Decrease In Rapid Eye Movement Sleep Research Articles

Emergence of mature cortical activity in wakefulness and sleep in healthy preterm and full-term infants.

Study ObjectivesCortical activity patterns develop rapidly over the equivalent of the last trimester of gestation, in parallel with the establishment of sleep architecture. However, the emergence of mature cortical activity in wakefulness compared with sleep states in healthy preterm infants is poorly understood.MethodsTo investigate whether the cortical activity has a different developmental profile in each sleep–wake state, we recorded 11-channels electroencephalography (EEG), electrooculography (EOG), and respiratory movement for 1 hr from 115 infants 34 to 43 weeks–corrected age, with 0.5–17 days of postnatal age. We characterized the trajectory of δ, θ, and α-β oscillations in wakefulness, rapid eye movement (REM) sleep, and non-REM sleep by calculating the power spectrum of the EEG, averaged across artifact-free epochs.Resultsδ-Oscillations in wakefulness and REM sleep decrease with corrected age, particularly in the temporal region, but not in non-REM sleep. θ-Oscillations increase with corrected age in sleep, especially non-REM sleep, but not in wakefulness. On the other hand, α-β oscillations decrease predominantly with postnatal age, independently of sleep–wake state, particularly in the occipital region.ConclusionsThe developmental trajectory of δ and θ rhythms is state-dependent and results in changed cortical activity patterns between states with corrected age, which suggests that these frequency bands may have particular functional roles in each state. Interestingly, postnatal age is associated with a decrease in α-β oscillations overlying primary visual cortex in every sleep–wake state, suggesting that postnatal experience (including the first visual input through open eyes during periods of wakefulness) is associated with resting-state visual cortical activity changes.

Adenosine A2A receptors in the olfactory bulb suppress rapid eye movement sleep in rodents.

Rapid eye movement (REM) sleep behavior disorder in humans is often accompanied by a reduced ability to smell and detect odors, and olfactory bulbectomized rats exhibit increased REM sleep, suggesting that the olfactory bulb (OB) is involved in REM-sleep regulation. However, the molecular mechanism of REM-sleep regulation by the OB is unknown. Adenosine promotes sleep and its A2A receptors (A2AR) are expressed in the OB. We hypothesized that A2AR in the OB regulate REM sleep. Bilateral microinjections of the A2AR antagonist SCH58261 into the rat OB increased REM sleep, whereas microinjections of the A2AR agonist CGS21680 decreased REM sleep. Similar to the A2AR antagonist, selective A2AR knockdown by adeno-associated virus carrying short-hairpin RNA for A2AR in the rat OB increased REM sleep. Using chemogenetics on the basis of designer receptors exclusively activated by designer drugs, we demonstrated that the inhibition of A2AR neurons increased REM sleep, whereas the activation of these neurons decreased REM sleep. Moreover, using a conditional anterograde axonal tract-tracing approach, we found that OB A2AR neurons innervate the piriform cortex and olfactory tubercle. These novel findings indicate that adenosine suppresses REM sleep via A2AR in the OB of rodents.

Effects of Macrophage Depletion on Sleep in Mice.

The reciprocal interaction between the immune system and sleep regulation has been widely acknowledged but the cellular mechanisms that underpin this interaction are not completely understood. In the present study, we investigated the role of macrophages in sleep loss- and cold exposure-induced sleep and body temperature responses. Macrophage apoptosis was induced in mice by systemic injection of clodronate-containing liposomes (CCL). We report that CCL treatment induced an immediate and transient increase in non-rapid-eye movement sleep (NREMS) and fever accompanied by decrease in rapid-eye movement sleep, motor activity and NREMS delta power. Chronically macrophage-depleted mice had attenuated NREMS rebound after sleep deprivation compared to normal mice. Cold-induced increase in wakefulness and decrease in NREMS, rapid-eye movement sleep and body temperature were significantly enhanced in macrophage-depleted mice indicating increased cold sensitivity. These findings provide further evidence for the reciprocal interaction among the immune system, sleep and metabolism, and identify macrophages as one of the key cellular elements in this interplay.

