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STUDY OBJECTIVES: Post hoc analysis to evaluate the effect of daridorexant on sleep architecture in people with insomnia, focusing on features associated with hyperarousal. METHODS: We studied sleep architecture in adults with chronic insomnia disorder from two randomized phase 3 clinical studies (Clinicaltrials.gov: NCT03545191 and NCT03575104) investigating 3 months of daridorexant treatment (placebo, daridorexant 25 mg, daridorexant 50 mg). We analyzed sleep-wake transition probabilities, EEG spectra, and sleep spindle properties including density, dispersion, and slow oscillation phase coupling. The wake EEG similarity index (WESI) was determined using a machine learning algorithm analyzing the spectral profile of the EEG. RESULTS: At month 3, daridorexant 50 mg decreased wake-to-wake transition probabilities (p

Sleep disruption is a frequent problem of advancing age, often accompanied by low-grade chronic central and peripheral inflammation. We examined whether chronic neuroinflammation in the preoptic and basal forebrain area (POA-BF), a critical sleep-wake regulatory structure, contributes to this disruption. We developed a targeted viral vector designed to overexpress tumor necrosis factor-alpha (TNFα), specifically in astrocytes (AAV5-GFAP-TNFα-mCherry), and injected it into the POA of young mice to induce heightened neuroinflammation within the POA-BF. Compared to the control (treated with AAV5-GFAP-mCherry), mice with astrocytic TNFα overproduction within the POA-BF exhibited signs of increased microglia activation, indicating a heightened local inflammatory milieu. These mice also exhibited aging-like changes in sleep-wake organization and physical performance, including (a) impaired sleep-wake functions characterized by disruptions in sleep and waking during light and dark phases, respectively, and a reduced ability to compensate for sleep loss; (b) dysfunctional VLPO sleep-active neurons, indicated by fewer neurons expressing c-fos after suvorexant-induced sleep; and (c) compromised physical performance as demonstrated by a decline in grip strength. These findings suggest that inflammation-induced dysfunction of sleep- and wake-regulatory mechanisms within the POA-BF may be a critical component of sleep-wake disturbances in aging.

Consolidating memories for long-term storage depends on reactivation. Reactivation occurs both consciously, during wakefulness, and unconsciously, during wakefulness and sleep. While considerable work has examined conscious awake and unconscious sleep reactivation, in this study, we directly compare the consequences of conscious and unconscious reactivation during wakefulness. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., fruits, vehicles) such that we could examine consequences of reactivation on semantically related memories. After an intensive learning protocol, we systematically reactivated some of the triads by presenting the adjective as a cue. Reactivation was done so that it was consciously experienced for some triads, and only unconsciously processed for others. Memory for spatial positions, the most distal part of the association, was affected by reactivation in a consciousness-dependent and memory-strength-dependent manner. Conscious reactivation resulted in weakening of semantically related memories that were strong initially, resonating with prior findings of retrieval-induced forgetting. Unconscious reactivation, on the other hand, selectively benefited weak reactivated memories, as previously shown for reactivation during sleep. Semantically linked memories were not impaired, but rather were integrated with the reactivated memory. These results taken together demonstrate that conscious and unconscious reactivation have qualitatively different consequences. Results support a consciousness-dependent inhibition account, whereby unconscious reactivation entails less inhibition than conscious reactivation, thus allowing more liberal spread of activation. Findings set the stage for additional exploration into the role of conscious experience in memory storage and structuring.

Enhanced memory for emotional experiences is hypothesized to depend on amygdala-hippocampal interactions during memory consolidation. Here we show using intracranial recordings from the human amygdala and the hippocampus during an emotional memory encoding and discrimination task increased awake ripples after encoding of emotional, compared to neutrally-valenced stimuli. Further, post-encoding ripple-locked stimulus similarity is predictive of later memory discrimination. Ripple-locked stimulus similarity appears earlier in the amygdala than in hippocampus and mutual information analysis confirms amygdala influence on hippocampal activity. Finally, the joint ripple-locked stimulus similarity in the amygdala and hippocampus is predictive of correct memory discrimination. These findings provide electrophysiological evidence that post-encoding ripples enhance memory for emotional events.

