Rapid Eye Movement Sleep Pressure Research Articles

Cerebral capillary blood flow upsurge during REM sleep is mediated by A2a receptors.

Sleep is generally viewed as a period of recovery, but how the supply of cerebral blood flow (CBF) changes across sleep/wake states has remained unclear. Here, we directly observe red blood cells (RBCs) within capillaries, where the actual substance exchange between the blood and neurons/glia occurs, by two-photon microscopy. Across multiple cortical areas, average capillary CBF is largely increased during rapid eye movement (REM) sleep, whereas it does not differ between periods of active wakefulness and non-REM sleep. Capillary RBC flow during REM sleep is further elevated following REM sleep deprivation, suggesting that capillary CBF reflects REM sleep pressure. At the molecular level, signaling via adenosine A2a receptors is crucial; in A2a-KO mice, capillary CBF upsurge during REM sleep is dampened, and effects of REM sleep pressure are abolished. These results provide evidence regarding the dynamics of capillary CBF across sleep/wake states and insights to the underlying mechanisms.

Regulation of REM and Non-REM Sleep by Periaqueductal GABAergic Neurons

Mammalian sleep consists of distinct rapid eye movement (REM) and non-REM (NREM) states. The midbrain region ventrolateral periaqueductal gray (vlPAG) is known to be important for gating REM sleep, but the underlying neuronal mechanism is not well understood. Here, we show that activating vlPAG GABAergic neurons in mice suppresses the initiation and maintenance of REM sleep while consolidating NREM sleep, partly through their projection to the dorsolateral pons. Cell-type-specific recording and calcium imaging reveal that most vlPAG GABAergic neurons are strongly suppressed at REM sleep onset and activated at its termination. In addition to the rapid changes at brain state transitions, their activity decreases gradually between REM sleep and is reset by each REM episode in a duration-dependent manner, mirroring the accumulation and dissipation of REM sleep pressure. Thus, vlPAG GABAergic neurons powerfully gate REM sleep, and their firing rate modulation may contribute to the ultradian rhythm of REM/NREM alternation.

Sleep and mental disorders: A meta-analysis of polysomnographic research.

Investigating sleep in mental disorders has the potential to reveal both disorder-specific and transdiagnostic psychophysiological mechanisms. This meta-analysis aimed at determining the polysomnographic (PSG) characteristics of several mental disorders. Relevant studies were searched through standard strategies. Controlled PSG studies evaluating sleep in affective, anxiety, eating, pervasive developmental, borderline and antisocial personality disorders, attention-deficit-hyperactivity disorder (ADHD), and schizophrenia were included. PSG variables of sleep continuity, depth, and architecture, as well as rapid-eye movement (REM) sleep were considered. Calculations were performed with the "Comprehensive Meta-Analysis" and "R" software. Using random effects modeling, for each disorder and each variable, a separate meta-analysis was conducted if at least 3 studies were available for calculation of effect sizes as standardized means (Hedges' g). Sources of variability, that is, sex, age, and mental disorders comorbidity, were evaluated in subgroup analyses. Sleep alterations were evidenced in all disorders, with the exception of ADHD and seasonal affective disorders. Sleep continuity problems were observed in most mental disorders. Sleep depth and REM pressure alterations were associated with affective, anxiety, autism and schizophrenia disorders. Comorbidity was associated with enhanced REM sleep pressure and more inhibition of sleep depth. No sleep parameter was exclusively altered in 1 condition; however, no 2 conditions shared the same PSG profile. Sleep continuity disturbances imply a transdiagnostic imbalance in the arousal system likely representing a basic dimension of mental health. Sleep depth and REM variables might play a key role in psychiatric comorbidity processes. Constellations of sleep alterations may define distinct disorders better than alterations in 1 single variable. (PsycINFO Database Record

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation

Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water ("flower pot") method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melanin-concentrating hormone (MCH) expressing neurons in the hypothalamus. MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS. We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons. Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats. During the 3-h-long "rebound sleep", electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry. During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease. All these effects of REMS deprivation were significantly attenuated by escitalopram treatment. Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound. These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel. Escitalopram caused a shift from REMS to slow wave sleep during the rebound. Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders.

