Duration Of Wakefulness Research Articles

Soriano award lecture: Light, circadian rhythms and sleep: Mechanisms to new therapeutics

Until recently, it seemed inconceivable to most vision researchers and ophthalmologists that there could be an unrecognised class of light sensor (photoreceptor) within the eye. However, by studying how circadian rhythms and sleep are regulated by the dawn/dusk cycle we demonstrated that there exists a “3rd class” of photoreceptor within the eye based upon a small number of photosensitive retinal ganglion cells (pRGCs) that utilise the blue light sensitive photopigment melanopsin (OPN4). The first part of the presentation will consider the discovery and clinical importance of the “third” photoreceptor system of the eye. The second part of the talk will address how these photoreceptors signal light to the molecular clockwork and by what means this pathway is modified by sleep history. There has been remarkable progress in understanding the complex intracellular mechanisms that generate circadian rhythms, the molecular pathways whereby the pRGCs entrain circadian biology and sleep has remained poorly understood. The suprachiasmatic nuclei (SCN) are the site of the primary circadian pacemakers within the mammalian brain. Until recently, the model for entrainment involved a simple linear pathway whereby glutamate release from the pRGCs resulted in Ca2+ influx and raised intracellular cAMP in SCN neurones, which in turn resulted in CREB phosphorylation leading to increased transcription of two key clock genes, Per1 and Per2. This signal then advanced or delayed the molecular clockwork. However, an important feature of entrainment is that circadian responses to light are limited – as typified by jet-lag. Full recovery from jet-lag requires a day for every time-zone crossed. We addressed this issue and have identified and characterized a key role for Salt Inducible Kinase 1 (SIK1) and the CREB-regulated transcription co-activator 1 (CRTC1) in clock re-setting. However, our most recent findings have shown that light entrainment also involves the parallel activation of a Ca2+-ERK1/2-AP-1 signalling pathway. Thus both CRE and AP-1 regulatory elements drive light-induced clock gene expression. In addition, whilst light activation of the Ca2+-ERK1/2-AP-1 signalling pathway increases Per1 and Per2 expression, sleep/wake behaviour alters the effects of light on the clock. Our proposed mechanism suggests that adenosine acts as a signalling molecule that encodes wake duration. Adenosine acts via inhibitory A1 receptors on the SCN to inhibit the Ca2+-ERK1/2-AP-1 signalling pathway, which in turn, reduces the expression of Per1 and Per2. Thus sleep/wake history, encoded by adenosine, reduces the phase shifting effects of light upon the circadian system, altering sleep/wake timing. Finally, the talk will explore how such signalling pathways provide a new target for the regulation of circadian rhythms and the “pharmacological” replacement of light for sleep/wake re-setting in individuals lacking eyes or other individuals with severe circadian rhythm disruption.

Sleep homeostasis during daytime food entrainment in mice.

Twenty-four hour rhythms of physiology and behavior are driven by the environment and an internal endogenous timing system. Daily restricted feeding (RF) in nocturnal rodents during their inactive phase initiates food anticipatory activity (FAA) and a reorganization of the typical 24-hour sleep–wake structure. Here, we investigate the effects of daytime feeding, where food access was restricted to 4 hours during the light period ZT4-8 (Zeitgeber time; ZT0 is lights on), on sleep–wake architecture and sleep homeostasis in mice. Following 10 days of RF, mice were returned to ad libitum feeding. To mimic the spontaneous wakefulness associated with FAA and daytime feeding, mice were then sleep deprived between ZT3-6. Although the amount of wake increased during FAA and subsequent feeding, total wake time over 24 hours remained stable as the loss of sleep in the light phase was compensated for by an increase in sleep in the dark phase. Interestingly, sleep that followed spontaneous wake episodes during the dark period and the extended period of wake associated with FAA, exhibited lower levels of slow-wave activity (SWA) when compared to baseline or after sleep deprivation, despite a similar duration of waking. This suggests an evolutionary mechanism of reducing sleep drive during negative energy balance to enable greater arousal for food-seeking behaviors. However, the total amount of sleep and SWA accumulated during the 24 hours was similar between baseline and RF. In summary, our study suggests that despite substantial changes in the daily distribution and quality of wake induced by RF, sleep homeostasis is maintained.

Effect of mean apnea-hypopnea duration in patients with obstructive sleep apnea on clinical and polysomnography parameter.