Experimental work across species has demonstrated that spontaneously generated behaviors are robustly coupled to variations in neural activity within the cerebral cortex. Functional magnetic resonance imaging data suggest that temporal correlations in cortical networks vary across distinct behavioral states, providing for the dynamic reorganization of patterned activity. However, these data generally lack the temporal resolution to establish links between cortical signals and the continuously varying fluctuations in spontaneous behavior observed in awake animals. Here, we used wide-field mesoscopic calcium imaging to monitor cortical dynamics in awake mice and developed an approach to quantify rapidly time-varying functional connectivity. We show that spontaneous behaviors are represented by fast changes in both the magnitude and correlational structure of cortical network activity. Combining mesoscopic imaging with simultaneous cellular-resolution two-photon microscopy demonstrated that correlations among neighboring neurons and between local and large-scale networks also encode behavior. Finally, the dynamic functional connectivity of mesoscale signals revealed subnetworks not predicted by traditional anatomical atlas-based parcellation of the cortex. These results provide new insights into how behavioral information is represented across the neocortex and demonstrate an analytical framework for investigating time-varying functional connectivity in neural networks.

Summary: Although a period of sleep seems to benefit the retention of declarative memories, recent studies have challenged both the size of this effect and its active influence on memory consolidation. This study aimed to further investigate the effect of sleep and its time dependency on the consolidation of factual information. In a within‐subjects design, 48 participants (Mage = 24.37 ± 4.18 years, 31F) were asked to learn several facts in a multi‐sensory "flashcard‐like" memory task at 21:00 hours (sleep first condition) or at 09:00 hours (wake first condition). Then, in each condition, participants performed an immediate recall test (T0), and two delayed tests 12 hr (T1) and 24 hr (T2) later. Participants' sleep was recorded at their homes with a portable device. Results revealed that memory retention was better after a night of sleep compared with wakefulness, regardless of the delay from encoding (a few hr versus 12+ hr), but the sleep effect was modest. The decline in memory during the wake period following sleep was smaller compared with the decline observed during the 12 hr of wakefulness after encoding. However, after 24 hr from the encoding, when all participants experienced a period of both sleep and wakefulness, memory performance in the two conditions was similar. Overall, our data suggest that sleep exerts a small, yet beneficial, influence on memory retention by likely reducing interference and actively stabilizing memory traces. [ABSTRACT FROM AUTHOR]

Summary: During drowsiness, maintaining consistent attention becomes difficult, leading to behavioural lapses. Bursts of oscillations in the electroencephalogram (EEG) might predict such lapses, given that alpha bursts increase during inattention and theta bursts increase with time spent awake. Paradoxically, however, alpha bursts decrease with time awake and theta bursts increase during focussed attention and cognitive tasks. Therefore, we investigated to what extent theta and alpha bursts predicted performance in a sustained attention task, either when well rested (baseline, BL) or following 20 h of extended wakefulness (EW). High‐density EEG was measured in 18 young adults, and the timing of bursts was related to trial outcomes (fast, slow, and lapse trials). To increase the likelihood of lapses, the task was performed under soporific conditions. Against expectations, alpha bursts were more likely before fast trials and less likely before lapses at baseline, although the effect was substantially reduced during extended wakefulness. Theta bursts showed no significant relationship to behavioural outcome either at baseline or extended wakefulness. However, following exploratory analyses, we found that large‐amplitude theta and alpha bursts were more likely to be followed by lapse trials during extended wakefulness but not baseline. In summary, alpha bursts during baseline anticipated better trial outcomes, whereas large‐amplitude theta and alpha bursts during extended wakefulness anticipated worse outcomes. Therefore, neither theta nor alpha bursts maintain a consistent relationship with behaviour under different levels of overall vigilance. [ABSTRACT FROM AUTHOR]

Summary: The accreditation of sleep centres aims to ensure high‐quality diagnosis and management of sleep centres. European accreditation standards were introduced in 2006, and were aimed at centres offering inpatient polysomnography and vigilance tests (Mean Sleep Latency Test and Maintenance of Wakefulness Test). Since then, the practice of sleep medicine has evolved, with greater use of ambulatory polysomnography and polygraphy. As a result, in many sleep centres, actual clinical practice, although of a high standard, is no longer in accordance with the published guidelines. The current criteria have been revised with the introduction of level‐based criteria. Level 1 and 2 centres offer full diagnostic testing in a laboratory‐based setting. Level 1 practices will usually be university affiliated, and have a full teaching and active research role. Level 3 and 4 practices may offer both inpatient and ambulatory testing. Level 3 practices perform polysomnography, while level 4 practices (usually monodisciplinary and focussed on sleep apnea) perform polygraphy only. The role of the medical and paramedical team, training, appropriate equipment, patient care pathways and patient management according to national/European recommendations is underlined for accreditation at each level. It is anticipated that the guidelines will be reviewed and if necessary revised after 4 years. [ABSTRACT FROM AUTHOR]

