Manipulating REM sleep in older adults by selective REM sleep deprivation and physiological as well as pharmacological REM sleep augmentation methods

Experimental approaches to manipulate REM sleep within the cognitive neuroscience of sleep are usually based on sleep deprivation paradigms and focus on younger adults. In the present study, a traditional selective REM sleep deprivation paradigm as well as two alternative manipulation paradigms targeting REM sleep augmentation were investigated in healthy older adults. The study sample consisted of 107 participants, male and female, between the ages of 60 and 82 years, who had been randomly assigned to five experimental groups. During the study night, a first group was deprived of REM sleep by selective REM sleep awakenings, while a second group was woken during stage 2 NREM sleep in matched frequency. Physiological REM sleep augmentation was realized by REM sleep rebound after selective REM sleep deprivation, pharmacological REM sleep augmentation by administering an acetylcholinesterase inhibitor in a double-blind, placebo-controlled design. Deprivation and augmentation paradigms manipulated REM sleep significantly, the former affecting more global measures such as REM sleep minutes and percentage, the latter more organizational aspects such as stage shifts to REM sleep, REM latency, REM density (only pharmacological augmentation) and phasic REM sleep duration. According to our findings, selective REM sleep deprivation seems to be an efficient method of REM sleep manipulation in healthy older adults. While physiological rebound-based and pharmacological cholinergic REM sleep augmentation methods both failed to affect global measures of REM sleep, their efficiency in manipulating organizational aspects of REM sleep extends the traditional scope of REM sleep manipulation methods within the cognitive neuroscience of sleep.     

M1 muscarinic acetylcholine receptor agonism alters sleep without affecting memory consolidation

Preclinical studies have implicated cholinergic neurotransmission, specifically M1 muscarinic acetylcholine receptor (mAChR) activation, in sleep-associated memory consolidation. In the present study, we investigated the effects of administering the direct M1 mAChR agonist RS-86 on pre-post sleep memory consolidation. Twenty healthy human participants were tested in a declarative word-list task and a procedural mirror-tracing task. RS-86 significantly reduced rapid eye movement (REM) sleep latency and slow wave sleep (SWS) duration in comparison with placebo. Presleep acquisition and postsleep recall rates were within the expected ranges. However, recall rates in both tasks were almost identical for the RS-86 and placebo conditions. These results indicate that selective M1 mAChR activation in healthy humans has no clinically relevant effect on pre-post sleep consolidation of declarative or procedural memories at a dose that reduces REM sleep latency and SWS duration.     

Changes in sleep architecture following motor learning depend on initial skill level

Previous research has linked both rapid eye movement (REM) sleep and Stage 2 sleep to procedural memory consolidation. The present study sought to clarify the relationship between sleep stages and procedural memory consolidation by examining the effect of initial skill level in this relationship in young adults. In-home sleep recordings were performed on participants before and after learning the pursuit rotor task. We divided the participants into low- and high-skill groups based on their initial performance of the pursuit rotor task. In high-skill participants, there was a significant increase in Stage 2 spindle density after learning, and there was a significant correlation between the spindle density that occurred after learning and pursuit rotor performance at retest 1 week later. In contrast, there was a significant correlation between changes in REM density and performance on the pursuit rotor task during retest 1 week later in low-skill participants, although the actual increase in REM density failed to reach significance in this group. The results of the present study suggest the presence of a double dissociation in the sleep-related processes that are involved in procedural memory consolidation in low- and high-skill individuals. These results indicate that the changes in sleep microarchitecture that take place after learning depend on the initial skill level of the individual and therefore provide validation for the model proposed by Smith et al. [Smith, C. T., Aubrey, J. B., & Peters, K. R. Different roles for REM and Stage 2 sleep in motor learning. Psychologica Belgica, 44, 79-102, 2004]. Accordingly, skill level is an important variable that needs to be considered in future research on sleep and memory consolidation.     