Apnea-hypopnea index is the number of apnea-hypopnea events observed during polysomnography within an hour. Mean apnea-hypopnea duration is the mean duration of all apneas and hypopneas. In this study, we aimed to investigate the association of mean apnea-hypopnea duration in patients with obstructive sleep apnea with clinical and polysomnographic parameters. In our hospital, a total of 764 patients were diagnosed with OSA by polysomnography in 2017. Age, body mass index, and the current diseases were recorded. Sleep structures obtained from polysomnography readings, blood oxygen levels, apnea-hypopnea index, and mean average duration were recorded. Patients with mean average duration of 20s or more were assigned to the long average duration group and those with less than 20s were assigned to the short average duration group. Groups were compared in terms of clinical and polysomnographic parameters. Snoring, witnessed apnea, morning tiredness, and hypertension were significantly higher in the long average duration group. There was statistically significantly more male patients and higher neck circumference in the MAD group. Total wake duration, percentage of sleep, stage 3, stage 1, and mean oxygen saturation percentage of the long average duration group were significantly reduced. In present study, the patients with obstructive sleep apnea with long average duration were found to have more negative effects of sleep apnea than the patients with short average duration. We think that the use of mean apnea-hypopnea duration as an indicator with apnea-hypopnea index will be beneficial for the follow-up and treatment of the disease.

Perceived Workload Is Associated with Cabin Crew Fatigue on Ultra-Long Range Flights

ABSTRACTObjective: This study aimed to determine whether on ultra-long range (ULR) flights, perceived workload is an independent predictor of cabin crew fatigue at top-of-descent (TOD) and if so, to what degree it is associated with cabin crew fatigue relative to sleep-related factors.Background: Current ULR scheduling for cabin crew is predominantly based on flight crew data. However, cabin crew workload is very different in nature to that of flight crew.Method: Fifty-five cabin crew wore an actigraph and completed a sleep/duty diary to monitor sleep during a ULR trip. At TOD, crewmembers completed a 5-min Psychomotor Vigilance Task (PVT), rated their sleepiness (Karolinska Sleepiness Scale) and fatigue (Samn-Perelli Crew Status Check), and after landing their workload (NASA Task Load Index).Results: When workload was perceived as higher, crewmembers felt more sleepy and fatigued and had more PVT lapses at TOD. The effect of workload on sleepiness was larger (Cohen’s ƒ2 = .27) than the duration of wakefulness (Cohen’s ƒ2 = .14), but the effect of workload on fatigue (Cohen’s ƒ2 = .17) was smaller than the duration of wakefulness (Cohen’s ƒ2 = .24). Lapses were not associated with sleep history, whereas workload had a small effect (Cohen’s ƒ2 = .14).Conclusion: Workload as a fatigue factor for cabin crew warrants ongoing monitoring. This can be achieved by including a workload question in fatigue reports as an essential component in Fatigue Risk Management Systems.

SAT-207 The Effects of the Menstrual Cycle and Caloric Restriction on Sleep in Young Women