Purpose: Intensive care patients often struggle to communicate due to the technical equipment used for mechanical ventilation and their critical illness. The aim of the study was to achieve a deeper understanding of how mechanically ventilated intensive care patients construct meaning in the unpredictable trajectory of critical illness. Methods: The study was a part of a larger study in which ten patients were video recorded while being in the intensive care. Five patients engaged in interviews about their experiences from the intensive care stay after being discharged and were offered the possibility to see themselves in the video recordings. A narrative, thematic analysis was applied to categorize the patients' experiences from the intensive care. Results: A pattern of shared experiences among intensive care patients were identified. Three main themes capture the patient's experiences: 1) perceiving the intensive care stay as a life-changing turning point, 2) being dependent on and cared for by others, and 3) living with negative and positive ICU experiences. Conclusion: The patients' narratives revealed how being critically ill affected them, and how they understood their experiences in relation to themselves and their surroundings. The results can be used to pose important questions about our current clinical practice. [ABSTRACT FROM AUTHOR]

Disorders of consciousness represent altered mental status at its most severe, comprising a continuum between coma, the vegetative state/unresponsive wakefulness syndrome, the minimally conscious state, and emergence from the minimally conscious state. Patients often transition between these levels throughout their recovery, and determining a patient's current level can be challenging, particularly in the acute care setting. Although healthcare providers have classically relied on a bedside neurological exam or the Glasgow Coma Scale to aid with assessment of consciousness, studies have identified multiple limitations of doing so. Neurobehavioral assessment measures, such as the Coma Recovery Scale-Revised, have been developed to address these shortcomings. Each behavioral metric has strengths as well as weaknesses when applied in the acute care setting. In this review, we appraise common assessment approaches, outline alternative measures for fine-tuning these assessments in the acute care setting, and highlight strategies for implementing these practices in an interdisciplinary manner. [ABSTRACT FROM AUTHOR]

Electrodermal lability is a trait-like measure of spontaneous sympathetic resting activity. In the present study, we addressed whether interindividual differences in this lability have an impact on the reaction time (RT) and on two physiological indicators of a goal-oriented sensorimotor preparation in a long-running, forewarned RT task (S1-S2 paradigm). The two indicators were the brain's contingent negative variation (CNV) and a heart rate deceleration (HRD). The interindividual differences were determined by counting spontaneous skin conductance fluctuations during a 5-min resting phase and dividing the subjects into two groups: individuals below (stable) and above (labile) the median of these fluctuations. In the task, labile individuals had a shorter RT compared with stable individuals and showed in the final phase of preparation in both physiological indicators the stronger response. Thus, lability-dependent effects in forewarned RT tasks cannot be explained by differences in stimulus-driven or passively controlled processes alone. Rather, goal-oriented, deliberately controlled processes that serve to adequately prepare for an imperative stimulus—the S2 in our paradigm—also must be considered to explain them. Labile individuals not only react faster than stable ones but also intentionally prepare themselves more appropriately for the imperative stimulus. A norepinephrine hypothesis focusing on the tonic activity of the locus coeruleus (LC) is proposed as an explanation for these and other lability-dependent effects. The frequency of spontaneous electrodermal fluctuations at rest may represent a peripheral, noninvasive, and easily measurable indicator of the baseline LC activity during wakefulness. [ABSTRACT FROM AUTHOR]

Background: Human circadian clocks are synchronized daily with the external light-dark cycle and entrained to the 24-hour day. There is increasing evidence that a lack of synchronization and circadian entrainment can lead to adverse health effects. Beyond vision, light plays a critical role in modulating many so-called non-visual functions, including sleep-wake cycles, alertness, mood and endocrine functions. To assess (and potentially optimize) the impact of light on non-visual functions, it is necessary to know the exact 'dose' (i.e. spectral irradiance and exposure duration at eye level) of 24-hour light exposures, but also to include metadata about the lighting environment, individual needs and resources. Problem statement: To address this problem, a new assessment tool is needed that uses existing metrics to provide metadata and information about light quality and quantity from all sources. In this commentary, we discuss the need to develop an evidence-based integrative lighting score that is tailored to specific audiences and lighting environments. We will summarize the most compelling evidence from the literature and outline a future plan for developing such a lighting score using internationally accepted metrics, stakeholder and user feedback. Conclusion: We propose a weighting system that combines light qualities with physiological and behavioral effects, and the use of mathematical modelling for an output score. Such a scoring system will facilitate a holistic assessment of a lighting environment, integrating all available light sources. [ABSTRACT FROM AUTHOR]

