Onset Rapid Eye Movement Research Articles

Sleep physiology in patients with epilepsy: Influence of seizures on rapid eye movement (REM) latency and REM duration.

A well-established bidirectional relationship exists between sleep and epilepsy. Patients with epilepsy tend to have less efficient sleep and shorter rapid eye movement (REM) sleep. Seizures are far more likely to arise from sleep transitions and non-REM sleep compared to REM sleep. Delay in REM onset or reduction in REM duration may have reciprocal interactions with seizure occurrence. Greater insight into the relationship between REM sleep and seizure occurrence is essential to our understanding of circadian patterns and predictability of seizure activity. We assessed a cohort of adults undergoing evaluation of drug-resistant epilepsy to examine whether REM sleep prior to or following seizures is delayed in latency or reduced in quantity. We used a spectrogram-guided approach to review the video-electroencephalograms of patients' epilepsy monitoring unit admissions for sleep scoring to determine sleep variables. In our cohort of patients, we found group- and individual-level delay of REM latency and reduced REM duration when patients experienced a seizure before the primary sleep period (PSP) of interest or during the PSP of interest. A significant increase in REM latency and decrease in REM quantity were observed on nights where a seizure occurred within 4 h of sleep onset. No change in REM variables was found when investigating seizures that occurred the day after the PSP of interest. Our study is the first to provide insight about a perisleep period, which we defined as 4-h periods before and after the PSP. Our results demonstrate a significant relationship between seizures occurring prior to the PSP, during the PSP, and in the 4-h perisleep period and a delay in REM latency. These findings have implications for developing a biomarker of seizure detection as well as longer term seizure risk monitoring.

A predictive propensity measure to enter REM sleep.

During sleep periods, most mammals alternate multiple times between rapid-eye-movement (REM) sleep and non-REM (NREM) sleep. A common theory proposes that these transitions are governed by an "hourglass-like" homeostatic need to enter REM sleep that accumulates during the inter-REM interval and partially discharges during REM sleep. However, markers or mechanisms for REM homeostatic pressure remain undetermined. Recently, an analysis of sleep in mice demonstrated that the cumulative distribution function (CDF) of the amount of NREM sleep between REM bouts correlates with REM bout duration, suggesting that time in NREM sleep influences REM sleep need. Here, we build on those results and construct a predictive measure for the propensity to enter REM sleep as a function of time in NREM sleep since the previous REM episode. The REM propensity measure is precisely defined as the probability to enter REM sleep before the accumulation of an additional pre-specified amount of NREM sleep. Analyzing spontaneous sleep in mice, we find that, as NREM sleep accumulates between REM bouts, the REM propensity exhibits a peak value and then decays to zero with further NREM accumulation. We show that the REM propensity at REM onset predicts features of the subsequent REM bout under certain conditions. Specifically, during the light phase and for REM propensities occurring before the peak in propensity, the REM propensity at REM onset is correlated with REM bout duration, and with the probability of the occurrence of a short REM cycle called a sequential REM cycle. Further, we also find that proportionally more REM sleep occurs during sequential REM cycles, supporting a correlation between high values of our REM propensity measure and high REM sleep need. These results support the theory that a homeostatic need to enter REM sleep accrues during NREM sleep, but only for a limited range of NREM sleep accumulation.

Assessing sleep architecture and cognition in older adults with depressive symptoms attending a memory clinic

BackgroundWhile depression is intrinsically and bidirectionally linked with both sleep disturbance and cognition, the inter-relationships between sleep, cognition, and brain integrity in older people with depression, especially those with late-onset depression are undefined. MethodsOne hundred and seventy-two older adults (mean age 64.3 ± 6.9 years, Depression: n = 66, Control: n = 106) attending a memory clinic underwent a neuropsychological battery of declarative memory, executive function tasks, cerebral magnetic resonance imaging and overnight polysomnography with quantitative electroencephalography. ResultsThe time spent in slow-wave sleep (SWS) and rapid eye movement (REM) sleep, slow-wave activity, sleep spindles, hippocampal volume and prefrontal cortex thickness did not differ between depression and control and depression onset groups. However, sleep onset latency (p = 0.005) and REM onset latency (p = 0.02) were later in the Depression group compared to controls. Less SWS was associated with poorer memory (r = 0.31, p = 0.023) in the depression group, and less SWS was related to better memory in the control group (r = −0.20, p = 0.043; Fishers r-to-z = −3.19). LimitationsLongitudinal studies are needed to determine if changes in sleep in those with depressive symptoms predict cognitive decline and illness trajectory. ConclusionOlder participants with depressive symptoms had delayed sleep initiation, suggestive of delayed sleep phase. The association between SWS and memory suggests SWS may be a useful target for cognitive intervention in older adults with depression symptoms. Reduced hippocampal volumes did not mediate this relationship, indicating a broader distributed neural network may underpin these associations.