The Effects of Benzodiazepine and Nonbenzodiazepine Agents, Ramelteon, Low-dose Doxepin, Suvorexant, and Selective Serotonin 5-HT2A Receptor Antagonists and Inverse Agonists on Sleep and Wakefulness

Several agents are known to improve sleep induction and/or maintenance in patients with insomnia disorder. These include the benzodiazepine (BZD) and non-BZD receptor allosteric modulators, the melatonin receptor agonist ramelteon, low-dose doxepin, and suvorexant. One of the drawbacks of the BZDs is their known reduction in both N3 sleep [also known as slow wave sleep or delta sleep and characterized by the occurrence of slow high amplitude delta (0.5–2 Hz) waves] and rapid eye movement (REM) sleep. Low-dose doxepin has shown similar association with decrease in REM sleep. By contrast, suvorexant increases REM sleep. The available evidence tends to indicate that irrespective of their mechanisms of action, the selective serotonin 5-HT2A receptor antagonists and inverse agonists, including volinanserin, pruvanserin, and nelotanserin, when given in isolated administration, increases slow wave sleep in laboratory animals. Wakefulness and REM sleep were decreased in some studies. Moreover, subjects with normal sleep showed significant increase in N3 sleep following the administration of eplivanserin, nelotanerin, and pimavanserin. Nelotanserin has also been shown to augment N3 sleep in patients with chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. Taken together, these evidences suggest that the coadministration of a selective 5-HT2A receptor antagonist or inverse agonist with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with insomnia disorder. Additionally, the 5-HT2A receptor agents may have a potential value for improving the cognition and memory deficits in patients with a chronic insomnia disorder as well as elderly patients who show reductions in N3 sleep.

Pedunculopontine Gamma Band Activity and Development.

This review highlights the most important discovery in the reticular activating system in the last 10 years, the manifestation of gamma band activity in cells of the reticular activating system (RAS), especially in the pedunculopontine nucleus, which is in charge of waking and rapid eye movement (REM) sleep. The identification of different cell groups manifesting P/Q-type Ca2+ channels that control waking vs. those that manifest N-type channels that control REM sleep provides novel avenues for the differential control of waking vs. REM sleep. Recent discoveries on the development of this system can help explain the developmental decrease in REM sleep and the basic rest-activity cycle.

State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154 – Relation to antipsychotic-like drug effects

Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M1/M4-preferring mAChR agonist xanomeline. VU0467154 induced state-dependent alterations in sleep architecture and arousal including delayed Rapid Eye Movement (REM) sleep onset, increased cumulative duration of total and Non-Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N-methyl-d-aspartate subtype of glutamate receptor (NMDAR) antagonist MK-801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile.

Peripheral and central blockade of interleukin-6 trans-signaling differentially affects sleep architecture.

The immune system is known to essentially contribute to the regulation of sleep. Whereas research in this regard focused on the pro-inflammatory cytokines interleukin-1 and tumor necrosis factor, the role of interleukin-6 (IL-6) in sleep regulation has been less intensely studied, probably due to the so far seemingly ambiguous results. Yet, this picture might simply reflect that the effects of IL-6 are conveyed via two different pathways (with possibly different actions), i.e., in addition to the 'classical' signaling pathway via the membrane bound IL-6 receptor (IL-6R), IL-6 stimulates cells through the alternative 'trans-signaling' pathway via the soluble IL-6R. Here, we concentrated on the contributions of the trans-signaling pathway to sleep regulation. To characterize this contribution, we compared the effect of blocking IL-6 trans-signaling (by the soluble gp130Fc fusion protein) in the brain versus body periphery. Thus, we compared sleep in transgenic mice expressing the soluble gp130Fc protein only in the brain (GFAP mice) or in the body periphery (PEPCK mice), and in wild type mice (WT) during a 24-h period of undisturbed conditions and during 18 h following a 6-h period of sleep deprivation. Compared with WT mice, PEPCK mice displayed less sleep, particularly during the late light phase, and this was accompanied by decreases in slow wave sleep (SWS) and rapid eye movement (REM) sleep. Following sleep deprivation PEPCK mice primarily recovered REM sleep rather than SWS. GFAP mice showed a slight decrease in REM sleep in combination with a profound and persistent increase in EEG theta activity. In conclusion, peripheral and central nervous IL-6 trans-signaling differentially influences brain activity. Peripheral IL-6 trans-signaling appears to more profoundly contribute to sleep regulation, mainly by supporting SWS.

