Sleep and protein synthesis-dependent synaptic plasticity: impacts of sleep loss and stress

Sleep has been ascribed a critical role in cognitive functioning. Several lines of evidence implicate sleep in the consolidation of synaptic plasticity and long-term memory. Stress disrupts sleep while impairing synaptic plasticity and cognitive performance. Here, we discuss evidence linking sleep to mechanisms of protein synthesis-dependent synaptic plasticity and synaptic scaling. We then consider how disruption of sleep by acute and chronic stress may impair these mechanisms and degrade sleep function

Validation of peripheral arterial tonometry as tool for sleep assessment in chronic obstructive pulmonary disease

Obstructive sleep apnea (OSA) worsens outcomes in Chronic Obstructive Pulmonary Disease (COPD), and reduced sleep quality is common in these patients. Thus, objective sleep monitoring is needed, but polysomnography (PSG) is cumbersome and costly. The WatchPAT determines sleep by a pre-programmed algorithm and has demonstrated moderate agreement with PSG in detecting sleep stages in normal subjects and in OSA patients. Here, we validated WatchPAT against PSG in COPD patients, hypothesizing agreement in line with previous OSA studies. 16 COPD patients (7 men, mean age 61 years), underwent simultaneous overnight recordings with PSG and WatchPAT. Accuracy in wake and sleep staging, and concordance regarding total sleep time (TST), sleep efficiency (SE), and apnea hypopnea index (AHI) was calculated. Compared to the best fit PSG score, WatchPAT obtained 93% sensitivity (WatchPAT = sleep when PSG = sleep), 52% specificity (WatchPAT = wake when PSG = wake), 86% positive and 71% negative predictive value, Cohen’s Kappa (κ) = 0.496. Overall agreement between WatchPat and PSG in detecting all sleep stages was 63%, κ = 0.418. The mean(standard deviation) differences in TST, SE and AHI was 25(61) minutes (p = 0.119), 5(15) % (p = 0.166), and 1(5) (p = 0.536), respectively. We conclude that in COPD-patients, WatchPAT detects sleep stages in moderate to fair agreement with PSG, and AHI correlates well.Obstructive sleep apnea (OSA) worsens outcomes in Chronic Obstructive Pulmonary Disease (COPD), and reduced sleep quality is common in these patients. Thus, objective sleep monitoring is needed, but polysomnography (PSG) is cumbersome and costly. The WatchPAT determines sleep by a pre-programmed algorithm and has demonstrated moderate agreement with PSG in detecting sleep stages in normal subjects and in OSA patients. Here, we validated WatchPAT against PSG in COPD patients, hypothesizing agreement in line with previous OSA studies. 16 COPD patients (7 men, mean age 61 years), underwent simultaneous overnight recordings with PSG and WatchPAT. Accuracy in wake and sleep staging, and concordance regarding total sleep time (TST), sleep efficiency (SE), and apnea hypopnea index (AHI) was calculated. Compared to the best fit PSG score, WatchPAT obtained 93% sensitivity (WatchPAT = sleep when PSG = sleep), 52% specificity (WatchPAT = wake when PSG = wake), 86% positive and 71% negative predictive value, Cohen’s Kappa (κ) = 0.496. Overall agreement between WatchPat and PSG in detecting all sleep stages was 63%, κ = 0.418. The mean(standard deviation) differences in TST, SE and AHI was 25(61) minutes (p = 0.119), 5(15) % (p = 0.166), and 1(5) (p = 0.536), respectively. We conclude that in COPD-patients, WatchPAT detects sleep stages in moderate to fair agreement with PSG, and AHI correlates well.publishedVersio

A randomized controlled trial on the effects of blue-blocking glasses compared to partial blue-blockers on sleep outcomes in the third trimester of pregnancy