Background: Dynamic changes in reproductive hormone levels across the menstrual cycle have been hypothesized to disrupt normal sleep patterns. While some studies reported increased sleep disruption in the luteal phase, others did not. In addition, metabolic hormones including ghrelin and cortisol are linked to both sleep regulation and the reproductive axis. However, studies have focused on the responses of these hormones to sleep, rather than their effects on sleep. The purpose of this study was to evaluate the effects of hormonal changes across the menstrual cycle and decreased energy availability on Actigraphy-defined objective sleep measures in an in-home setting in young, regularly-cycling women. Methods: As a part of a larger study, reproductive hormones were collected from 10 healthy, regularly-cycling women aged 18-28 years over the course of two menstrual cycles. Daily Actigraphic sleep data (n=578 sleep episodes) and urinary concentrations of LH, estrone-3-glucuronide (E1G), and pregnanediol-3-glucuronide (PDG) were collected. Subjects completed two 5-day diet interventions (neutral versus decreased energy availability) during the early follicular phases (EFP) of separate cycles. Cycles were centered on day of ovulation and standardized to 14-day follicular and 14-day luteal phases. Sleep data were analyzed using linear mixed models by menstrual phase, diet interventions, and reproductive hormones, adjusting for weekday vs weekend. Results: Hormonal measurements confirmed ovulation in both cycles in all subjects (age 24.5 ± 2.5, BMI 22.2 ± 2.1). There was an effect of menstrual phase on sleep efficiency (SE, p=0.005), wake after sleep onset (WASO, p=0.04), number of awakenings per night (p=0.02), and sleep fragmentation index (SFI, p=0.06), consistent with increased sleep disruption in the late luteal phase (LLP). In comparison with the EFP, SE decreased by 3.3% (p=0.0002), WASO increased by 15 minutes (p=0.001), and number of awakenings increased by 3 (p=0.04) in the LLP. Decreased energy availability increased sleep disruption, as indicated by decreased SE (p<0.05), increased WASO (p=0.03), and increased SFI (p=0.07). With decreased energy availability, post-hoc analyses showed increased sleep disruption in both the late follicular phase (LFP) and LLP. E1G was associated with an increase in number of awakenings (p=0.007), such that an increase of E1G by 50 mcg/g Cr increased the number of awakenings by 2.4. PDG was associated with a trend toward increased SFI (p=0.07). Conclusions: Among healthy, young women, objective sleep varies across the menstrual cycle, marked by decreased SE, increased WASO, and increased number and duration of awakenings in the LLP. In addition, decreased energy availability in the EFP increases sleep disruption, with greatest effects in the LFP and LLP.

Sleepiness and driving events in shift workers: the impact of circadian and homeostatic factors.

We aimed to characterize objective and subjective sleepiness and driving events during short work commutes and examine the impact of circadian and homeostatic factors across different shift types in a shift worker population. Thirty-three nurses were monitored for 2 weeks over day (07:00-15:30), evening (13:00-21:30), and night shifts (21:00-07:30). Sleep was measured via daily sleep logs and wrist actigraphy. Driving logs were completed for each work commute, reporting driving events and a predrive Karolinska Sleepiness Scale (KSS). Ocular data from a subset of participants (n = 11) assessed objective sleepiness using infrared oculography during commutes. Circadian phase was assessed at three time points via urinary 6-sulphatoxymelatonin (aMT6s) collected over 24-48 hours. Subjective and objective sleepiness and sleep-related and hazardous driving events significantly increased following night shift compared with preshift. There were significant shift differences with KSS, sleep-related and inattention-related events highest during the postnight shift commute, compared with day and evening shifts. Sleep-related events were highest following the first night shift, while inattention-related events were most frequent after consecutive night shifts. KSS, sleep-related and hazardous events were increased during drives following ≥16 hours of wakefulness. KSS and sleep-related events increased during drives within ±3 hours of aMT6s acrophase. An interaction between homeostatic and circadian processes was observed, with KSS and sleep-related events highest within ±3 hours of acrophase, when wakefulness was ≥16 hours. In naturalistic conditions, subjective and objective sleepiness and driving events are increased following night shifts, even during short (~30 minutes) commutes and exacerbated by an interaction between circadian phase and duration of wakefulness.

The Impact of Shift Work on Sleep, Alertness and Performance in Healthcare Workers

Shift work is associated with impaired alertness and performance due to sleep loss and circadian misalignment. This study examined sleep between shift types (day, evening, night), and alertness and performance during day and night shifts in 52 intensive care workers. Sleep and wake duration between shifts were evaluated using wrist actigraphs and diaries. Subjective sleepiness (Karolinska Sleepiness Scale, KSS) and Psychomotor Vigilance Test (PVT) performance were examined during day shift, and on the first and subsequent night shifts (3rd, 4th or 5th). Circadian phase was assessed using urinary 6-sulphatoxymelatonin rhythms. Sleep was most restricted between consecutive night shifts (5.74 ± 1.30 h), consecutive day shifts (5.83 ± 0.92 h) and between evening and day shifts (5.20 ± 0.90 h). KSS and PVT mean reaction times were higher at the end of the first and subsequent night shift compared to day shift, with KSS highest at the end of the first night. On nights, working during the circadian acrophase of the urinary melatonin rhythm led to poorer outcomes on the KSS and PVT. In rotating shift workers, early day shifts can be associated with similar sleep restriction to night shifts, particularly when scheduled immediately following an evening shift. Alertness and performance remain most impaired during night shifts given the lack of circadian adaptation to night work. Although healthcare workers perceive themselves to be less alert on the first night shift compared to subsequent night shifts, objective performance is equally impaired on subsequent nights.