Evidence for 2-stage models of sleep and memory: Learning-dependent changes in spindles and theta in rats

What processes are involved in the formation of enduring memory traces? Sleep has been proposed to play a role in memory consolidation and the present study provides evidence to support 2-stage models of sleep and memory including both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Previous research has shown REM sleep increases following avoidance learning and memory is impaired if REM deprivation occurs during these post-training periods indicating that REM sleep may have a role in memory consolidation processes. These discrete post-training periods have been termed REM sleep windows (RSWs). It is not known whether the electroencephalogram has unique characteristics during the RSW. Further investigation of the RSW was one of the primary goals of this study. We investigated the epidural-recorded electrophysiological learning-related changes following avoidance training in rats. Theta power increased in the learning group during the RSW, suggesting that theta is involved in memory consolidation during this period. Sleep spindles subsequently increased in slow wave sleep (SWS). The results suggest that both NREM and REM sleep are involved in sleep-dependent memory consolidation, and provide support for existing 2-stage models. Perhaps first theta increases to organize and consolidate material via hippocampal–neocortical dialogue, followed by subsequent refinement in the cortex by spindles during SWS.     

Sleep and memory: a molecular perspective

This review synthesizes data from behavioral studies examining the role of sleep in memory storage with what is known about the molecular mechanisms of memory consolidation. There are striking similarities in the effects on memory storage of post-training pharmacological manipulations and post-training manipulations of sleep. For example, inhibition of protein synthesis is most effective if it occurs at a time post-training when rapid eye movement (REM) sleep is required for memory consolidation. The neurochemical changes that occur across sleep/wake states, especially the cholinergic changes that occur in the hippocampus during REM sleep, might provide a mechanism by which sleep modulates specific cellular signaling pathways involved in hippocampus-dependent memory storage.     

Demonstration of ponto-geniculo-occipital waves in the albino rat

Monophasic waves that resemble the ponto-geniculo-occipital (PGO) waves recorded in cats were electrophysiologically recorded in the albino rat. These waves were most prominent within rapid eye movement (REM) sleep episodes and in the segments of slow-wave sleep just preceding both REM sleep periods and spontaneous awakenings. Administration of para-chlorophenylalanine (300 mg/kg) caused a change in distribution of the waves—an increase in the proportion occurring in waking and a decrease in REM sleep. REM sleep deprivation carried out by hand awakenings caused an increase in the proportion of waves occurring prior to REM sleep onset as well as a decrease in the proportion of waves in REM sleep. The waves recorded in the albino rat were so similar in their appearance to the PGO waves recorded in the cat as well as in their temporal distribution, and susceptibility to manipulation, that this activity appeared to constitute the rat homolog of PGO waves.     

Effects of cortisol suppression on sleep-associated consolidation of neutral and emotional memory.

BACKGROUND: Previous research indicates that hippocampus-dependent declarative memory benefits from early nocturnal sleep, when slow-wave sleep (SWS) prevails and cortisol release is minimal, whereas amygdala-dependent emotional memory is enhanced through late sleep, when rapid eye movement (REM) sleep predominates. The role of the strong cortisol rise accompanying late sleep for emotional memory consolidation has not yet been investigated. METHODS: Effects of the cortisol synthesis inhibitor metyrapone on sleep-associated consolidation of memory for neutral and emotional texts were investigated in a randomized, double-blind, placebo-controlled study in 14 healthy men. Learning took place immediately before treatment, which was followed by 8 hours of sleep. Retrieval was tested at 11 am the next morning. RESULTS: Metyrapone suppressed cortisol during sleep and blocked particularly the late-night rise in cortisol. It reduced SWS and concomitantly impaired the consolidation of neutral texts. Emotional texts were spared from this impairing influence, however. Metyrapone even amplified emotional enhancement in text recall indicating amygdala-dependent memory. CONCLUSIONS: Cortisol blockade during sleep impairs hippocampus-dependent declarative memory formation but enhances amygdala-dependent emotional memory formation. The natural cortisol rise during late sleep may thus protect from overshooting emotional memory formation, a mechanism possibly pertinent to the development of posttraumatic stress disorder.     