Selective REM sleep deprivation in narcolepsy

Narcolepsy is characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, including cataplexy. The aim of this study was to assess REM sleep pressure and homeostasis in narcolepsy. Six patients with narcolepsy and six healthy controls underwent a REM sleep deprivation protocol, including one habituation, one baseline, two deprivation nights (D1, D2) and one recovery night. Multiple sleep latency tests (MSLTs) were performed during the day after baseline and after D2. During D1 and D2 REM sleep was prevented by awakening the subjects at the first polysomnographic signs of REM sleep for 2 min. Mean sleep latency and number of sleep-onset REM periods (SOREMs) were determined on all MSLT. More interventions were required to prevent REM sleep in narcoleptics compared with control subjects during D1 (57 ± 16 versus 24 ± 10) and D2 (87 ± 22 versus 35 ± 8, P = 0.004). Interventions increased from D1 to D2 by 46% in controls and by 53% in narcoleptics (P < 0.03). Selective REM sleep deprivation was successful in both controls (mean reduction of REM to 6% of baseline) and narcoleptics (11%). Both groups had a reduction of total sleep time during the deprivation nights (P = 0.03). Neither group had REM sleep rebound in the recovery night. Narcoleptics had, however, an increase in the number of SOREMs on MSLT (P = 0.005). There was no increase in the number of cataplexies after selective REM sleep deprivation. We conclude that: (i) REM sleep pressure is higher in narcoleptics; (ii) REM sleep homeostasis is similar in narcoleptics and controls; (iii) in narcoleptics selective REM sleep deprivation may have an effect on sleep propensity but not on cataplexy.

Preoptic Area Neurons and the Homeostatic Regulation of Rapid Eye Movement Sleep

The median preoptic nucleus (MnPN) and the ventral lateral preoptic area (vlPOA) of the hypothalamus express sleep-related Fos immunoreactivity, and a subset of Fos-immunoreactive neurons (IRNs) in these nuclei contain glutamic acid decarboxylase (GAD), a marker of GABAergic cells. We recently showed that the numbers of Fos-positive (Fos+) and Fos+ GAD-IRNs in both the MnPN and the vlPOA are positively correlated with the total amount of preceding sleep. The present study was designed to clarify whether or not activation of sleep-related neurons in the rat MnPN and vlPOA is associated with rapid eye movement (REM) sleep regulation. Expression of c-fos in MnPN and vlPOA neurons was examined under conditions of spontaneous sleep, REM sleep restriction, and REM sleep recovery after REM sleep restriction. Across all conditions, the number of Fos-IRNs was highest in REM-sleep-restricted rats displaying the highest levels of REM sleep homeostatic pressure/drive, i.e., those rats exhibiting the most frequent attempts to enter REM sleep. This finding provides the first evidence that activation of subsets of MnPN and vlPOA neurons is more strongly related to REM sleep pressure than to REM sleep amount.

Counterpointing the functional role of the forebrain and of the brainstem in the control of the sleep-waking system.