Sleep and Neurochemical Modulation by DZNep and GSK-J1: Potential Link With Histone Methylation Status.

Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-β-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity.

Sleep Duration in Infants Was Not Associated With Myopia at 3 Years.

To investigate the association of sleep duration and quality at 12 months and myopia at 3 years. Cohort study. The Growing Up in Singapore Towards Healthy Outcomes (GUSTO) birth cohort recruited pregnant women at 2 major public maternity hospitals (n = 1236). We included 376 children of Chinese, Malay, and Indian ethnicity who had completed caregiver questionnaires on the child's sleep at 12 months of age [Brief Infant Sleep Questionnaire (BISQ)] and also completed cycloplegic autorefraction and eye axial length (AL) measurement at 3 years of age. Data on total sleep duration and number of night wakings were collected by BISQ. Univariable and multivariable regression models adjusting for potential confounders (age, sex, ethnicity, parental myopia, maternal education level, outdoor time, near work, and height) were used. Thirteen (3.5%) participants were myopic and mean spherical equivalent (SE) was 0.89 diopters (D) (SD 0.88) at 3 years. Total sleep duration and number of night wakings at 12 months were not associated with SE at 3 years (P > 0.05). The total sleep duration (P = 0.07) and number of night wakings (P = 0.49) were not associated with AL in the multivariate model. Total sleep duration in tertile 2 was not associated with AL (P = 0.11) compared with tertile 1. Only total sleep duration in tertile 3 was associated with longer AL (P = 0.006), but there was no association with SE. Sleep duration and quality at 12 months of age were not associated with refractive error at 3 years.

Effectiveness of Infant Massage on Strengthening Bonding and Improving Sleep Quality

Background : Baby massage is the oldest and most popular touch therapy known to mankind, which is also the art of health care and treatment that has been practiced for centuries. This study aims to determine the effect of infant massage on bonding attachments between mother and baby and the quality of infant sleep. Subjects an d Met h od: This was experimental study with Randomized Controlled Trial (RCT) design conducted in five health centers in Ponorogo Regency, East Java in March to April 2019. The total sample was 120 mothers and infants aged 3 to 6 months divided between massage groups (treatment) and not massage (control) based on The dependent variable of this study was bonding attachment and sleep quality. The independent variable in this study was infant massage. Data collection was using questionnaires and checklists. This study used the Mann-Whitney test Result : Infant massage effectively increased bonding attachment (effect size = 6.19; p <0.001), increased infant sleep duration (effect size= 2.79, p <0.001), decreases the number of baby awakened (effect size = -2.78; p <0.001), decreased duration awakened (effect size= -0.80; p= 0.001), Conclusion : Baby massage effectively increased bonding attachment and sleep duration, and effectively decreased the number of awakenings and the duration of awakening. K eywords : baby massage, bonding attachment, sleep quality Co r responden ce : Ainurrizma Tri Hartanti, Public Health Postgraduate Program, Universitas Sebelas Maret. Jl. Ir. Sutami 36 A, Surakarta 57126, Central Java. Email: ainurrizma.th@yahoo.co.id . Mobile: 085784939555 Indonesian Journal of Medicine (2019), 4(2): 165-175 https://doi.org/10.26911/theijmed.2019.04.02.10

Chronic Consumption of Fructose Induces Behavioral Alterations by Increasing Orexin and Dopamine Levels in the Rat Brain.

It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleep–wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleep–wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleep–wake cycle.

Percutaneous Nephrolithotomy with Different Temperature Irrigation and Effects on Surgical Complications and Anesthesiology Applications.