Summary In analogical problem solving, the solution to a previously experienced problem (source) is used to solve a new but structurally similar problem (target). Yet, analogical transfer is seldom successful, as structural commonalities between source and target problems can be difficult to recognise. Theoretically, memory consolidation processes during REM sleep may help to identify and strengthen connections between weakly related memories, improving the ability to use analogical transfer. In the current experiment, participants attempted to solve source problems, were told the solutions, and then attempted to solve new but structurally similar target problems. After a 2‐h break including a nap (n = 28) or wakefulness (n = 30), participants attempted to solve target problems they were unable to solve before the break. Measures of source problem memory and perceived similarity between source and target problems were also obtained. The nap group solved a greater proportion of target problems after the break than the wake group, despite no group differences in solution rates before the break or source problem memory. The nap group also perceived greater similarity between source and target problems after the break than the wake group, and the time spent in REM sleep predicted the proportion of post‐break target problems solved. These results indicate that sleep improves the ability to solve target problems that could not be initially solved and suggest that REM sleep improves the use of analogical transfer by highlighting commonalities between source and target problems that were unnoticed before a nap. [ABSTRACT FROM AUTHOR]

Summary The aim of the study was to examine associations between moderate‐to‐vigorous physical activity and sedentary time with sleep quality and quantity among preschool girls and boys using objective methods. Children (5–6 years old) attending kindergarten were recruited (n = 676). Measures included accelerometer‐derived 24‐hr activity and sleep for seven consecutive days. Longer time spent in moderate‐to‐vigorous physical activity was associated with higher sleep efficiency both in boys (p < 0.0001) and girls (p = 0447), and with lower Sleep Fragmentation Index in boys (p = 0.0042) and girls (p = 0.0494). Moreover, among boys, moderate‐to‐vigorous physical activity was inversely associated with wakefulness after sleep onset (p = 0.0006), number of awakenings (p = 0.0081) and Fragmentation Index (p = 0.0041), while in girls with sleep duration (p = 0.0405), Movement Index (p = 0.0128) and Sleep Fragmentation Index (p = 0.0494). Longer time spent sedentary was associated with lower sleep efficiency, and higher wakefulness after sleep onset, number of awakenings, Movement Index and Sleep Fragmentation Index—all with p < 0.0001. Furthermore, sedentary time was inversely associated with sleep duration both in boys (p < 0.0001) and girls (p = 0.0006), and directly associated with Fragmentation Index but only in boys (p = 0.0069). Meeting the recommended level of moderate‐to‐vigorous physical activity was associated with better sleep efficiency, lower wakefulness after sleep onset and number of awakenings among boys. All sleep‐related variables showed significant differences between quartile groups according to sedentary time (p < 0.05) in both the total group and the boys. The sedentary time had the strongest, negative effect on sleep‐related parameters in preschool children, therefore sedentary time reduction may contribute more to improving sleep quality than increasing moderate‐to‐vigorous physical activity. [ABSTRACT FROM AUTHOR]