This paper reviews the lifetime contributions of the author to the field of sleep-wakefulness (S-W), reinterprets results of the early studies, and suggests new conclusions and perspectives. Long-term cats with mesencephalic transection show behavioral/polygraphic rapid eye movement sleep (REMS), including the typical oculo-pupillary behavior, even when the section is performed in kittens prior to S-W maturation. REMS can be induced as a reflex. Typical non-rapid eye movement S (NREMS) is absent and full W/arousal is present only after a precollicular section. The isolated forebrain (IF) rostral to the transection exhibits all features of W/arousal and NREMS [with electroencephalographic (EEG) spindles and delta waves], arousal to olfactory stimuli, and including the appropriate oculo-pupillary behaviors. These features also mature normally after neonatal transection. REMS is absent from the IF. After deprivation there is NREMS pressure and rebound in the IF, but the decerebrate cat only shows pressure for REMS. Most IF reactions to pharmacologic agents are within expectations, except for the tolerance/withdrawal effects of long-term morphine use which are absent. In contrast, these effects are supported by the brainstem (i.e. seen in the decerebrate cat). In cats with ablation of the telencephalon, or diencephalic cats, delta waves are absent in the thalamus. EEG thalamic spindle waves are seen triggering S for only 4-5 days after ablation. Therefore, true NREMS is absent in chronic diencephalic cats although pre- and postsomniac behaviors persist. These animals are hyperactive and show a pronounced, permanent insomnia; however, a low dose of barbiturate triggers a dramatic REMS/atypical NREMS rebound. Cats without the thalamus (athalamic cats), initially show a dissociation between behavioral hyperactivity/insomnia and the neocortical EEG, which for 15-20 days exhibits only delta and slower oscillations. Fast, low-voltage W rhythms appear later on, first during REMS, but spindle waves and S postures are absent from the start, such that these cats also display only atypical NREMS. Athalamic cats also show barbiturate-sensitive insomnia. Cats with ablation of the frontal cortices or the caudate nuclei remain permanently hyperactive. They also show a mild, but significant hyposomnia, which is permanent in afrontal cats, but lasts for about a month in acaudates. The polygraphic/behavioral features of their S-W states remain normal. We conclude and propose that: (a) the control of the S-W system is highly complex and distributed, but is organized hierarchically in a well-defined rostro-caudal manner; the rostral-most or highest level (telencephalon), is the most functionally complex/adaptative and regulates the lower levels; the diencephalic/basal forebrain, or middle level, has a pivotal role in inducing switching between S and W and in coordinating the lowest (brainstem) and highest levels; (b) W can occur independently in both the forebrain and brainstem, but true NREMS- and REMS-generating mechanisms exist exclusively in the forebrain and brainstem, respectively; (c) forebrain and brainstem S-W processes can operate independently from each other and are preprogrammed at birth; this helps understanding normal and abnormal polygraphic/behavioral dissociations in humans and normal dissociations/splitting in aquatic mammals; (d) NREMS homeostasis is present in the IF, but only REMS pressure after deprivation persists in the decerebrate cat; (e) the thalamus engages in both NREMS and W; (f) insomnia in diencephalic cats is the result of an imbalance between antagonistic W- and S-promoting cellular groups in the ventral brain (normally modulated by the telencephalon); (g) the EEG waves, which are signature for each S-W state, appear to truly drive the concomitant behaviors, e.g. a hypothetical human IF could alternate between behavioral NREMS and W/arousal/awareness; (h) a role for REMS is to keep the individual sleeping at the end of the self-limiting NREMS periods. The need for accelerating research on telencephaling NREMS periods. The need for accelerating research on telencephalic S-W processes and downstream control of the lower S-W system levels is emphasized.

The disconnected brain stem does not support rapid eye movement sleep rebound following selective deprivation.

To determine whether the brain stem can independently support the processes of rapid eye movement sleep rebound and pressure that follow deprivation. Cats with a brain-stem separation from the forebrain were compared to intact subjects on their response to rapid eye movement sleep deprivation. Eight adult mongrel cats of both sexes. All cats had electrodes implanted for polygraphic recordings, and 4 subjects sustained a mesencephalic transection. Weeks later, a 24-hour undisturbed sleep-wakefulness recording session was performed, and the next day, a similar session started with a 6-hour deprivation period, which was followed by 18 hours of undisturbed sleep. Deprivation produced 90.1% and 87.8 % losses of rapid eye movement sleep time in intact and decerebrate cats, respectively. However, no significant changes in non-rapid eye movement sleep, drowsiness, or waking time percentages were seen in either group of animals when comparing the 6-hour time blocks of the deprivation and baseline sessions, indicating selective rapid eye movement sleep deprivation. During the 6-hour block following deprivation, rapid eye movement sleep time increased a significant 34.6% in intact cats while, in contrast, there was no rapid eye movement sleep rebound in decerebrate animals. The number of aborted episodes of rapid eye movement sleep during deprivation exceeded the number of episodes during the same period of the baseline day by 3 and 5 folds in intact and decerebrate cats, respectively, indicating an increase in rapid eye movement sleep pressure. Rebound in rapid eye movement sleep after deprivation cannot be sustained by the brain stem alone; in contrast, rapid eye movement sleep pressure persisted in the decerebrate cat, demonstrating that this process does not depend on descending forebrain influences. This indicates that rebound and pressure are 2 different components of the recovery process after rapid eye movement sleep deprivation and that, as such, are likely controlled by different mechanisms.