Effects of chronic caffeine on patterns of brain blood flow and behavior throughout the sleep-wake cycle in freely behaving mice.

Caffeine has significant effects on neurovascular activity and behavior throughout the sleep-wake cycle. We used a minimally invasive microchip/video system to continuously record effects of caffeine in the drinking water of freely behaving mice. Chronic caffeine shifted both rest and active phases by up to 2 h relative to the light-dark cycle in a dose-dependent fashion. There was a particular delay in the onset of rapid eye movement (REM) sleep as compared with non-REM sleep during the rest phase. Chronic caffeine increased wakefulness during the active phase and consolidated sleep during the rest phase; overall, there was no net change in the amount of time spent in the wake, sleep, or REM sleep states during caffeine administration. Despite these effects on wakefulness and sleep, chronic caffeine decreased mean cerebral blood volume (CBV) during the active phase and increased mean CBV during the rest phase. Chronic caffeine also increased heart rate variability in both the sleep and wake states. These results provide new insight into the effects of caffeine on the biology of the sleep-wake cycle. Increased blood flow during sleep caused by chronic caffeine may have implications for its potential neuroprotective effects through vascular mechanisms of brain waste clearance.

Assessment of glymphatic function in narcolepsy using DTI-ALPS index

IntroductionSleep is a modulator of glymphatic activity which is altered in various sleep disorders. Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness (EDS), rapid onset of rapid eye movement (REM) sleep, cataplexy, disturbed night sleep with fragmentation. It is categorized into two types, type 1 (NT1) and type 2 (NT2) depending on the presence of cataplexy and/or absence of orexin. We sought for alterations in glymphatic activity in narcoleptic patients using diffusion tensor imaging (DTI) along perivascular space (ALPS) index on magnetic resonance imaging (MRI). Material and methodsAdult patients diagnosed with NT1 or NT2 who had polysomnography (PSG) and MRI with DTI were included in the study. Sleep recording included Epworth Sleepiness Scale (ESS) score, sleep latency during multiple sleep latency test (MSLT), sleep efficiency during night PSG, wake after sleep onset (WASO), REM sleep latency during PSG, percentage of non-REM (NREM), REM sleep and wakefulness during night PSG. DTI-ALPS index was calculated for each patient and age-sex matched healthy control(HC)s. ResultsThe study group was composed of 25 patients [F/M = 15/10, median age = 34 (29.5–44.5)], 14 with NT1 and 11 with NT2 disease. ESS, WASO and percentage of wakefulness were significantly higher in NT1 patients (p < 0.05). Mean DTI-ALPS was not significantly different neither between narcoleptic patients and HCs, nor between NT1 and NT2 patients (all, p > 0.05). However, DTI-ALPS was negatively correlated with WASO (r = −0.745, p = 0.013) and percentage of wakefulness (r = −0.837, p = 0.005) in NT1 patients. DTI-ALPS correlated negatively with percentage of N1 sleep (r = −0.781, p = 0.005) but positively with REM percentage (r = 0.618, p = 0.043) in NT2 patients. ConclusionIn this study, DTI-ALPS was not significantly different in narcoleptic patients than the HCs. However, the glymphatic index as assessed by DTI-ALPS correlated with PSG parameters; negatively with WASO, percentage of wakefulness in NT1, percentage of N1 sleep in NT2, and positively with REM sleep in NT2. A tendency for a reduction in DTI-ALPS in NT1 patients compared to both NT2 patients and HCs was also found. These findings might show the first evidence of an alteration of glymphatic activity, especially in NT1 patients, thus warrant further prospective studies in larger size of narcoleptic patient cohorts.