D2 dopamine receptor regulation of learning, sleep and plasticity

Dopamine and sleep have been independently linked with hippocampus-dependent learning. Since D2 dopaminergic transmission is required for the occurrence of rapid-eye-movement (REM) sleep, it is possible that dopamine affects learning by way of changes in post-acquisition REM sleep. To investigate this hypothesis, we first assessed whether D2 dopaminergic modulation in mice affects novel object preference, a hippocampus-dependent task. Animals trained in the dark period, when sleep is reduced, did not improve significantly in performance when tested 24h after training. In contrast, animals trained in the sleep-rich light period showed significant learning after 24h. When injected with the D2 inverse agonist haloperidol immediately after the exploration of novel objects, animals trained in the light period showed reduced novelty preference upon retesting 24h later. Next we investigated whether haloperidol affected the protein levels of plasticity factors shown to be up-regulated in an experience-dependent manner during REM sleep. Haloperidol decreased post-exploration hippocampal protein levels at 3h, 6h and 12h for phosphorylated Ca2+/calmodulin-dependent protein kinase II, at 6h for Zif-268; and at 12h for the brain-derived neurotrophic factor. Electrophysiological and kinematic recordings showed a significant decrease in the amount of REM sleep following haloperidol injection, while slow-wave sleep remained unaltered. Importantly, REM sleep decrease across animals was strongly correlated with deficits in novelty preference (Rho=0.56, p=0.012). Altogether, the results suggest that the dopaminergic regulation of REM sleep affects learning by modulating post-training levels of calcium-dependent plasticity factors.

Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion.

Patients with Parkinson's disease (PD) display significant sleep disturbances and daytime sleepiness. Dopaminergic treatment dramatically improves PD motor symptoms, but its action on sleep remains controversial, suggesting a causal role of nondopaminergic lesions in these symptoms. Because the pedunculopontine nucleus (PPN) regulates sleep and arousal, and in view of the loss of its cholinergic neurons in PD, the PPN could be involved in these sleep disorders. The aims of this study were as follows: (1) to characterize sleep disorders in a monkey model of PD; (2) to investigate whether l-dopa treatment alleviates sleep disorders; and (3) to determine whether a cholinergic PPN lesion would add specific sleep alterations. To this end, long-term continuous electroencephalographic monitoring of vigilance states was performed in macaques, using an implanted miniaturized telemetry device. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment induced sleep disorders that comprised sleep episodes during daytime and sleep fragmentation and a reduction of sleep efficiency at nighttime. It also induced a reduction in time spent in rapid eye movement (REM) sleep and slow-wave sleep and an increase in muscle tone during REM and non-REM sleep episodes and in the number of awakenings and movements. l-Dopa treatment resulted in a partial but significant improvement of almost all sleep parameters. PPN lesion induced a transient decrease in REM sleep and in slow-wave sleep followed by a slight improvement of sleep quality. Our data demonstrate the efficacy of l-dopa treatment in improving sleep disorders in parkinsonian monkeys, and that adding a cholinergic PPN lesion improves sleep quality after transient sleep impairment.