Insomnia, alcoholism and relapse.

Insomnia and alcoholism are significantly associated in community surveys and patient samples. Insomnia occurs in 36-72% of alcoholic patients and may last for weeks to months after initiating abstinence from alcohol. Some correlates of insomnia in alcoholic patients are identical to those observed in non-alcoholic insomniacs, including anxiety and depression, tobacco smoking, and the use of alcohol to aid sleep. Other studies suggest that as the severity of alcoholism increases, so does the likelihood of insomnia in alcoholic patients. In the sleep laboratory, alcoholic patients who complain of insomnia have disrupted sleep continuity when compared to alcoholic patients without insomnia complaints. Recently sober alcoholics are also more likely than non-alcoholics to have sleep-disordered breathing and increased periodic leg movements, which might contribute to insomnia in some alcoholic patients. The co-occurrence of insomnia and alcoholism is clinically significant because alcoholism can exacerbate the adverse consequences of insomnia (e.g. mood changes and performance decrements) and because insomnia among patients entering treatment for alcoholism has been significantly associated with subsequent alcoholic relapse. Baseline polysomnographic correlates of subsequent relapse include prolonged sleep latency, decreased sleep efficiency and total sleep time, increased rapid eye movement sleep pressure, and decreased slow wave sleep. Whether treatment of insomnia in alcoholic patients reduces relapse rates is unknown, but preliminary treatment guidelines that accommodate the special characteristics of alcoholic patients are provided, with a goal to reduce daytime impairment and psychological distress.

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.

Short-term homeostasis of REM sleep assessed in an intermittent REM sleep deprivation protocol in the rat.

An intermittent rapid eye movement (REM) sleep deprivation protocol was applied to determine whether an increase in REM sleep propensity occurs throughout an interval without REM sleep comparable with the spontaneous sleep cycle of the rat. Seven chronically implanted rats under a 12 : 12 light-dark schedule were subjected to an intermittent REM sleep deprivation protocol that started at hour 6 after lights-on and lasted for 3 h. It consisted of six instances of a 10-min REM sleep permission window alternating with a 20-min REM sleep deprivation window. REM sleep increased throughout the protocol, so that total REM sleep in the two REM sleep permission windows of the third hour became comparable with that expected in the corresponding baseline hour. Attempted REM sleep transitions were already increased in the second deprivation window. Attempted transitions to REM sleep were more frequent in the second than in the first half of any 20-min deprivation window. From one deprivation window to the next, transitions to REM sleep changed in correspondence to the amount of REM sleep in the permission window in-between. Our results suggest that: (i) REM sleep pressure increases throughout a time segment similar in duration to a spontaneous interval without REM sleep; (ii) it diminishes during REM sleep occurrence; and (iii) that drop is proportional to the intervening amount of REM sleep. These results are consistent with a homeostatic REM sleep regulatory mechanism that operates in the time scale of spontaneous sleep cycle.

Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence

Background: The present study investigated polysomnographically assessed sleep parameters in alcohol-dependent patients after withdrawal and in healthy control subjects during baseline and after a cholinergic stimulation paradigm. The aim of the study was to test whether sleep parameters, especially rapid eye movement (REM) sleep variables, may serve as predictors for relapse in alcohol-dependent patients. Methods: Forty patients diagnosed with alcohol dependence were admitted to a specialized ward for alcohol withdrawal and were investigated by polysomnography at three time points: 2–3 weeks after withdrawal (T0) and at follow-up investigations 6 (T1) and 12 (T2) months after discharge from the hospital. A subgroup of patients ( n = 17) was studied at T0 after challenge with galanthamine, a reversible cholinesterase inhibitor (cholinergic REM induction test, CRIT). Patients were compared with two control groups: a) 30 healthy control subjects (matched for age- and gender-distribution) for comparison at baseline conditions; and b) 17 age- and gender-matched control subjects for comparison with the CRIT. Results: At baseline the patients showed significant disturbances of sleep continuity and sleep architecture (decreased slow-wave sleep, SWS) and exhibited an increase of “REM sleep pressure” (a combined index of REM latency, REM density, and REM sleep percent). Galanthamine provoked significant alterations of sleep continuity, sleep architecture (reduced SWS), and increased most of the components of REM pressure, taking patients and control subjects together. Apart from SWS %SPT (sleep period time) no significant drug-group interactions occurred. Patients who remained abstinent ( n = 11) for at least 6 months at follow-up exhibited significantly less abnormalities of REM sleep at T0 compared to the group of patients that relapsed at 6 months follow-up. Conclusions: It is concluded that increased REM sleep pressure after alcohol withdrawal is a robust predictor of vulnerability to relapse. Thus, a subgroup of alcoholic patients appears to exhibit distinct neurobiological abnormalities assessable by polysomnography that are related to an increased vulnerability for alcoholism and early relapse.