Summary This is the first study to provide valuable insights into the effects of the Israeli Navy's 20‐h rotating watch schedule on submariners’ alertness, mood states, risk‐taking behaviours, and sleep. Specifically, we assessed the impact of the non‐circadian‐aligned schedule on cognitive performance, mood, and behavioural outcomes in a highly controlled submarine environment. A total of 20 male submariners participated in an at‐sea mission, where their cognitive performance, mood states, risk‐taking propensity, and caffeine consumption were measured. A psychomotor vigilance task (PVT) assessed alertness, the propensity for risky behaviour (Evaluation of Risks Scale) measured risk‐taking behaviours, and the Profile of Mood States evaluated mood disturbances. Actigraphy was used to monitor sleep times. Data were analysed according to seven watch schedule segments. Submariners slept a mean (standard error of the mean [SEM]) of 8.3 (0.2) h/24 h, fragmented into 3.7 (0.8) h epochs. Caffeine consumption decreased at sea (mean [SEM] 149.3 [6.0] mg) compared to land (mean [SEM] 205.5 [7.2] mg; p = 0.027). In the PVT, premature responses significantly increased during Watch VI (5:00–8:00 p.m.) and Watch VII (8:00 p.m.–12:00 a.m.; p = 0.014). In the mood subscales, tension was significantly higher during Watch II (4:00–8:00 a.m.; p = 0.002), indicating greater stress. Risk‐taking propensity significantly increased during afternoon shifts (p = 0.050). The 20‐h watch schedule led to fragmented sleep, reduced alertness in the evening, worsened mood states in the early morning, and increased risk‐taking propensity in the afternoon. These findings suggest the need for the Israeli Navy to establish evidence‐based caffeine guidelines and optimise the watch schedule to improve submariners’ sleep, performance, and overall well‐being. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fentanyl was administered at dark onset and sleep-wakefulness (S-W) was examined. • Fentanyl administration significantly increased wakefulness for the first 6 h. • This initial increase in wakefulness was followed by a rebound sleep for next 6 h. • Sulpiride was injected in the accumbal core before fentanyl and S-W was examined. • D2R blockade by sulpiride in the core attenuated the effects of fentanyl on S-W. Fentanyl, a potent analgesic and addictive substance, significantly impacts sleep-wakefulness (S-W). Acutely, it promotes wake, whereas chronic abuse leads to severe sleep disruptions, including insomnia, which contributes to opioid use disorders (OUD), a chronic brain disease characterized by compulsive opioid use and harmful consequences. Although the critical association between sleep disruptions and fentanyl addiction is acknowledged, the precise mechanisms through which fentanyl influences sleep remain elusive. Recent studies highlight the role of the dopaminergic system of the nucleus accumbens (NAc) in S-W regulation, but its specific involvement in mediating fentanyl's effects on S-W remains unexplored. We hypothesized that dopamine D2 receptors mediate fentanyl-induced effects on S-W. To test this hypothesis, male C57BL/6J mice, instrumented with sleep recording electrodes and bilateral guide cannulas above the accumbal core region (NAcC), were utilized in this study. At dark onset, animals were bilaterally administered sulpiride (D2 receptors antagonist; 250 ng/side) in the NAcC followed by an intraperitoneal injection of fentanyl (1.2 mg/Kg). S-W was examined for the next 12 h. We found that systemic administration of fentanyl significantly increased wakefulness during the first 6 h of the dark which was followed by a significant increase in NREM and REM sleep during the second 6 h of the dark period. D2-receptor blockade significantly reduced this effect as evidenced by a significant reduction in fentanyl-induced wakefulness during first 6 h of dark period and sleep rebound during the second 6 h. Our findings suggest that D2 receptors in the NAcC plays a vital role in mediating the fentanyl-induced changes in S-W. [ABSTRACT FROM AUTHOR]

Background: Cytokines, known for their pro- and anti-inflammatory roles, are also key regulators of sleep–wake cycles. Classical pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), are associated with increased sleep, particularly slow-wave sleep (SWS), while anti-inflammatory cytokines, like interleukin-10 (IL-10), generally reduce sleep duration. Given the essential role of sleep in memory consolidation, this study aimed to investigate whether interleukin-12 (IL-12), a pro-inflammatory cytokine, could increase sleep duration following a memory acquisition task and subsequently improve memory performance. Male Swiss mice were surgically implanted with electrodes for electrocorticogram (ECoG) and electromyogram (EMG) recordings to track their sleep–wake cycles. After a recovery period, baseline sleep–wake activity was recorded. The mice were then randomly assigned to two groups and treated with either IL-12 (0.5 µg, i.p.) or a phosphate-buffered saline (PBS, i.p.) control, administered immediately before the multiple-trial inhibitory avoidance (MTIA) task, a behavioral test used to assess memory performance. Following the memory acquisition session, sleep–wake activity was immediately recorded for a continuous 24-h period. Results: Mice treated with IL-12 exhibited longer latency to cross into the dark compartment during the MTIA test, indicating improved memory retention compared to the control group. Interestingly, this improved performance was associated with prolonged wakefulness, particularly in the first three hours after task acquisition. Conclusion: The study shows that IL-12 can improve memory retention through prolonged wake episodes rather than increased sleep. This finding challenges the conventional understanding that sleep is the primary state for memory consolidation, suggesting that under specific conditions, wakefulness may also play a key role in supporting memory processes. Further research is needed to explore the underlying mechanisms of IL-12's cognitive effects. [ABSTRACT FROM AUTHOR]