REM sleep without atonia and vestibular-evoked myogenic potentials: clinical brainstem dysfunction in early-stage Parkinson's disease and isolated REM sleep behavior disorder

ObjectiveTo determine whether the onset of rapid eye movement (REM) sleep behavior disorder (RBD) is associated with changes in brainstem neuronal pathway dysfunction as reflected by vestibular-evoked myogenic potentials (VEMPs) and to evaluate associations between VEMPs and REM sleep without atonia (RSWA) in patients with early-stage Parkinson's disease (PD) and isolated RBD (iRBD). MethodsEighty-two early-stage PD patients, 40 iRBD patients, and 41 healthy control individuals underwent one-night video-polysomnography (vPSG) and VEMPs examination. We compared cervical (cVEMP), ocular (oVEMP), and masseter (mVEMP) VEMP parameters among PD with RBD (PD + RBD), PD without RBD (PD-RBD), iRBD, and control groups and analyzed correlations between VEMPs and RSWA in PD and iRBD groups. ResultsThe PD + RBD group showed delays in bilateral cVEMP (Lp13, Ln23, Rn23: all p < 0.05) and oVEMP (Ln10, Rn10, Rp15: all p < 0.05) peak latencies compared with the PD-RBD group. Total cVEMP scores were higher in the PD + RBD group than in the iRBD group (p = 0.033). In PD patients, phasic RSWA was correlated with total cVEMP scores (p = 0.003), and tonic RSWA was correlated with left oVEMP scores (p = 0.013). ConclusionsBrainstem neurophysiology as evidenced by altered VEMPs in patients with PD and iRBD could reflect disease evolvement. Moreover, VEMPs alterations may vary depending on the presence of RBD in PD patients. The associations between altered RSWA and VEMP parameters highlight the meaningfulness of detecting brainstem dysfunction in early-stage PD.

P120 The Relationship Between Sleep Architecture And Cognition In Late-Life Depression

Abstract Introduction Depression in older people is associated with changes in sleep, however associations between sleep architecture and cognition have not yet been delineated. We examined sleep architecture in older people with and without depressive symptoms, and relationships with neuropsychological performance. Methods Adults over 50 years underwent overnight polysomnography and memory and executive function tests. Depression and controls groups were defined by a Geriatric Depression Scale-15 cut off score of 6. Sleep architectural outcomes included amount of slow wave sleep (SWS), rapid eye movement (REM) sleep, REM onset latency (ROL), NREM slow wave activity (SWA, 0.5–4 Hz), N2 sleep spindle density and REM density. Results The sample comprised of 71 participants with depressive symptoms and 101 controls (mean age both groups = 64, mean GDS-15 dep= 9.3, con= 1.8). There were no significant group differences in time spent in SWS, REM, REM density or SWA. Those with depressive symptoms had later ROL (p=.008) and less N2 sleep spindles (p=.03) compared to controls. A differential association was observed with less SWS being associated with poor memory recall in the depression group only (z=.342, p=0.008). No associations between sleep and executive function performance were observed. Discussion The link between less time in SWS and poorer memory in those with depressive symptoms could suggest that SWS is particularly pertinent for cognition in depression or that both sleep and cognition mechanisms are influenced by depressive state. Further studies are needed to determine if changes in sleep are linked with underlying neurobiological changes.

EEG and Sleep Effects of Tramadol Suggest Potential Antidepressant Effects with Different Mechanisms of Action.

Tramadol is a widely used, centrally acting, opioid analgesic compound, with additional inhibitory effects on the synaptic reuptake of serotonin and noradrenaline, as well as on the 5-HT2 and NMDA receptors. Preclinical and clinical evidence also suggests its therapeutic potential in the treatment of depression and anxiety. The effects of most widely used antidepressants on sleep and quantitative electroencephalogram (qEEG) are well characterized; however, such studies of tramadol are scarce. Our aim was to characterize the effects of tramadol on sleep architecture and qEEG in different sleep–wake stages. EEG-equipped Wistar rats were treated with tramadol (0, 5, 15 and 45 mg/kg) at the beginning of the passive phase, and EEG, electromyogram and motor activity were recorded. Tramadol dose-dependently reduced the time spent in rapid eye movement (REM) sleep and increased the REM onset latency. Lower doses of tramadol had wake-promoting effects in the first hours, while 45 mg/kg of tramadol promoted sleep first, but induced wakefulness thereafter. During non-REM sleep, tramadol (15 and 45 mg/kg) increased delta and decreased alpha power, while all doses increased gamma power. In conclusion, the sleep-related and qEEG effects of tramadol suggest antidepressant-like properties, including specific beneficial effects in selected patient groups, and raise the possibility of a faster acting antidepressant action.