EPA-0169 – Effects of antidepressants on sleep architecture

Introduction Sleep disturbances are an integral part of the biological syndrome of depression and relief from this is often essential to enhance compliance with medications and psychological treatments. Anti-depressants, which are the mainstay of treatment of depressive illnesses, have varying effects on our sleep architecture. It is important for researchers and clinicians to be aware of these effects. Objectives We looked at the available literature on how antidepressants affect sleep patterns and tried to synthesize the findings in this poster. Aims The primary aim of our effort was to look at how antidepressants alter our sleeping behaviour and how they affect the different stages of sleep. Methods We tried to look at the available literature and product summary sheets of various antidepressants and have attempted to summarize how they alter our sleep architecture. Results SSRIs and TCAs have marked dose-dependent effects on REM sleep in both healthy volunteers and depressed patients, with increased REM-onset latency and decreased REM sleep. Other antidepressants have modest or minimal effects on REM sleep. The effects on sleep are most likely mediated by 5-HT1 receptors. Conclusions Most antidepressants affect sleep and the physiological patterns of different sleep stages. These effects are greatest and most consistent on rapid eye movement (REM) sleep, and tend to be in the opposite direction to the sleep abnormalities found in depression.

Sleep disturbances and changes in urinary 6‐sulphatoxymelatonin levels in patients with breast cancer undergoing lumpectomy

Sleep disturbances and changes in self-reported discomfort and melatonin secretion are common in the post-operative period. We aimed to study the distribution of sleep stages in the perioperative period and evaluate changes in secretion of the melatonin metabolite aMT6s and subjective parameters of sleepiness, pain, general well-being and fatigue in patients undergoing surgery for breast cancer. Twelve patients, 30-70 years, undergoing lumpectomy were included. Polysomnography was performed the night before surgery (PREOP), the night after (PO1) and 14 days after (PO14). Recordings were scored as awake, light-sleep, slow-wave sleep and rapid-eye-movement (REM) sleep. Sleep stages were analysed as % of total sleep time (TST). Self-reported discomfort was assessed using questions about the level of fatigue, well-being, pain and sleepiness. Urinary aMT6s was measured by radioimmunoassay. There was significantly decreased REM sleep on PO1 (5.9% of TST) compared with PREOP (18.7% of TST) (P < 0.005). An increase in light sleep was observed on PO1 (68.4% of TST) compared with PREOP (55.0% of TST) (P < 0.05). No significant changes in TST, sleep latency, sleep period or total time awake were found. The observed sleep changes were normalised after 2 weeks. No significant changes were found in pain, well-being, fatigue or sleepiness. Night secretion of aMT6s showed a trend towards a decrease from PREOP to PO1 (P = 0.09) and normalisation on PO14 (P = 0.27 between PREOP and PO14). Patients with breast cancer undergoing lumpectomy had significantly disturbed sleep architecture the night after surgery, and these changes were normalised after 2 weeks.

The Acute Effects of Alcohol on Sleep Architecture in Late Adolescence

Alcohol consumption is prevalent in late adolescence; however, little is known about its effect on sleep in this group. In mature adults, alcohol decreases sleep onset latency (SOL) and sleep efficiency (SE) and increases wake after sleep onset (WASO). It also increases slow wave sleep (SWS) and decreases rapid eye movement (REM) sleep in the first half of the night, with the inverse occurring in the second half. Alcohol's effect on sleep during late adolescence is of interest given that this age group shows both dramatic increases in alcohol consumption and significant developmental changes in the central nervous system. This study examined the effect of alcohol on sleep architecture in women and men aged 18 to 21 years and whether previously reported sleep architecture effects may have been as an artificial result of changes to sleep cycle length. Twenty-four (12 women) healthy 18- to 21-year-old light social drinkers (19.1 ± 1.0 years) underwent 2 conditions: presleep alcohol (target breath alcohol concentration [BAC] 0.10%) and placebo-administered under controlled conditions, followed by standard polysomnography. In the alcohol condition, mean BAC at lights out was 0.084 ± 0.016%. Time in bed, total sleep time, and SOL (all p > 0.05) did not differ between conditions. However, there was less REM (p = 0.011) and more stage-2 sleep (p = 0.035) in the alcohol condition. Further, alcohol increased SWS (p = 0.02) and decreased REM sleep (p < 0.001) in the first half of the night and disrupted sleep in the second half, with increased WASO (interaction: p = 0.034), and decreased SE (p = 0.04) and SWS (p = 0.01) and no REM sleep rebound in the second half of the night (p = 0.262). Additionally, alcohol had no effect on sleep cycle length (p = 0.598). The results were broadly consistent with the adult literature with the novel extension that half night sleep architecture effects could not be attributed to changes in sleep cycle length. However, alcohol did not reduce SOL, or result in a REM rebound following reduced REM in the first half of the night. The results suggest that the effects of alcohol on sleep are modified by sleep's prevailing developmental stage.