The whats and whens of sleep-dependent memory consolidation

Sleep benefits memory consolidation. The reviewed studies indicate that this consolidating effect is not revealed under all circumstances but is linked to specific psychological conditions. Specifically, we discuss to what extent memory consolidation during sleep depends on the type of learning materials, type of learning and retrieval test, different features of sleep and the subject population. Post-learning sleep enhances consolidation of declarative, procedural and emotional memories. The enhancement is greater for weakly than strongly encoded associations and more consistent for explicitly than implicitly encoded memories. Memories associated with expected reward gain preferentially access to sleep-dependent consolidation. For declarative memories, sleep benefits are more consistently revealed with recall than recognition procedures at retrieval testing. Slow wave sleep (SWS) particularly enhances declarative memories whereas rapid eye movement (REM) sleep preferentially supports procedural and emotional memory aspects. Declarative memory profits already from rather short sleep periods (1–2 h). Procedural memory profits seem more dose-dependent on the amount of sleep following the day after learning. Children's sleep with high amounts of SWS distinctly enhances declarative memories whereas elderly and psychiatric patients with disturbed sleep show impaired sleep-associated consolidation often of declarative memories. Based on the constellation of psychological conditions identified we hypothesize that access to sleep-dependent consolidation requires memories to be encoded under control of prefrontal-hippocampal circuitry, with the same circuitry controlling subsequent consolidation during sleep.     

Daytime naps improve procedural motor memory

BACKGROUND AND PURPOSE: To investigate the impact of a short daytime nap on procedural and declarative memory consolidation. PATIENTS AND METHODS: Following a normal night's sleep, 34 young healthy subjects were randomly assigned to a nap or wake condition of about 45min in the early afternoon after learning procedural and declarative memory tasks. Subjects were controlled for alertness and cortisol secretion. RESULTS: The afternoon naps were dominated by sleep stage 2 but contained some slow wave sleep (SWS) and rapid eye movement (REM) sleep as well. Naps significantly improved procedural, but not declarative, memory. Females showed more improvement than males in the declarative memory tasks irrespective of nap or wake. There was no difference between groups with respect to cortisol secretion or alertness. CONCLUSIONS: A short nap is favorable for consolidation of procedural memory. The possibly confounding effect of gender should always be considered in research on sleep and memory.     

Impaired Declarative Memory Consolidation During Sleep in Patients With Primary Insomnia: Influence of Sleep Architecture and Nocturnal Cortisol Release

BACKGROUND: A central cognitive function of sleep is to consolidate newly acquired memories for long-term storage. Here, we investigated whether the overnight consolidation of declarative memory in patients with chronic sleep disturbances is impaired, owing to less slow wave sleep (SWS) and an increased cortisol release. METHODS: Polysomnographic recordings, serum cortisol concentrations, and overnight memory consolidation in 16 patients with primary insomnia were compared with those of 13 healthy control subjects. RESULTS: Patients displayed distinctly less overnight consolidation of declarative memory (p < .05), which was significantly correlated with SWS in the control subjects (r = .69) but with rapid eye movement (REM) sleep in the patients (r = .56), who had a diminished amount of SWS (p < .05). Increased cortisol levels in the middle of the night were associated with impaired retrieval of declarative memory after sleep for both control subjects (r = -.52) and patients (r = -.46). CONCLUSIONS: Primary insomnia is associated with a diminished sleep-related consolidation of declarative memory. Efficient overnight consolidation of declarative memory is associated with high amounts of SWS and low serum cortisol levels during the early part of the night. Where SWS is decreased, REM sleep might play a partly compensatory role in the consolidation of declarative memory.     

Changes in 24-hour urinary excretion of MHPG after four continuous nights of REM sleep deprivation in human volunteers

Eight healthy volunteers were deprived of rapid eye movement (REM) sleep for 4 consecutive nights. Twenty-four-hour urine samples were collected to determine levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) during basal, REM sleep deprivation, and REM recovery conditions. A control experiment was carried out in four subjects who were awakened in non-REM sleep for 4 consecutive nights. Subjects deprived of REM sleep showed significant MHPG increases on night 4 of sleep deprivation. MHPG levels in the control condition decreased, but not significantly. When MHPG levels in both experimental and control conditions were compared in the same four subjects, a significant difference was observed, indicating an effect of the control condition. Increased MHPG levels were related to REM sleep reduction and to the time and number of awakenings. Our findings seem to support an inverse homeostatic relationship between norepinephrine metabolism and REM sleep.     