A role for spindles in the onset of rapid eye movement sleep

Sleep spindle generation classically relies on an interplay between the thalamic reticular nucleus (TRN), thalamo-cortical (TC) relay cells and cortico-thalamic (CT) feedback during non-rapid eye movement (NREM) sleep. Spindles are hypothesized to stabilize sleep, gate sensory processing and consolidate memory. However, the contribution of non-sensory thalamic nuclei in spindle generation and the role of spindles in sleep-state regulation remain unclear. Using multisite thalamic and cortical LFP/unit recordings in freely behaving mice, we show that spike-field coupling within centromedial and anterodorsal (AD) thalamic nuclei is as strong as for TRN during detected spindles. We found that spindle rate significantly increases before the onset of rapid eye movement (REM) sleep, but not wakefulness. The latter observation is consistent with our finding that enhancing spontaneous activity of TRN cells or TRN-AD projections using optogenetics increase spindle rate and transitions to REM sleep. Together, our results extend the classical TRN-TC-CT spindle pathway to include non-sensory thalamic nuclei and implicate spindles in the onset of REM sleep.

The impact of sleep characteristics and epilepsy variables on memory performance in patients with focal seizures

Disturbed sleep can negatively affect overnight memory retention as well as new learning the subsequent day. In healthy participants, positive associations between memory performance and sleep characteristics (e.g., time spent in slow-wave sleep [SWS]) have been detected. In a previous study, we found that SWS was much reduced in patients with focal seizures, but when correlations between memory complaints and various sleep characteristics were considered, the only significant relationship was with the time to onset of rapid eye movement (REM) sleep (i.e., REM latency). In this study, we investigated the relationships between sleep, epilepsy, and objective memory performance variables. Twenty-five patients with focal seizures had their memory tested while undergoing a two-day ambulatory electroencephalography (EEG). The sleep variables of interest were the percentage of time spent in SWS (%SWS) and REM latency. Epilepsy variables included the presence of (1) seizures, (2) interictal epileptiform discharges, and/or (3) hippocampal lesions as well as site of seizure origin (temporal vs extratemporal). Overnight retention (of autobiographical events, a story, and a complex geometric figure) and the ability to learn a word list on day 2 were the measures of memory. A significant positive correlation was found between word-list learning and %SWS during the previous night. A significant negative correlation was observed between REM latency and overnight retention of autobiographical events. Overnight retention scores for the story and geometric figure were not related to sleep characteristics but were negatively affected by the presence of epileptiform activity. Story retention was also worse for temporal lobe epilepsy (TLE) than for patients with extratemporal epilepsy (ETE). Those with hippocampal lesions were more impaired than those without lesions on word-list learning, autobiographical events' retention, and story retention. When multiple contributing factors were entered into regression analyses, %SWS was found to be the best predictor of subsequent word-list learning, whereas the presence of a hippocampal lesion was the best predictor of overnight retention of autobiographical events and a story. These findings provide further evidence of the ways in which particular sleep characteristics are associated with memory and suggest that treatment of sleep disturbances in patients with epilepsy might be helpful for improving their performance.

Sleep stage dynamics in neocortex and hippocampus.

Mammalian sleep comprises the stages of slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Additionally, a transition state is often discriminated which in rodents is termed intermediate stage (IS). Although these sleep stages are thought of as unitary phenomena affecting the whole brain in a congruent fashion, recent findings have suggested that sleep stages can also appear locally restricted to specific networks and regions. Here, we compared in rats sleep stages and their transitions between neocortex and hippocampus. We simultaneously recorded the electroencephalogram (EEG) from skull electrodes over frontal and parietal cortex and the local field potential (LFP) from the medial prefrontal cortex and dorsal hippocampus. Results indicate a high congruence in the occurrence of sleep and SWS (>96.5%) at the different recording sites. Congruence was lower for REM sleep (>87%) and lowest for IS (<36.5%). Incongruences occurring at sleep stage transitions were most pronounced for REM sleep which in 36.6 per cent of all epochs started earlier in hippocampal LFP recordings than in the other recordings, with an average interval of 17.2 ± 1.1 s between REM onset in the hippocampal LFP and the parietal EEG (p < 0.001). Earlier REM onset in the hippocampus was paralleled by a decrease in muscle tone, another hallmark of REM sleep. These findings indicate a region-specific regulation of REM sleep which has clear implications not only for our understanding of the organization of sleep, but possibly also for the functions, e.g. in memory formation, that have been associated with REM sleep.