Objective Sleep disturbances are common in pregnancy. Blocking blue light has been shown to improve sleep and may be a suitable intervention for sleep problems during pregnancy. The present study investigated the effects of blue light blocking in the evening and during nocturnal awakenings among pregnant women on primary sleep outcomes in terms of total sleep time, sleep efficiency and mid-point of sleep. Methods In a double-blind randomized controlled trial, 60 healthy nulliparous pregnant women in the beginning of the third trimester were included. They were randomized, using a random number generator, either to a blue-blocking glass intervention (n = 30) or to a control glass condition constituting partial blue-blocking effect (n = 30). Baseline data were recorded for one week and outcomes were recorded in the last of two intervention/control weeks. Sleep was measured by actigraphy, sleep diaries, the Bergen Insomnia Scale, the Karolinska Sleepiness Scale and the Pre-Sleep Arousal Scale. Results The results on the primary outcomes showed no significant mean difference between the groups at posttreatment, neither when assessed with sleep diary; total sleep time (difference = .78[min], 95%CI = -19.7, 21.3), midpoint of sleep (difference = -8.9[min], 95%CI = -23.7, 5.9), sleep efficiency (difference = -.06[%], 95%CI = -1.9, 1.8) and daytime functioning (difference = -.05[score points], 95%CI = -.33, .22), nor by actigraphy; total sleep time (difference = 13.0[min], 95%CI = -9.5, 35.5), midpoint of sleep (difference = 2.1[min], 95%CI = -11.6, 15.8) and sleep efficiency (difference = 1.7[%], 95%CI = -.4, 3.7). On the secondary outcomes, the Bergen Insomnia Scale, the Karolinska Sleepiness Scale and the Pre-Sleep Arousal Scale the blue-blocking glasses no statistically significant difference between the groups were found. Transient side-effects were reported in both groups (n = 3). Conclusions The use of blue-blocking glasses compared to partially blue-blocking glasses in a group of healthy pregnant participants did not show statistically significant effects on sleep outcomes. Research on the effects of blue-blocking glasses for pregnant women with sleep-problems or circadian disturbances is warranted.publishedVersio

A randomized controlled trial on the effect of blue-blocking glasses compared to partial blue-blockers on melatonin profile among nulliparous women in third trimester of the pregnancy

Objective In pregnancy melatonin regulates circadian rhythms, induce sleep, and has a neuroprotective positive effect on fetal development. Artificial blue light in the evening delays and suppresses melatonin production. Thus, we investigated the effect of blocking blue light on the melatonin profile. Methods A randomized controlled trial (n=30 blue-blocking glasses vs. n=30 control glasses with partial blue-blocking effect) including healthy nulliparous pregnant women in the beginning of the third trimester. Salivary melatonin and subjective sleep were measured before and after two weeks of intervention/control condition. Saliva was sampled at 30-min intervals from 3 h before normal bedtime. Melatonin onset was set at 4.0 pg/ml. Results Due to missing data melatonin onset was estimated for 47 participants. At posttreatment, melatonin onset advanced by 28 min in the blue-blocking group compared with the control condition (p=.019). Melatonin levels were significantly higher, favoring the blue-blocking glass condition, at clock time 20:00, 21:00 and 22:00 h, and for sample number 3 and 4. The phase angle (time interval) between melatonin onset and sleep bedtime and sleep onset time increased within the blue blocking group (+45 min and +41 min, respectively), but did not reach statistical significance compared to control condition (+13 min and +26 min, respectively). Conclusion Blocking blue light in the evening had a positive effect on the circadian system with an earlier onset and rise of melatonin levels in healthy nulliparous pregnant women. This demonstrated the effectiveness and feasibility of a simple non-pharmacological chronobiological intervention during pregnancy.publishedVersio

Bright light exposure during simulated night work improves cognitive flexibility

Under embargo until: 2023-03-28Night work leads to sleepiness and reduced vigilant attention during work hours, and bright light interventions may reduce such effects. It is also known that total sleep deprivation impairs cognitive flexibility as measured by reversal learning tasks. Whether night work impairs reversal learning task performance or if bright light can mitigate reversal learning deficits during night work is unclear. In this counterbalanced crossover study (ClinicaTrials.gov Identifier NCT03203538), young healthy individuals completed a reversal learning task twice during each of three consecutive simulated night shifts (23:00–07:00 h). The night shifts were performed in a laboratory under a full-spectrum (4000 K) bright light (~900 lx) and a standard light (~90 lx) condition. Reversal learning task performance was reduced towards the end of the night shifts (04:50 h), compared to the first part of the night shifts (00:20 h) in both light conditions. However, with bright light, the reversal learning task performance improved towards the end of the night shifts, compared to standard light. The study shows that bright light may mitigate performance deficits on a reversal learning task during night work and implies that bright light interventions during night work may be beneficial not only for vigilant attention but also for cognitive flexibility.acceptedVersio