Declarative and procedural memory consolidation during sleep in patients with borderline personality disorder

Borderline personality disorder (BPD) is characterized by changes in subjective and objective measures of sleep quality. As recent findings point to the importance of sleep in memory consolidation, sleep-related memory consolidation was investigated in 15 female BPD patients (mean age 26.1+/-6.1 years) and 15 female healthy controls (mean age 25.6+/-6.8 years). Before and after the study night, declarative and procedural memory performance was tested by a paired associate list and a mirror tracing task. Subjective sleep quality was assessed by a sleep questionnaire, objective sleep quality was measured by a portable sleep recording device. During the study night the restorative value of sleep was significantly reduced in BPD patients (p<0.001), while objective sleep quality showed a trend for longer REM sleep duration (p=0.054). No significant differences were found regarding overnight performance improvement in the declarative and procedural memory tasks. Present findings suggest that declarative and procedural memory consolidation during sleep is intact in BPD patients.     

Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep.

Transection, lesion and unit recording studies have localized rapid eye movement (REM) sleep mechanisms to the pons. Recent work has emphasized the role of pontine cholinergic cells, especially those of the pedunculopontine tegmentum (PPT). The present study differentiated REM sleep deficits associated with lesions of the PPT from other pontine regions implicated in REM sleep generation, including those with predominantly cholinergic vs non-cholinergic cells. Twelve hour polygraphic recordings were obtained in 18 cats before and 1-2 weeks after bilateral electrolytic or radio frequency lesions of either: (1) PPT, which contains the dorsolateral pontine cholinergic cell column; (2) laterodorsal tegmental nucleus (LDT), which contains the dorsomedial pontine cholinergic cell column; (3) locus ceruleus (LC), which contains mostly noradrenergic cells; or (4) subceruleus (LC alpha, peri-LC alpha and the lateral tegmental field), which also contains predominantly noncholinergic cells. There were three main findings: (i) Only lesions of PPT and subceruleus significantly affected REM sleep time. These lesions produced comparable reductions in REM sleep time but influenced REM sleep components quite differently: (ii) PPT lesions, estimated to damage 90 +/- 4% of cholinergic cells, reduced the number of REM sleep entrances and phasic events, including ponto-geniculooccipital (PGO) spikes and rapid eye movements (REMs), but did not prevent complete atonia during REM sleep: (iii) Subceruleus lesions eliminated atonia during REM sleep. Mobility appeared to arouse the cat prematurely from REM sleep and may explain the brief duration of REM sleep epochs seen exclusively in this group. Despite the reduced amount of REM sleep, the total number of PGO spikes and REM sleep entrances increased over baseline values. Collectively, the results distinguish pontine loci regulating phasic events vs atonia. PPT lesions reduced phasic events, whereas subceruleus lesions created REM sleep without atonia. Severe REM sleep deficits after large pontine lesions, including PPT and subceruleus, might be explained by simultaneous production of both REM sleep syndromes. However, extensive loss of ACh neurons in the PPT does not disrupt REM sleep atonia.     

Senior Vipassana Meditation practitioners exhibit distinct REM sleep organization from that of novice meditators and healthy controls

Abstract/Summary

The present study is aimed to ascertain whether differences in meditation proficiency alter rapid eye movement sleep (REM sleep) as well as the overall sleep-organization. Whole-night polysomnography was carried out using 32-channel digital EEG system. 20 senior Vipassana meditators, 16 novice Vipassana meditators and 19 non-meditating control subjects participated in the study. The REM sleep characteristics were analyzed from the sleep-architecture of participants with a sleep efficiency index?>85%. Senior meditators showed distinct changes in sleep-organization due to enhanced slow wave sleep and REM sleep, reduced number of intermittent awakenings and reduced duration of non-REM stage 2 sleep. The REM sleep-organization was significantly different in senior meditators with more number of REM episodes and increased duration of each episode, distinct changes in rapid eye movement activity (REMA) dynamics due to increased phasic and tonic activity and enhanced burst events (sharp and slow bursts) during the second and fourth REM episodes. No significant differences in REM sleep organization was observed between novice and control groups. Changes in REM sleep-organization among the senior practitioners of meditation could be attributed to the intense brain plasticity events associated with intense meditative practices on brain functions.     