Retinal nerve fiber layer thinning: a window into rapid eye movement sleep behavior disorders in Parkinson’s disease

Retinal nerve fiber layer (RNFL) thinning occurs in Parkinson's disease (PD) and other neurodegenerative diseases. Idiopathic RBD (iRBD) is a well-established prodromal hallmark of synucleinopathies and occurs secondary to many neurodegenerative diseases, including PD. The aim of this study is to determine whether or not retinal structures are altered with the onset of rapid eye movement (REM) sleep behavior disorders (RBD). In all, a total of 63 patients with PD, 14 patients with idiopathic RBD, and 26 sex- and age-matched healthy controls were enrolled and underwent optical coherence tomography measurements (HD-OCT (Zeiss) ) for the average and every quadrant of RNFL thickness. The REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was used to classify PD patients with clinically probable RBD (PD+pRBD) or without probable RBD (PD-pRBD). Patients with iRBD were identified by polysomnography. For patients with RBD (idiopathic or secondary to PD), we found a significant decrease in RNFL thickness compared with groups without RBD (PD-pRBD and healthy controls) (all p<0.05). Average RNFL thickness in patients with iRBD is significantly thinner than in healthy controls (p<0.05). In PD, the average RNFL thickness was dramatically thinner in the PD+pRBD group than the PD-pRBD group (p<0.005). Compared with healthy controls, RNFL thickness was slightly thinner in the drug-naive PD group but not the PD group with drug treatment. Multiple linear regression analysis showed that RBDSQ score was negatively associated with average and inferior RNFL variation in PD (all p<0.005). The findings show that RNFL was slightly but significantly thinner in idiopathic RBD. In PD, RNFL thickness may vary depending on the presence of RBD.

Orexin Receptor Antagonism Improves Sleep and Reduces Seizures in Kcna1-null Mice.

Comorbid sleep disorders occur in approximately one-third of people with epilepsy. Seizures and sleep disorders have an interdependent relationship where the occurrence of one can exacerbate the other. Orexin, a wake-promoting neuropeptide, is associated with sleep disorder symptoms. Here, we tested the hypothesis that orexin dysregulation plays a role in the comorbid sleep disorder symptoms in the Kcna1-null mouse model of temporal lobe epilepsy. Rest-activity was assessed using infrared beam actigraphy. Sleep architecture and seizures were assessed using continuous video-electroencephalography-electromyography recordings in Kcna1-null mice treated with vehicle or the dual orexin receptor antagonist, almorexant (100 mg/kg, intraperitoneally). Orexin levels in the lateral hypothalamus/perifornical region (LH/P) and hypothalamic pathology were assessed with immunohistochemistry and oxygen polarography. Kcna1-null mice have increased latency to rapid eye movement (REM) sleep onset, sleep fragmentation, and number of wake epochs. The numbers of REM and non-REM (NREM) sleep epochs are significantly reduced in Kcna1-null mice. Severe seizures propagate to the wake-promoting LH/P where injury is apparent (indicated by astrogliosis, blood-brain barrier permeability, and impaired mitochondrial function). The number of orexin-positive neurons is increased in the LH/P compared to wild-type LH/P. Treatment with a dual orexin receptor antagonist significantly increases the number and duration of NREM sleep epochs and reduces the latency to REM sleep onset. Further, almorexant treatment reduces the incidence of severe seizures and overall seizure burden. Interestingly, we report a significant positive correlation between latency to REM onset and seizure burden in Kcna1-null mice. Dual orexin receptor antagonists may be an effective sleeping aid in epilepsy, and warrants further study on their somnogenic and ant-seizure effects in other epilepsy models.

Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism.

Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine. Here we investigated clinically meaningful doses (80–90% SERT occupancy) of vortioxetine and paroxetine on sleep-EEG in rats to further elucidate the serotoninergic receptor mechanisms mediating this difference. Cortical EEG, electromyography (EMG), and locomotion were recorded telemetrically for 10 days, following an acute dose, from rats receiving vortioxetine-infused chow or paroxetine-infused water and respective controls. Sleep stages were manually scored into active wake, quiet wake, and non-REM or REM sleep. Acute paroxetine or vortioxetine delayed REM onset latency (ROL) and decreased REM episodes. After repeated administration, vortioxetine yielded normal sleep-wake rhythms while paroxetine continued to suppress REM. Paroxetine, unlike vortioxetine, increased transitions from non-REM to wake, suggesting fragmented sleep. Next, we investigated the role of 5-HT3 receptors in eliciting these differences. The 5-HT3 receptor antagonist ondansetron significantly reduced paroxetine’s acute effects on ROL, while the 5-HT3 receptor agonist SR57227A significantly increased vortioxetine’s acute effect on ROL. Overall, our data are consistent with the clinical findings that vortioxetine impacts REM sleep differently than paroxetine, and suggests a role for 5-HT3 receptor antagonism in mitigating these differences.