The critical role of sleep spindles in hippocampal-dependent memory: a pharmacology study.

An important function of sleep is the consolidation of memories, and features of sleep, such as rapid eye movement (REM) or sleep spindles, have been shown to correlate with improvements in discrete memory domains. Because of the methodological difficulties in modulating sleep, however, a causal link between specific sleep features and human memory consolidation is lacking. Here, we experimentally manipulated specific sleep features during a daytime nap via direct pharmacological intervention. Using zolpidem (Ambien), a short-acting GABAA agonist hypnotic, we show increased sleep spindle density and decreased REM sleep compared with placebo and sodium oxybate (Xyrem). Naps with increased spindles produced significantly better verbal memory and significantly worse perceptual learning but did not affect motor learning. The experimental spindles were similar to control spindles in amplitude and frequency, suggesting that the experimental intervention enhanced normal sleep processes. Furthermore, using statistical methods, we demonstrate for the first time a critical role of spindles in human hippocampal memory performance. The gains in memory consolidation exceed sleep-alone or control conditions and demonstrate the potential for targeted, exceptional memory enhancement in healthy adults with pharmacologically modified sleep.

Progressive reduction of sleep time and quality in rats with hepatic encephalopathy caused by portacaval shunts

Patients with liver cirrhosis show sleep disturbances. Insight into their relationship with hepatic encephalopathy (HE) can be obtained using animal models of HE. The aims of this work were to assess (1) whether rats with portacaval shunts (PCS), a model of HE, show alterations in sleep and if they are similar to those in patients with HE; (2) Whether hyperammonemia plays a role in these sleep alterations; and (3) the time course of sleep alterations in these animal models. Rats were subjected to PCS to induce HE. Another group of rats was fed an ammonium-containing diet to induce hyperammonemia. Polysomnographic recordings were acquired for 24 h and sleep architecture was analyzed in control, PCS, and hyperammonemic rats at 4, 7, and 11 weeks after surgery or diet, respectively. PCS rats show a significant reduction in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep time and increased sleep fragmentation, whereas reduced sleep occurs at 4 weeks and worsens at 7 and 11 weeks, sleep fragmentation appears at 7 weeks and worsens at 11 weeks. Hyperammonemic rats show decreased REM sleep, starting at 7 weeks and worsening at 11 weeks, with no changes in NREM sleep or sleep fragmentation. Therefore, PCS rats are a good model to study sleep alterations in HE, their mechanisms, and potential treatment. Mild hyperammonemia mainly impacts mechanisms involved in REM generation and/or maintenance but does not seem to be involved in sleep fragmentation.