What in sleep is for memory

Since the seminal research by Jenkins and Dallenbach in the 1920s, it has been well proven that sleep has a major effect on the memory of pre-sleep material. However, there is still sparse knowledge about exactly which features of sleep have the most impact. Studies which examined separately the role of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep provided largely controversial results and aroused harsh scientific debate, and the investigation of the link of specific sleep patterns to different memory systems (e.g. declarative vs. procedural) did not fully reconcile these inconsistencies. New research perspectives have been proposed in recent years to overcome the limits of the previous 'single state' approach. Psychological, neurophysiological and neuroanatomical data have recently suggested that NREM and REM sleep both play a part in memory consolidation. We here present the hypothesis that NREM and REM are complementary for memory processes during sleep, thanks to their close interaction within the NREM-REM cycle, and discuss experimental data which prove the critical role of the sleep cycle for the morning recall of verbal material.     

The effect of donepezil on sleep in elderly, healthy persons: a double-blind placebo-controlled study

INTRODUCTION: Previous research in younger individuals has shown that acetylcholinesterase inhibitors tend to enhance REM sleep. METHODS: Forty-two healthy elderly persons participated in a double-blind placebo-controlled polysomnographic study (parallel group design). RESULTS: The present study indicates that in the elderly persons, donepezil, an acetylcholinesterase inhibitor also exerts a marked effect on REM sleep parameters: REM density was increased whereas REM latency was reduced, thus, confirming the findings of our pilot study described earlier. CONCLUSION: Whether the cholinergic stimulation measured by polysomnography is related to treatment efficacy is a very interesting but an open question. Based on the findings that REM sleep is associated with memory consolidation, the question whether REM sleep augmentation enhances memory performance-as suggested by the findings of the pilot study-seems to be an interesting topic for future research.     

Density of rapid eye movements during active sleep in preterm newborn infants

Rapid eye movement (REM) density has been helpful as a reliable index of phasic eye movements activity during REM (active) sleep in adults. We evaluated this index in 28 newborns, at 34 to 39 weeks of conceptional age (CA). The 5 hours polysomnographic recording during sleep included electroencephalogram, electrooculogram, electrocardiogram, pneumogram, nasal thermistor for detecting airflow, and continuous oxygen saturation (tcPO2) monitoring. REM density was measured by two distinct criteria: REM density as the duration of phasic eye movements in relation to REM periods (REMP). Such index varied from 10.6 to 14.1% and was higher in the 36-37 weeks CA group. REM density was calculated as a percentage of 10-second epochs of REM sleep in which phasic eye movements occurred. This criterion confirmed the narrow range of such index in this age bracket (39.9-44.6%), was higher in the first REMP and in the 36-37 weeks CA group. Our data suggest that REM density is a consistent phasic REM sleep feature in preterm newborns with levels close to the adult population, in spite of the gradual decrease of REM sleep duration with age. Higher indices were also found in the first REMP and in the 36-37 weeks CA group by both methods.     

Pontine control of rapid eye movement sleep and fear memory

Aims

We often experience dreams of strong irrational and negative emotional contents with postural muscle paralysis during rapid eye movement (REM) sleep, but how REM sleep is generated and its function remain unclear. In this study, we investigate whether the dorsal pontine sub-laterodorsal tegmental nucleus (SLD) is necessary and sufficient for REM sleep and whether REM sleep elimination alters fear memory.