Alcohol and Sleep Review: Sound Statistics and Valid Conclusions

HANK YOU FOR forwarding to us the letter fromPressman and colleagues (2015) and for inviting ourresponse.The role of alcohol and its impact on sleep has been stud-ied for more than a century, and a substantial knowledgebase has been created. The studies, like most scientific stud-ies, are dependent on the technology available at the timeandtheavailabilityofdata.Thisissomethingwetookintoconsiderationwhenprepar-ing our qualitative review on the impact of alcohol on nor-malsleep.Theissuesraisedcanbesummarizedasfollows:1. The use of percentages to represent the difference inthe mean values of sleep architecture variables in ourtables,2. Our results and conclusions as they pertain to the impactofalcohol onslowwavesleep(SWS),3. Ourinclusion–exclusioncriteriaforstudies,and4. Alcohol, N3, sleepwalking, and medico-legal conse-quences.1. The use of the mean value as a percentage to representsleeparchitecturevariables:1.1. In our article, we made clear how we have presentedthedata:Valuesforsleep architecturevariablesareprovidedinper-centage terms only. Where the researchers have reportedsleep stage data in minutes we have converted these intopercentages. Some variables, such as sleep onset latencyand rapid eye movement onset latency are reported inminutes only. Only the mean value is displayed for allvariables in the tables to enable a uniform approachthroughout(Ebrahimet al.,2013).1.2. This was accepted by the Journal and the peerreviewers as this review was based on highlighting 2specificareas:1.2.1. The impact of various alcohol doses and their tim-ing on nocturnal sleep in healthy controls and nor-mal populations.1.2.2. The impact of these alcohol doses on various sleepstages.1.3. Asthis was a qualitative reviewand not a quantitativemeta-analysis, it was our aim to provide a broadunderstanding to the “nonsleep specialist”readershipoftheimpactofalcoholonsleep.1.4. Furthermore, in routine clinical practice, sleepstages are reported both in actual time and as apercentage of total sleep, a simple difference in themeans between alcohol and placebo nights wasthought to be the best way to demonstrate theeffect.2. Alcohol andSWS:2.1. Alcohol andfirsthalfofnightSWS(N3):2.1.1. Low dose alcohol studies—Of the 4 studiesreported, 2 showed a significant increase in SWS(MacLean and Cairns, 1982; Van Reen et al., 2011)and the other 2 studies failed to find a significantdifference;2.1.2. Moderatedose studies—Ofthe 5 studies reported,2studies demonstrated a significant increase in SWS(Roehrs et al., 1999; Williams et al., 1983). Theother3 studiesfailedtodemonstrateany significantfindings;2.1.3. High dose studies—Five of the 9 studies reported astatistically significant increase in SWS with alco-hol (Arnedt et al., 2011; Feige et al., 2006;MacLean and Cairns, 1982; Prinz et al., 1980; Wil-liams et al., 1983) and 4 studies did not show anysignificantdifferences.The direction of evidence confirms that at low and moder-ate doses alcohol is not clearly associated with increased

Endurance exercise, tryptophan availability to the brain, and sleep electrophysiology in older men