Percutaneous nephrolithotomy (PCNL) is a widely accepted and frequently performed operation for large kidney stones. However, there is not much information about the effects of irrigation fluid temperature as well as many other factors that affect success and complications during the operation. In this study, we aimed to investigate the surgical and anesthesiological effects of irrigation fluid used in body temperature and room temperature during and after PCNL. A total of 108 PCNL patients were performed between June 2016 and April 2018. The half of these patients (54) were performed with body temperature (37°C) irrigation fluid, hence known as body temperature group (BTG), and the other half with room temperature (22°C) irrigation fluid, called as room temperature group (RTG). For the study, we recorded the body temperature of the patients during and after the operation, the amount of irrigation fluid used, the size and location of the kidney stones, the duration of the operation, postoperative shivering time during the patient's wake-up period, pre- and postoperative hemoglobin value, additional blood requirements, postoperative analgesic requirements, and postoperative urinary tract infections. The age of patients, gender distribution, height, weight, body mass index, stone size, and postoperative analgesic requirement showed no significant differences in two groups. The postoperative body heat was significantly higher in the BTG than the RTG. The duration of waking was significantly higher in the RTG than the BTG. The amount of hemorrhage was significantly less in the patients who were irrigated in the RTG. The temperature of the irrigation fluid can affect many parameters in the PCNL. We recommend using irrigation in room temperature especially with patients having bleeding risks and irrigation fluid in body temperature especially with patients having anesthetic risks for easier waking process.

CBT-I and HT-I group therapy for adults with insomnia in comparison to those with insomnia and comorbid depression - a pilot study.

PurposeThe aim of this study was to examine the effectiveness of a combined cognitive-behavioral therapy for insomnia (CBT-I) and hypnotherapy for insomnia (HT-I) program for insomnia patients with or without additional depression regarding depressive symptoms and various sleep parameters.Patients and methodsA sample of 63 patients suffering from insomnia received a six-session sleep intervention, which combined cognitive-behavioral and hypnotherapeutical elements. Due to violating exclusion criteria, data of 37 patients were analyzed. Ten patients had insomnia comorbid with depression, whereas 27 patients had insomnia only. Sleep diaries were implemented to measure various sleep parameters, whereas depressive symptomatology was assessed with the anxiety and depression scale and Symptom-Checklist-90-R at baseline, before and after the intervention, as well as at 3-months follow-up.ResultsDepressive symptoms decreased from pre to post measurement and follow-up for patients with insomnia comorbid with depression, whereas scores of patients with only insomnia remained relatively on a low level. Both groups showed a significant increase of sleep efficiency and a significant decrease of the duration of wake after sleep onset. However, only patients with insomnia and depression revealed a significant reduction of sleep-onset latency and a higher level of regeneration. Nondepressive insomniacs, on the other hand, showed a significant increase of performance from post measurement to follow-up. For both groups, no change over time was found for number of wake after sleep onset, total sleep time, mood in the morning and evening.ConclusionCombining CBT-I and HT-I is effective in reducing depressive symptoms and improving sleep. Therefore, nonresponders to other forms of therapy, eg, pharmacological, interpersonal, or cognitive-behavioral therapy, might benefit from the combined CBT-I/HT-I intervention.

Last night's sleep in relation to academic achievement and neurocognitive testing performance in adolescents with and without ADHD

Objectives/backgroundObjectives were to (1) examine previous night's sleep in relation to next day performance on standardized academic achievement and neurocognitive assessments in adolescents, and (2) explore whether previous night's sleep is differentially associated with testing performance for adolescents with and without attention-deficit/hyperactivity disorder (ADHD). Participants/methodsParticipants were 300 adolescents (ages 12–14 years; 55% male). Approximately half (53.6%) were diagnosed with ADHD. Adolescents provided ratings of their previous night's sleep quality, sleep duration, and number of night wakings and were administered standardized tests of processing speed and working memory, as well as word reading, numerical operations, and math fluency academic achievement. ResultsIn analyses controlling for sex, race, medication use, time of testing, and ADHD group status, more night wakings the previous night were associated with significantly lower numerical operations and math fluency achievement scores and marginally lower working memory scores. Previous night's sleep was not associated with processing speed or reading achievement. ADHD status did not moderate sleep in relation to academic/neurocognitive performance. Participants reporting ≥2 night wakings the previous night had slightly over half a standard deviation lower scores on average compared to participants reporting 0 night wakings. ConclusionsThis preliminary study suggests that previous night's wakings are associated with poorer mathematics performance the next day, regardless of ADHD status. This may be due to the detrimental effect of interrupted and fragmented sleep on attention and executive control. These findings have implications for clinicians and educators when considering contextual factors that may impact academic and neurocognitive testing performance.