Methods

To investigate whether activation of SLD neurons is sufficient for REM sleep induction, we expressed channelrhodopsin-2 (ChR2) in SLD neurons by bilaterally injecting AAV1-hSyn-ChR2-YFP in rats. We next selectively ablated either glutamatergic or GABAergic neurons from the SLD in mice in order to identify the neuronal subset crucial for REM sleep. We finally  investigated the role of REM sleep in consolidation of fear memory using rat model with complete SLD lesions.

Results

We demonstrate the sufficiency of the SLD for REM sleep by showing that photo-activation of ChR2 transfected SLD neurons selectively promotes transitions from non-REM (NREM) sleep to REM sleep in rats. Diphtheria toxin-A (DTA) induced lesions of the SLD in rats or specific deletion of SLD glutamatergic neurons but not GABAergic neurons in mice completely abolish REM sleep, demonstrating the necessity of SLD glutamatergic neurons for REM sleep. We then show that REM sleep elimination by SLD lesions in rats significantly enhances contextual and cued fear memory consolidation by 2.5 and 1.0 folds, respectively, for at least 9 months. Conversely, fear conditioning and fear memory trigger doubled amounts of REM sleep in the following night, and chemo-activation of SLD neurons projecting to the medial septum (MS) selectively enhances hippocampal theta activity in REM sleep; this stimulation immediately after fear acquisition reduces contextual and cued fear memory consolidation by 60% and 30%, respectively.

Conclusion

SLD glutamatergic neurons generate REM sleep and REM sleep and SLD via the hippocampus particularly down-regulate contextual fear memory.     

Sleep states and memory processes in humans: procedural versus declarative memory systems

The present paper focuses on human studies attempting to relate sleep states to memory processes. These studies typically present learning material to participants and then examine their ability to recall this material after intervening post-training sleep or sleep deprivation. Most experiments utilize either sleep recording or sleep deprivation following task acquisition to reach their conclusions, although cueing and position emission tomography (PET) scan studies have also been done. Results strongly suggest that REM sleep is involved with the efficient memory processing of cognitive procedural material but not declarative material. Although there are some data to suggest that stage 3/4 or NREM sleep is necessary for declarative memory consolidation, NREM may in fact simply be occurring at the same time as another factor that is actually involved in the memory processing. Preliminary results suggest that the length of the NREM–REM sleep cycle may be important for declarative memory. Preliminary data also suggest that stage 2 sleep may be involved with the memory for motor procedural but not cognitive procedural tasks. Sleep researchers would do well to capitalize on the latest advancements in memory research by choosing tasks that represent special memory systems and examining their relationships to sleep states.     

Rapid eye movement density shows trends across REM periods but is uncorrelated with NREM delta in young and elderly human subjects

Saccade-like eye movements are the most prominent phasic component of rapid eye movement (REM) sleep. Eye movement density (EMD) appears to be negatively related to sleep depth. Thus, EMD is depressed by sleep deprivation. We sought to determine in 19 young normal (YN) and 19 elderly normal (EN) subjects: (a) whether EMD is correlated with delta EEG in baseline sleep; (b) whether EMD is increased by daytime naps; and (c) whether EMD patterns across sleep cycles differ in the two age groups. Subjects participated in four separate 2-day recording sessions, each consisting of a baseline night, a daytime nap, and post nap night. EMD was measured as 0.3-2 Hz integrated amplitude (IA)/20 s stage REM. EMD was not correlated with rate of non rapid eye movement (NREM) delta production (power/min) in the baseline sleep of either group. Changes in EMD and delta power/min on post nap nights also were uncorrelated. These data indicate that very strong changes in sleep depth (state) are required to overcome the individual stability (traits) of NREM delta and eye movement density. ANOVA for EMD across REM periods 1-4 showed a significant cycle effect and a significant age x cycle interaction. These effects were mainly due to YNs having depressed EMD in the first REM period, likely due to the low arousal level early in sleep in these subjects. Compared with waking saccades the saccade eye movements of REM sleep have received little investigation. Further study of these movements could shed new light on neurophysiology of REM sleep. Such studies might also be clinically useful because the density of these movements appears to be related to depression and (independently) to cognitive function in individuals with brain impairment.