Normal aging entails significant changes in serotonergic activity and function. Noteworthy, these alterations might predispose older individuals to develop depressive symptoms and contribute to age-related changes in sleep. This study verified if exercise increases tryptophan (Trp) availability to the brain and affects sleep depth and architecture in older men. Nineteen men (aged 64 ± 3 years) undertook a series of 4 tests, which was repeated at follow-up (after 16 weeks of training) as follows: (i) dual-energy X-ray absorptiometry (body composition); (ii) peak O2 consumption, ventilatory threshold, and respiratory compensation point (cardiopulmonary testing); (iii) blood withdrawals immediately before, during, and after exercise for analysis of glucose, lactate, ammonia, free fatty acids (FFA), total proteins, albumin, prolactin, valine, leucine, isoleucine, adiponectin, leptin, free and total Trp, and calculated variable: branched-chain amino acids (BCAA); and (iv) sleep electrophysiology (wake, stage 1, stage 2, stages 3+4 or slow-wave sleep (SWS), stage 5 or rapid eye movements, movement time, leg movements during sleep, apneas, hypopneas, and derivative variables). The intervention consisted of supervised exercise (3× per week × 45 min, 65%–70% peak oxygen uptake (V̇O2peak) whereas experimental exercise consisted of 1 h of inclined treadmill (∼68% V̇O2peak). Variations in serum prolactin and free Trp/BCAA served as proxies of 5-hydroxytryptamine activity and synthesis rate, respectively. A series of 3 nights was assessed before and after training using laboratory-based sleep electrophysiology (polysomnography: electroelectroencephalography and electromyography and electro-oculography) as follows: (i) familiarization, (ii) inactive trial, and (iii) exercise trial. Aerobic taining increased oxygen uptake at both ventilatory thresholds, whereas body mass decreased. Acute exercise increased free Trp/BCAA ratio by more than 100% of that at rest and remained elevated postexercise. This ratio shared a positive association with FFA levels. After 1 h of exercise, prolactin was higher than that at rest and was positively associated with free Trp/BCAA. However, the acute response to exercise was attenuated following training for many compounds, including free Trp/BCAA, prolactin, lactate, and FFA. Analyses revealed significant main effects of exercise on wake after sleep onset, rapid eye movement onset latency, and time awake overnight. As compared with the inactive trial at baseline, a higher proportion of SWS was observed during the night subsequent to exercise following training. In addition, we found a positive association between resting adiponectin and SWS. The results support the hypothesis that increases in serotonin synthesis and activity might be involved in the antidepressant outcome of exercise in older men. Inasmuch as training lowered the increase in Trp supply during exercise, Trp requirement by the brain in response to exercise might be attenuated by training. Despite gains in cardiorespiratory fitness after training, a day without exercise led to SWS values similar to those at baseline. However, exercise increased the proportion of SWS during subsequent sleep but this could only be found after training. These results provide evidence that not only sleep quantity (duration) but also quality (SWS) could affect circulating adiponectin levels. Finally, a positive correlation was found between sleep depth and circulating adiponectin levels.

Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM) sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM) and REM sleep following oral dosing (10 and 30 mg/kg) at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion). When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg) increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg) did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic.

Effect of Evening Postexercise Cold Water Immersion on Subsequent Sleep

This study investigated the effect of cold water immersion after evening exercise on subsequent sleep quality and quantity in trained cyclists. In the evenings (~1900 h) on three separate occasions, male cyclists (n = 11) underwent either no exercise (control, CON), exercise only (EX), or exercise followed by cold water immersion (CWI). EX comprised cycling for 15 min at 75% peak power, then a 15-min maximal time trial. After each condition, a full laboratory-based sleep study (polysomnography) was performed. Core and skin temperature, heart rate, salivary melatonin, ratings of perceived fatigue, and recovery were measured in each trial. No differences were observed between conditions for any whole night sleep measures, including total sleep time, sleep efficiency, sleep onset latency, rapid eye movement onset latency, wake after sleep onset, or proportion of the night spent in different sleep stages. Core temperature in EX and CWI trials was higher than CON, until it decreased below that of EX and CON until bedtime in CWI. After bedtime, core temperature was similar for all conditions throughout the night, except for a 90-min period where it was lower for CWI than EX and CON (3.5-4.5 h postexercise). Heart rates for EX and CWI were both significantly higher than CON postexercise until bedtime, whereas skin temperature after CWI was significantly lower than EX and CON, remaining lower than EX until 3 h postexercise. Melatonin levels and recovery ratings were similar between conditions. Fatigue ratings were significantly elevated after exercise in both CWI and EX conditions, with EX still being elevated compared with CON at bedtime. Whole night sleep architecture is not affected by evening exercise alone or when followed by CWI.

Narcolepsy or Sleep Apnea?: Not Everything is What it Appears to be!