Changes in EEG power density during sleep laboratory adaptation.

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

Repeated partial sleep deprivation progressively changes in EEG during sleep and wakefulness.

The effect of repeated partial sleep deprivation on sleep stages and electroencephalogram (EEG) power spectra during sleep and wakefulness was investigated in nine healthy young subjects. Three baseline nights of 8 hours (2300-0700 hours) were followed by four nights with 4 hours of sleep (2300-0300 hours) and three recovery nights of 8 hours (2300-0700 hours). Sleep restriction curtailed sleep stages 1 and 2 as well as rapid eye movement (REM) sleep, but left slow wave sleep largely unaffected. In the first two recovery nights, total sleep time and REM sleep were enhanced, and sleep latency was shortened. Slow wave sleep was increased only in the first recovery night. In accordance with the prediction of the two-process model of sleep regulation, slow wave activity (SWA; spectral power density in the 0.75-4.5-Hz range) in nonrapid eye movement (NREM) sleep increased by approximately 20% in the first night following sleep restriction, remained at this level in the subsequent 3 nights and decreased immediately after the first recovery night. In contrast to these immediate changes, progressive and more persistent changes were seen in the EEG activity of higher frequencies. Thus, activity in the upper delta band tended to gradually increase from night to night during the sleep restriction period, whereas after an initial increase, activity in the theta-alpha band changed in the opposite direction. The progressive changes were also present in the EEG spectra of REM sleep and wakefulness. Because the time course of these changes paralleled the cumulative deficit in REM sleep, they may represent a correlate of REM sleep pressure.

Sleep in human narcolepsy revisited with special reference to prior wakefulness duration.

Sleep of 11 narcoleptic subjects was recorded on baseline and after 16 and 24 hours of prior wakefulness (16 and 24 hours sleep deprivation). Eleven sex- and age-matched control subjects were recorded for comparisons. All recordings in narcoleptic subjects were characterized by frequent sleep onset rapid eye movement (REM) episodes, increased amounts of wake time after sleep onset and low sleep efficiencies. Mean total sleep time (TST) was significantly decreased in narcoleptic subjects after sleep deprivation (SD). Recovery sleep after 24 hours SD showed reduced nonREM (NREM) sleep stage 2 percentage, whereas percentages of stage 4 and slow-wave sleep (SWS = stages 3 + 4) were significantly increased. The values of REM sleep percentage of TST were remarkably constant throughout and did not differ significantly as a function of experimental conditions, indicating a normal REM sleep pressure in narcolepsy. Sleep stage analysis per sleep cycles revealed significant differences between the two groups. Percentages of stage 4 and SWS were increased during the first cycle of recovery sleep in narcoleptic subjects. Stage 2 was decreased during the third cycle, and SWS decreased rapidly from cycle 1 to cycle 2 and slightly increased thereafter. These results indicate that sleep need is increased in narcolepsy, whereas its decrease over the first NREM-REM cycle is accelerated. We hypothesize that this could reflect an alteration of the homeostatic process of sleep regulation in narcolepsy.

Changes in pontine unit activity with REM sleep deprivation

Short term rapid eye movement (REM) sleep deprivation produced a decrease in waking discharge rates of presumably noradrenergic pontine ‘REM sleep-off’ cells and an increase in waking discharge rates of pontine ‘REM sleep-on’ cells. These changes can be viewed as a correlate of increased REM sleep pressure. Slowing of REM sleep-off cells in waking is hypothesized to counteract the functional effects of REM sleep loss on noradrenergic receptor sensitivity. This slowing and the resulting in norepinephrine release may contribute to the loss of vigilance seen with sleep deprivation.