Sleep and cognition at baseline and the effects of REM sleep diminution after 1 week of antidepressive treatment in patients with depression

It has been hypothesized that non-rapid eye movement (NREM) sleep facilitates declarative memory consolidation, and rapid eye movement (REM) sleep is particularly important in promoting procedural learning. The aim of this study was to examine the effects of pharmacological REM sleep suppression on performance in different neuropsychological tasks. For our baseline, we chose 41 moderately depressed patients (age range 19-44 years), who were not taking antidepressants. In the morning after polysomnography, we tested memory recall and cognitive flexibility by assessment of verbal and figural fluency, a shift of attention task and the Trail Making Test B. After recording baseline values, patients were assigned randomly to one of three treatment groups: medication with citalopram; medication with reboxetine; or exclusive treatment with psychotherapy. Retesting took place 1 week after onset of treatment. The main results were: (1) an association of slow-wave sleep with verbal memory performance at baseline; (2) a suppression of REM sleep in patients taking citalopram and reboxetine; (3) no differences regarding neuropsychological performance within the treatment groups; and (4) no association of REM sleep diminution with decreases in memory performance or cognitive flexibility in patients treated with citalopram or reboxetine. In line with other studies, our results suggest that there are no negative effects of a decrease in REM sleep on memory performance in patients taking antidepressants.

Responses of developing pedunculopontine neurons to glutamate receptor agonists.

The pedunculopontine nucleus (PPN) is involved in the generation and maintenance of waking and rapid eye movement (REM) sleep, forming part of the reticular activating system. The PPN receives glutamatergic afferents from other mesopontine nuclei, and glutamatergic input is believed to be involved in the generation of arousal states. We tested the hypothesis that, from postnatal days 9 to 17 in the rat, there are developmental changes in the glutamate receptor subtypes that contribute to the responses of PPN neurons. Whole cell patch-clamp recordings were conducted using brainstem slices from 9- to 17-day-old rats. All cells (types I, II, and III; randomly selected or thalamic-projecting) responded to bath application of the glutamate receptor agonists N-methyl-d-aspartic acid (NMDA) and kainic acid (KA). A developmental decrease in the contribution of the NMDA receptor and developmental increase in the contribution of the KA receptor was observed following electrical stimulation-induced glutamate input. These changes were also observed following bath application in different cell types (randomly selected vs. thalamic-projecting). KA bath application produced an increase in the paired-pulse ratio (PPR) and a decrease in the frequency of miniature excitatory postsynaptic currents (mEPSCs), suggesting that presynaptic KA autoreceptors may decrease the probability of synaptic glutamate input. In contrast, NMDA application produced no changes in the PPR or mEPSCs. Changes in glutamatergic excitability of PPN cell types could underlie the developmental decrease in REM sleep.

Dreams in normal and pathological aging

Although most of scientific knowledge in dream research is based on young adult studies, this article provides a review of the effects of normal and pathological aging on dream psychology. It starts with preliminary comments about epistemological and methodological principles of dream research, its singularities in aged persons, and the modifications of sleep physiology with age. The whole literature agrees that dream recall progressively decreases from the beginning of adulthood - not in old age - and that dream reports become less intense, perceptually and emotionally. This evolution occurs faster in men than women, with gender differences in the content of dreams. The chronological modifications could be explained partly by changes in lifestyle and attitude towards dreams in early adulthood, but mainly by modifications of sleep physiology, particularly the decrease and qualitative changes of rapid eye movement (REM) sleep. Dreams have usually little subjective importance in the mental life of aged persons. However, working with dreams can be a valuable tool for psychotherapy in the aged. According to the few existing data, patients suffering degenerative dementia dream much less than healthy aged persons. In Alzheimer's disease, this could be linked to the decrease of REM sleep, and atrophy of associative sensory areas of the cerebral cortex. Most studied aspects of dreaming in degenerative cognitive disorders are REM sleep behavior disorders, and nightmares induced by cholinesterase inhibitors. More studies are needed to better characterize the evolution of dreams with age, particularly studies performed in sleep laboratory.