We are reluctant to intrude in a discussion in this case report. Based on their clinical observations of the patient (an 84-yearold woman with long-standing history of excessive daytime sleepiness (EDS), the study authors’ most likely diagnosis was late onset narcolepsy. However, we believe that some of the inferences made by Carlucci and Prasad (1) merit further comments. We see this as an interesting and important case report and professionally reported. However, we view the number of atypical symptoms and their significance from a perspective that is somewhat different from those of the authors. We believe that there are several fundamental questions that need to be addressed here. In areas where we do not agree with the authors, we have stated them with the rationale for our disagreement. We address our comments point by point as follows: The patient was reported to be morbidly obese (BMI = 36), and to have a large neck circumference (NC = 17), and a Mallampatti Gr III airway. Nevertheless the patient had a normal AHI which was just 0.9 with normal overnight oximetry. Further, the overnight hypnogram reveals that most, if not all, apneas are rapid eye movement (REM)-related, but not positional. Although not impossible, the inference that the apneas were almost exclusively a REM sleep phenomenon appears improbable. The first question is – was the observed low AHI related to the poor quality of sleep on the testing nights (sleep efficiency 64 and 71%). Second, this lady was not described having any other symptoms that had supported the diagnosis of narcolepsy viz., hypnagogic or hypnopompic hallucination. If they were present, their presence should be considered in presence of poor quality sleep in night, as recorded by two overnight polysomnograms. Third, the patient was described as excessively sleepy (ESS score: 11/24). The cut-off ESS score is an arbitrary one and based upon the population norm. Our concern is can a patient be categorized as excessively sleepy because she scored just 1 point more than the population norm, i.e., 10. We think, an important issue to consider is the compromise in daytime functioning because of sleepiness, especially when we are dealing with a single case. Moreover, the authors state that at the time of the study she was on multiple medicines including cyclobenzaprine, and hydrocodone, which were taken as needed. Hydrocodone and cyclobenzaprine both can produce drowsiness. Hence, ingestion of these medications should also have been taken into consideration while inferring the information about EDS. The report mentions that patient had goiter. The question is, whether the thyroid profile was within normal limits? Moreover, was the toxicology screening done to find out the reason for excessive daytime sleepiness? Fourth, was the quality and duration of nighttime sleep sufficient to justify performing an MSLT? (2). The inadequate sleep that the patient had the night before could also have resulted in daytime sleepiness and SOREMPs (3). Fifth, as per self-reports of the patient, the authors mentioned that she maintained a regular schedule (although no mention was made with regards to her usual bed time). Considering her age, is it possible that her habitual time of retiring was much earlier than the sleep time followed in laboratory (11:02 p.m. as per the study record); this could have produced an early onset of REM during the overnight polysomnogram. Sixth, as per the hypnogram, the patient had long period of self-awakenings from all of her REM periods. The interesting question is – would this have produced early REMs in her MSLT, especially during first MSLT session during the subsequent daytime study? For example, REM sleep onset latency (REMOL) in the first REM period in the MSLT was markedly reduced (3 min) while subsequent MSLT tests showed somewhat delayed REMOL. Another possibility when we see this data in association with poor sleep efficiency is that the patient might have been almost, if not already sleeping during the hookup of the first MSLT. Only a clear video recording review would prove this. It should be considered also that severe or complex psychiatric, neurological, or medical disorders, and the use of anticataplectic or stimulants can compromise the validity of the MSLT. In addition, sleep latency on MSLT and number of SOREMPs usually decreases as a function of age (4).

P.4.e.002 Standardised LORETA findings in patients with panic disorder before and after cognitive behavioural therapy

Brain activity preceding rapid eye movements (REM) during human REM sleep has remained poorly understood. Slow negative brain potential (pre-REM negativity) appears before REMs. Current sources of this potential were investigated to identify brain activity immediately preceding REMs.In this study, 22 young healthy volunteers (20–25 years old) participated. Polysomnograms were recorded during normal nocturnal sleep. Brain potentials between 200 ms before and 50 ms after the onset of REMs and pseudo-triggers (3000 ms before the onset of REMs) were averaged. Standardized low-resolution brain electromagnetic tomography (sLORETA) was used to estimate current sources of pre-REM negativity.Pre-REM negativity appeared with the maximal amplitude at right prefrontal sites immediately before REMs. However, this negativity did not appear before pseudo-triggers. Current sources of the pre-REM negativity were estimated in the ventromedial prefrontal cortex, uncus, insula, anterior cingulated cortex, basal forebrain, parahippocampal gyrus, premotor cortex and frontal eye field.The pre-REM negativity reflects brain activity coupled with the occurrence of REMs. Results of this study suggest that emotion, memory, and motor-related brain activity might occur before REMs.Pre-REM negativity is expected to be a psychophysiological index for elucidating functions of REM sleep.