NREM stages with similar responsivity. Ocular activity such as ponto‐geniculo‐occipital‐like waves and microsaccades are discussed as likely modulators of behavioural responsiveness and cortical processing of auditory information in the two REM sub‐states.     

Sleep and nighttime pruritus in children with atopic dermatitis

The number of scratching episodes and average frequency with which they started during each sleep stage as well as the effects of nighttime pruritus on objective sleep parameters in nine children with atopic dermatitis were assessed in the sleep laboratory. Scratching episodes occurred during rapid eye movement (REM) sleep and non-REM (NREM) sleep. The largest average frequency corresponded to stage 1, followed by stage 2, REM sleep, stage 4, and stage 3. Sleep maintenance was markedly altered. Total sleep time decrease was related mainly to smaller amounts of stage 4 NREM sleep. REM sleep percentage of total sleep time was increased as compared with normal children of the same age. Furthermore, in six of nine patients REM sleep latency was found to be decreased.     

Periodic leg movements during sleep and wakefulness in narcolepsy

The objectives of the study were to measure the prevalence of periodic leg movements during NREM and REM sleep (PLMS) and while awake (PLMW) and to assess the impact of PLMS on nocturnal sleep and daytime functioning in patients with narcolepsy. One hundred and sixty-nine patients with narcolepsy and 116 normal controls matched for age and gender were included. Narcoleptics with high and low PLMS indices were compared to assess the impact of PLMS on sleep and Multiple Sleep Latency Test (MSLT) variables. More narcoleptics than controls had a PLMS index greater than 5 per hour of sleep (67% versus 37%) and an index greater than 10 (53% versus 21%). PLMS indices were higher both in NREM and REM sleep in narcoleptic patients, but the between-group difference was greater for REM sleep. A significant increase of PLMS index was also found with aging in both narcoleptic patients and controls. PLMW indices were also significantly higher in narcoleptic patients. Patients with an elevated index of PLMS had a higher percentage of stage 1 sleep, a lower percentage of REM sleep, a lower REM efficiency and a shorter MSLT latency. The present study demonstrates a high frequency of PLMS and PLMW in narcolepsy, an association between the presence of PLMS and measures of REM sleep and daytime functioning disruption. These results suggest that PLMS represent an intrinsic feature of narcolepsy.     

Sleep interruption and exercise

Five men and five women participated in a study comparing the effects of sleep interruption with and without the imposition of physical activity. Subjects were awakened following the second REM period and returned to sleep 1 h later. In the IS condition they sat up and read during this period; in the ISE condition they exercised for 50 min at 60% VO2max. Relative to undisturbed sleep (US), IS resulted in a substantially shortened third non-REM (NREM) period, increased eye movement (EM) duration and density in the third REM period, and increased slow-wave sleep (SWS) in the fourth NREM period. The loss of delta sleep in the shortened NREM period was compensated for by an increase in delta sleep in the fourth NREM period (r = -0.90). However, total SWS obtained after interruption was unchanged from US. The ISE condition induced increases in cardiac output and temperature during sleep. No consistent changes in SWS were observed relative to IS, but the duration of the third REM period was reduced as well as EM duration and density within that REM period. Since REM sleep propensity is typically highest during the metabolic nadir of early morning sleep, the suppression of tonic and phasic components of REM sleep after ISE was concluded to result from the exercise-induced increase of metabolism and body temperature during sleep.     

The effects of sleep deprivation in humans: topographical electroencephalogram changes in non‐rapid eye movement (NREM) sleep versus REM sleep

Studies on homeostatic aspects of sleep regulation have been focussed upon non‐rapid eye movement (NREM) sleep, and direct comparisons with regional changes in rapid eye movement (REM) sleep are sparse. To this end, evaluation of electroencephalogram (EEG) changes in recovery sleep after extended waking is the classical approach for increasing homeostatic need. Here, we studied a large sample of 40 healthy subjects, considering a full‐scalp EEG topography during baseline (BSL) and recovery sleep following 40 h of wakefulness (REC). In NREM sleep, the statistical maps of REC versus BSL differences revealed significant fronto‐central increases of power from 0.5 to 11 Hz and decreases from 13 to 15 Hz. In REM sleep, REC versus BSL differences pointed to significant fronto‐central increases in the 0.5–7 Hz and decreases in the 8–11 Hz bands. Moreover, the 12–15 Hz band showed a fronto‐parietal increase and that at 22–24 Hz exhibited a fronto‐central decrease. Hence, the 1–7 Hz range showed significant increases in both NREM sleep and REM sleep, with similar topography. The parallel change of NREM sleep and REM sleep EEG power is related, as confirmed by a correlational analysis, indicating that the increase in frequency of 2–7 Hz possibly subtends a state‐aspecific homeostatic response. On the contrary, sleep deprivation has opposite effects on alpha and sigma activity in both states. In particular, this analysis points to the presence of state‐specific homeostatic mechanisms for NREM sleep, limited to <2 Hz frequencies. In conclusion, REM sleep and NREM sleep seem to share some homeostatic mechanisms in response to sleep deprivation, as indicated mainly by the similar direction and topography of changes in low‐frequency activity.     

The effect of estrogen replacement therapy on cardiac autonomic regulation

OBJECTIVE: To study the effects of estrogen replacement therapy (ERT) and sleep stage on autonomic cardiac regulation. SRUDY DESIGN: Seventy-one healthy postmenopausal women received transdermal ERT and placebo separated by a washout in a randomized, placebo-controlled, double-blind, cross-over trial. Polysomnography was conducted at the end of each treatment. Heart rate variability (HRV) was assessed in epochs of the awake state, stage 2, slow wave and REM sleep. The effects of estradiol and sleep stages on HRV were analyzed. RESULTS: ERT decreased heart rate in the awake state and quiet sleep, but not in REM sleep. ERT did not change the heart rate variability. Heart rate decreased and HRV increased during stage 2 and slow wave sleep compared with the awake state with placebo. In REM sleep, similarly, heart rate increased above awake values and the values of HRV parameters fell back to awake levels. CONCLUSIONS: The results suggest that ERT increases vagal tone, but does not change cardiac vagal modulation. Changes in HRV suggest a strong vagal influence in non-REM and a sympathetic influence in REM sleep.     

Rapid eye movement activity before spontaneous awakening in elderly subjects

Previous research in young subjects found that rapid eye movement (REM) density is higher in those REM phases which are followed by an awakening (REM-W) than in those preceding NREM (REM-N), suggesting a 'gating role' of REM sleep toward the awakening. It is not yet known whether this evidence is maintained in elderly subjects, who display, relative to young subjects, more awakenings, different sleep states from which the awakenings come (NREM in a high proportion of cases) and a general impairment of rapid eye movement activity (REMA). To investigate this issue, we have compared in three different age groups (young, old and 'old old' subjects) the features of REMA, including REM density and the amount and duration of REM bursts, between REM-W and REM-N. Whereas in the young REM density is higher in REM-W than in REM-N, this difference is already reduced in the old group and fully cancelled in the old old subjects. The evidence that old individuals spontaneously wake up despite the absence of an increase of REMA could imply that in the aged awakening is not preceded by an increase of the arousal level (expressed in REM sleep by the REMA). The similar duration of REM bursts for REM-W and REM-N in both groups of old subjects suggests that with age a marked impairment occurs in the organizational aspects of REMs, independently from the following state.