Lauflumide (NLS-4) Is a New Potent Wake-Promoting Compound

Psychostimulants are used for the treatment of excessive daytime sleepiness in a wide range of sleep disorders as well as in attention deficit hyperactivity disorder or cognitive impairment in neuropsychiatric disorders. Here, we tested in mice the wake-promoting properties of NLS-4 and its effects on the following sleep as compared with those of modafinil and vehicle. C57BL/6J mice were intraperitoneally injected with vehicle, NLS-4 (64 mg/kg), or modafinil (150 mg/kg) at light onset. EEG and EMG were recorded continuously for 24 h after injections and vigilance states as well as EEG power densities were analyzed. NLS-4 at 64 mg/kg induced significantly longer wakefulness duration than modafinil at 150 mg/kg. Although no significant sleep rebound was observed after sleep onset for both treatments as compared with their vehicles, modafinil-treated mice showed significantly more NREM sleep when compared to NLS-4. Spectral analysis of the NREM EEG after NLS-4 treatment indicated an increased power density in delta activity (0.75–3.5 Hz) and a decreased power in theta frequency range (6.25–7.25 Hz), while there was no differences after modafinil treatment. Also, time course analysis of the delta activity showed a significant increase only during the first 2 time intervals of sleep after NLS-4 treatment, while delta power was increased during the first 9 time intervals after modafinil. Our results indicate that NLS-4 is a highly potent wake-promoting drug with no sign of hypersomnia rebound. As opposed to modafinil, recovery sleep after NLS-4 treatment is characterized by less NREM amount and delta activity, suggesting a lower need for recovery despite longer drug-induced wakefulness.

The prospective relationship between postpartum PTSD and child sleep: A 2-year follow-up study

Background: The main aim of this study was to examine the prospective impact of maternal postpartum PTSD on several standardized child sleep variables two years postpartum in a large, population-based cohort of mothers. Moreover, we investigated the influence of numerous potential confounding maternal and child factors. Finally, we tested potential reverse temporal associations between child sleep eight weeks postpartum and maternal PTSD symptoms two years postpartum. Methods: This study is part of the population-based Akershus Birth Cohort, a prospective cohort study at Akershus University Hospital, Norway. Data from the hospital's birth record, from questionnaires at 17 weeks gestation, eight weeks and two years postpartum were used. At two years postpartum, 39% of the original participants could be retained, resulting in a study population of n = 1480. All child sleep variables significantly correlated with postpartum PTSD symptoms were entered into multiple linear regression analyses, adjusting for confounding factors. Results: Postpartum PTSD symptoms were related to all child sleep variables, except daytime sleep duration. When all significant confounding factors were included into multivariate regression analyses, postpartum PTSD symptoms remained a significant predictor for number and duration of night wakings (β = 0.10 and β = 0.08, respectively), duration of settling time (β = 0.10), and maternal rating of their child's sleep problems (β = 0.12, all p<.01. Child sleep at eight weeks postpartum was not significantly related to maternal sleep two years postpartum when controlling for postpartum PTSD at eight weeks. Limitations: Child outcomes were based on maternal reporting and might be influenced by maternal mental health. Conclusions: Our results showed for the first time that maternal postpartum PTSD symptoms were prospectively associated with less favorable child sleep, thus increasing the risk of developmental or behavioral problems through an indirect, but treatable pathway. Early detection and treatment of maternal postpartum PTSD may prevent or improve sleep problems and long-term child development.

The alerting effect of the wake maintenance zone during 40 hours of sleep deprivation

Under entrained conditions, the accumulation of homeostatic sleep pressure in the evening is opposed by a strong circadian arousal signal prior to the dim light melatonin onset, called the Wake Maintenance Zone (WMZ). This study aimed at investigating the impact of the WMZ on different cognitive performance tests, as well as on subjective and objective sleepiness. Twelve young male participants completed a constant routine protocol with 40 h of extended wakefulness that included two WMZs. Cognitive tests and saliva samples were assessed hourly, while the electroencephalogram (EEG) was recorded continuously. Participants improved in cognitive response inhibition during WMZ1 (13.5 h awake) and sustained attention during WMZ2 (37.5 h awake), but not in higher executive function tests. There were significant EEG power density reductions in the delta/theta frequency range during WMZ1 and in delta/theta, alpha, and sigma/beta ranges during WMZ2, with a greater change in the sigma/beta range during WMZ2 compared to WMZ1. EEG power reductions coincided during WMZ1 with stable subjective sleepiness and sustained attention. During WMZ2, EEG power reductions were more pronounced and coincided with improved sustained attention. Our results suggest the circadian arousal signal in the evening differently modulates cognitive functions and EEG power depending on the duration of prior wakefulness.