Blue-enriched white light improves performance but not subjective alertness and circadian adaptation during three consecutive simulated night shifts

Use of blue-enriched light has received increasing interest regarding its activating and performance sustaining effects. However, studies assessing effects of such light during night work are few, and novel strategies for lighting using light emitting diode (LED) technology need to be researched. In a counterbalanced crossover design, we investigated the effects of a standard polychromatic blue-enriched white light (7000 K; ∼200 lx) compared to a warm white light (2500 K), of similar photon density (∼1.6 × 1014 photons/cm2/s), during three consecutive simulated night shifts. A total of 30 healthy participants [10 males, mean age 23.3 (SD = 2.9) years] were included in the study. Dependent variables comprised subjective alertness using the Karolinska Sleepiness Scale, a psychomotor vigilance task (PVT) and a digit symbol substitution test (DSST), all administered at five time points throughout each night shift. We also assessed dim-light melatonin onset (DLMO) before and after the night shifts, as well as participants’ opinion of the light conditions. Subjective alertness and performance on the PVT and DSST deteriorated during the night shifts, but 7000 K light was more beneficial for performance, mainly in terms of fewer errors on the PVT, at the end of the first- and second- night shift, compared to 2500 K light. Blue-enriched light only had a minor impact on PVT response times (RTs), as only the fastest 10% of the RTs were significantly improved in 7000 K compared to 2500 K light. In both 7000 and 2500 K light, the DLMO was delayed in those participants with valid assessment of this parameter [n = 20 (69.0%) in 7000 K light, n = 22 (78.6%) in 2500 K light], with a mean of 2:34 (SE = 0:14) and 2:12 (SE = 0:14) hours, respectively, which was not significantly different between the light conditions. Both light conditions were positively rated, although participants found 7000 K to be more suitable for work yet evaluated 2500 K light as more pleasant. The data indicate minor, but beneficial, effects of 7000 K light compared to 2500 K light on performance during night work. Circadian adaptation did not differ significantly between light conditions, though caution should be taken when interpreting these findings due to missing data. Field studies are needed to investigate similar light interventions in real-life settings, to develop recommendations regarding illumination for night workers.publishedVersio

Blue-blocking glasses as additive treatment for mania: Effects on actigraphy-derived sleep parameters

Improvement of sleep is a central treatment goal for patients in a manic state. Blue‐blocking (BB) glasses as adjunctive treatment hasten overall recovery from mania. This method is an evolvement from dark therapy and builds on the discovery of the blue‐light‐sensitive retinal ganglion cell that signals daytime to the brain. We report effects of adjunctive BB glasses on actigraphy‐derived sleep parameters for manic inpatients as compared to placebo. Hospitalized patients with bipolar disorder in a manic state aged 18–70 years were recruited from five clinics in Norway from February 2012 to February 2015. The participants were randomly allocated to wearing BB glasses or placebo (clear glasses) as an adjunctive treatment from 18:00 to 08:00 hours for seven consecutive nights. Sleep and wake were monitored by actigraphy. From 32 eligible patients, 10 patients in each group qualified for the group analyses. The BB group's mean sleep efficiency was significantly higher at night 5 as compared to the placebo group (92.6% vs. 83.1%, p = .027). The 95% confidence interval (CI) was 89.4%–95.8% in the BB group and 75.9%–90.3% in the placebo group. There were fewer nights of interrupted sleep in the BB group: 29.6% versus 43.8% in the placebo group. The BB group received less‐intensive sleep‐promoting pharmacological treatment and showed significantly higher sleep efficiency and more consolidated sleep as compared to the placebo group. Our findings suggest sleep‐promoting effects through deactivating mechanisms. Adjunctive BB glasses seem to be useful for improving sleep for manic patients in the hospital setting.publishedVersio