Endogenous ouabain-like compounds in locus coeruleus modulate rapid eye movement sleep in rats

Although the detailed mechanism of spontaneous generation and regulation of rapid eye movement sleep (REMS) is yet unknown, it has been reported that noradrenergic REM-OFF neurons in the locus coeruleus (LC) cease firing during REMS and, if they are kept active, REMS is significantly reduced. On the other hand, the activity as well as expression of Na-K ATPase has been shown to increase in the LC following REMS deprivation. Ouabain is a specific inhibitor of Na-K ATPase, and endogenous ouabain-like compounds are present in the brain. These findings led us to propose that a decrease in the level of ouabain-like compounds spontaneously available in and around the LC would stimulate and increase the REM-OFF neuronal activities in this region and thus would reduce REMS. To test this hypothesis, we generated anti-ouabain antibodies and then microinjected it bilaterally into the LC in freely moving chronically prepared rats and recorded electrophysiological signals for evaluation of sleep-wakefulness states; suitable control experiments were also conducted. Injection of anti-ouabain antibodies into the LC, but not into adjacent brain areas, significantly reduced percent REMS (mean +/- SEM) from 7.12 (+/-0.74) to 3.63 (+/-0.65). The decrease in REMS was due to reduction in the mean frequency of REMS episode, which is likely due to increased excitation of the LC REM-OFF neurons. Control microinjections of normal IgG did not elicit this effect. These results support our hypothesis that interactions of naturally available endogenous ouabain-like compounds with the Na-K ATPase in the LC modulate spontaneous REMS.

Sleep-related sweating in obstructive sleep apnoea: association with sleep stages and blood pressure

The aim of this study was to investigate sleep-related sweating as a symptom of obstructive sleep apnoea (OSA). Fifteen otherwise healthy male non-smoking patients with untreated moderate-to-severe OSA underwent polysomnography, including measurements of skin and core body temperature and electrodermal activity (EDA) as an objective indicator of sweating. Evening and morning blood pressure was measured as well as catecholamines in nocturnal urine. All measurements were repeated after 3 months on successful continuous positive airway pressure (CPAP) treatment. The untreated OSA subjects had a mean (+/-SD) apnoea-hypopnoea index of 45.3 +/- 3.9 and a mean EDA index during sleep of 131.9 +/- 22.4 events per hour. Patients with higher EDA indices had higher systolic blood pressure in the evening and morning (P = 0.001 and 0.006) and lower rapid eye movement (REM) sleep percentage (P = 0.003). The EDA index decreased significantly to 78.5 +/- 17.7 in the patients on CPAP treatment (P = 0.04). The decrease correlated with lower evening systolic and diastolic blood pressure (P = 0.05 and 0.006) and an increase in REM% (P = 0.02). No relationship was observed between EDA and skin or core body temperature, or to catecholamine levels in urine. OSA patients who experience sleep-related sweating may have increased blood pressure and decreased REM sleep compared with other OSA patients. CPAP treatment appears to lower blood pressure and increase REM sleep to a higher extent in these patients compared with other OSA patients.

Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence

In alcohol dependence, markers of inflammation are associated with increases in rapid eye movement (REM) sleep, which is thought to be a prognostic indicator of alcohol relapse. This study was undertaken to test whether blockade of biologically active tumor necrosis factor-alpha (TNF-alpha) normalizes REM sleep in alcohol-dependent adults. In a randomized, placebo-controlled, double-blind, crossover trial, 18 abstinent alcohol-dependent male adults received a single dose of etanercept (25 mg) versus placebo in a counterbalanced order. Polysomnographic sleep was measured at baseline and for 3 nights after the acute dose of etanercept or placebo. Compared with placebo, administration of etanercept produced significant decreases in the amount and percentage of REM sleep. Decreases in REM sleep were robust and approached low levels typically found in age-comparable control subjects. Individual differences in biologically active drug as indexed by circulating levels of soluble tumor necrosis factor receptor II negatively correlated with the percentage of REM sleep. Pharmacologic neutralization of TNF-alpha activity is associated with significant reductions in REM sleep in abstinent alcohol-dependent patients. These data suggest that circulating levels of TNF-alpha may have a physiologic role in the regulation of REM sleep in humans.