Hypoglossal nerve stimulation on sleep and level of alertness in OSA: A preliminary study.

To quantify the effect of hypoglossal nerve stimulation (HNS), a novel therapy for patients with obstructive sleep apnea, on objective level of alertness (measured with Maintenance of Wakefulness Test [MWT] values) and nocturnal sleep architecture. Ten male patients (mean age 52.0 ± 9.4 years; mean body mass index 28.8 ± 3.3 kg/m2) noncompliant to continuous positive airway pressure received HNS (Inspire therapy) and were prospectively evaluated at baseline and 6 months after HNS therapy. Polysomnographic parameters (sleep breathing and sleep architecture) and objective level of alertness (MWT) were measured. The mean preimplantation apnea-hypopnea index of 46.7/h ± 12.2/h was reduced to 14.5/h ± 8.9/h at 6 months postimplantation (p < 0.001). The mean MWT latency improved from 25.0 ± 12.8 minutes at baseline to 36.8 ± 7.0 minutes after 6 months of treatment (p = 0.004). A reduction of N1% (11.8 ± 10.6 vs 4.2 ± 1.9, p = 0.04) was observed. The reduction in the duration of wake after sleep onset (WASO) was 71.4 ± 32.4 minutes vs 53.4 ± 13.5 minutes (p = 0.06) but was not significant. MWT latencies at 6 months were negatively correlated with the intensity of stimulation (r = -0.63, p = 0.05). Intensity of stimulation was positively correlated with WASO (r = 0.76, p = 0.01). HNS improved the objective level of alertness and changed nocturnal sleep architecture. The level of neural stimulation determines the amount of nocturnal WASO and the level of objective level of alertness.

Regulation of cortical activity and arousal by the matrix cells of the ventromedial thalamic nucleus

The “non-specific” ventromedial thalamic nucleus (VM) has long been considered a candidate for mediating cortical arousal due to its diffuse, superficial projections, but direct evidence was lacking. Here, we show in mice that the activity of VM calbindin1-positive matrix cells is high in wake and REM sleep and low in NREM sleep, and increases before cortical activity at the sleep-to-wake transition. Optogenetic stimulation of VM cells rapidly awoke all mice from NREM sleep and consistently caused EEG activation during slow wave anesthesia, while arousal did not occur from REM sleep. Conversely, chemogenetic inhibition of VM decreased wake duration. Optogenetic activation of the “specific” ventral posteromedial nucleus (VPM) did not cause arousal from either NREM or REM sleep. Thus, matrix cells in VM produce arousal and broad cortical activation during NREM sleep and slow wave anesthesia in a way that accounts for the effects classically attributed to “non-specific” thalamic nuclei.

Response to chronic sleep restriction, extension, and subsequent total sleep deprivation in humans: adaptation or preserved sleep homeostasis?

Sleep is regulated by a homeostatic process which in the two-process model of human sleep regulation is represented by electroencephalogram slow-wave activity (SWA). Many studies of acute manipulation of wake duration have confirmed the precise homeostatic regulation of SWA in rodents and humans. However, some chronic sleep restriction studies in rodents show that the sleep homeostatic response, as indexed by SWA, is absent or diminishes suggesting adaptation occurs. Here, we investigate the response to 7 days of sleep restriction (6 hr time in bed) and extension (10 hr time in bed) as well as the response to subsequent total sleep deprivation in 35 healthy participants in a cross-over design. The homeostatic response was quantified by analyzing sleep structure and SWA measures. Sleep restriction resulted primarily in a reduction of rapid eye movement (REM) sleep. SWA and accumulated SWA (slow-wave energy, SWE) were not much affected by sleep extension/restriction. The SWA responses did not diminish significantly in the course of the intervention and did not deviate significantly from the predictions of the two-process model. The response to total sleep deprivation consisted of an increase in SWA and rise rate of SWA and SWE and did not differ between the two conditions. The data show that changes in sleep duration within an ecologically relevant range have a marked effect on REM sleep and that SWA responds in accordance with predictions based on a saturating exponential increase during wake and an exponential decline in sleep of homeostatic sleep pressure during both chronic sleep restriction and extension.