State-Dependent Modulation of Visual Evoked Potentials in a Rodent Genetic Model of Electroencephalographic Instability

Despite normal sleep timing and duration, Egr3-deficient (Egr3−/−) mice exhibit electroencephalographic (EEG) characteristics of reduced arousal, including elevated slow wave (1–4 Hz) activity during wakefulness. Here we show that these mice exhibit state-dependent instability in the EEG. Intermittent surges in EEG power were found in Egr3−/− mice during wakefulness and rapid eye movement sleep, most prominently in the beta (15–35 Hz) range compared to wild type (Egr3+/+) mice. Such surges did not coincide with sleep onset, as the surges were not associated with cessation of electromyographic tone. Cortical processing of sensory information by visual evoked responses (VEP) were found to vary as a function of vigilance state, being of higher magnitude during slow wave sleep (SWS) than wakefulness and rapid eye movement sleep. VEP responses were significantly larger during quiet wakefulness than active wakefulness, in both Egr3−/− mice and Egr3+/+ mice. EEG synchronization in the beta range, previously linked to the accumulation of sleep need over time, predicted VEP magnitude. Egr3−/− mice not only displayed elevated beta activity, but in quiet wake, this elevated beta activity coincides with an elevated evoked response similar to that of animals in SWS. These data confirm that (a) VEPs vary as a function of vigilance state, and (b) beta activity in the EEG is a predictor of state-dependent modulation of visual information processing. The phenotype of Egr3−/− mice indicates that Egr3 is a genetic regulator of these phenomena

Mathematical modeling of sleep state dynamics in a rodent model of shift work

Millions of people worldwide are required to work when their physiology is tuned for sleep. By forcing wakefulness out of the body’s normal schedule, shift workers face numerous adverse health consequences, including gastrointestinal problems, sleep problems, and higher rates of some diseases, including cancers. Recent studies have developed protocols to simulate shift work in rodents with the intention of assessing the effects of night-shift work on subsequent sleep (Grønli et al., 2017). These studies have already provided important contributions to the understanding of the metabolic consequences of shift work (Arble et al., 2015; Marti et al., 2016; Opperhuizen et al., 2015) and sleep-wake-specific impacts of night-shift work (Grønli et al., 2017). However, our understanding of the causal mechanisms underlying night-shift-related sleep disturbances is limited. In order to advance toward a mechanistic understanding of sleep disruption in shift work, we model these data with two different approaches. First we apply a simple homeostatic model to quantify differences in the rates at which sleep need, as measured by slow wave activity during slow wave sleep (SWS) rises and falls. Second, we develop a simple and novel mathematical model of rodent sleep and use it to investigate the timing of sleep in a simulated shift work protocol (Grønli et al., 2017). This mathematical framework includes the circadian and homeostatic processes of the two-process model, but additionally incorporates a stochastic process to model the polyphasic nature of rodent sleep. By changing only the time at which the rodents are forced to be awake, the model reproduces some key experimental results from the previous study, including correct proportions of time spent in each stage of sleep as a function of circadian time and the differences in total wake time and SWS bout durations in the rodents representing night-shift workers and those representing day-shift workers. Importantly, the model allows for deeper insight into circadian and homeostatic influences on sleep timing, as it demonstrates that the differences in SWS bout duration between rodents in the two shifts is largely a circadian effect. Our study shows the importance of mathematical modeling in uncovering mechanisms behind shift work sleep disturbances and it begins to lay a foundation for future mathematical modeling of sleep in rodents

Gamma knife surgery as monotherapy with clinically relevant doses prolongs survival in a Human GBM Xenograft Model

Object. Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. Methods. GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12Gy or 18Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test. Results. In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls ( < 0.001). In a second experiment, survival was 72 days in the treatment group versus 54 days in controls ( < 0.006). Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment ( = 0.04). Conclusion.GKS administered with clinically relevant doses prolongs survival in rats harboringGBMxenografts, and the associated toxicity is mild.publishedVersio