The perception of taking a generic, relative to brand, medication has been demonstrated to exacerbate the nocebo effect. Conversely, positive attribute framing has been shown to attenuate the nocebo effect. However, little is known about the longevity of positive attribute framing nor how it interacts with generic versus brand treatment cues. Healthy participants (N = 205) were randomised to receive either sham‐modafinil capsules with a brand or generic appearance, in conjunction with standard negative side effect framing (brand‐negative: N = 42; generic‐negative: N = 41) or positive side effect framing (brand‐positive: N = 40; generic‐positive: N = 40). The remainder were randomised to a no‐treatment control (N = 42). Participants were informed that modafinil could enhance alertness and cognitive performance and reduce fatigue. Critically, modafinil was described as having several potential side effects. Treatment‐related side effects, alertness, fatigue and cognitive performance were measured at baseline, 30‐min post‐treatment and 24 h later. Nocebo and placebo effects were observed across modafinil‐treated participants relative to control. Positive framing significantly reduced warned side effects for 24 h. Perceived side effect likelihood, severity, and worry mediated the nocebo, but not framing, effect. Results have important implications for the presentation of side effect information, providing a potential route to reduce unwanted negative effects of generic medication. [ABSTRACT FROM AUTHOR]

Trace amine-associated receptor 1 (TAAR1) is a negative regulator of dopamine (DA) release. The partial TAAR1 agonist RO5263397 promotes wakefulness and suppresses NREM and REM sleep in rodents and non-human primates. We tested the hypothesis that the TAAR1-mediated effects on sleep/wake regulation were due, in part, to DA release. Male C57BL6/J mice (n = 8) were intraperitoneally administered the D1R antagonist SCH23390, the D2R antagonist eticlopride, a combination of D1R + D2R antagonists, or saline at ZT5.5, followed 30 min later by RO5263397 or vehicle per os. EEG, EMG, subcutaneous temperature, and activity were recorded across the 8 treatments and sleep architecture was analyzed for 6 h post-dosing. As described previously, RO5263397 increased wakefulness and delayed NREM and REM sleep onset. D1, D2, and D1 + D2 pretreatment reduced RO5263397-induced wakefulness for 1–2 h after dosing but only the D1 antagonist significantly reduced the TAAR1-mediated increase in NREM latency. Neither the D1 nor the D2 antagonist affected the TAAR1-mediated suppression of REM sleep. These results suggest that, whereas the TAAR1 effects on wakefulness are mediated, in part, through the D2R, D1R activation plays a role in reversing the TAAR1-mediated increase in NREM sleep latency. In contrast, the TAAR1-mediated suppression of REM sleep appears not to involve D1R or D2R mechanisms. [ABSTRACT FROM AUTHOR]

The nucleus accumbens (NAc) plays an important role in various emotional and motivational behaviors that rely on heightened wakefulness. However, the neural mechanisms underlying the relationship between arousal and emotion regulation in NAc remain unclear. Here, we investigated the roles of a specific subset of inhibitory corticotropin-releasing hormone neurons in the NAc (NAcCRH) in regulating arousal and emotional behaviors in mice. We found an increased activity of NAcCRH neurons during wakefulness and rewarding stimulation. Activation of NAcCRH neurons converts NREM or REM sleep to wakefulness, while inhibition of these neurons attenuates wakefulness. Remarkably, activation of NAcCRH neurons induces a place preference response (PPR) and decreased basal anxiety level, whereas their inactivation induces a place aversion response and anxious state. NAcCRH neurons are identified as the major NAc projection neurons to the bed nucleus of the stria terminalis (BNST). Furthermore, activation of the NAcCRH-BNST pathway similarly induced wakefulness and positive emotional behaviors. Taken together, we identified a basal forebrain CRH pathway that promotes the arousal associated with positive affective states. [ABSTRACT FROM AUTHOR]

Entrepreneurship scholars have much to gain from including time perspective in developing theory about entrepreneurs' alertness. In this study, interviews with 22 French entrepreneurs revealed associations between their alertness and past-positive, present-hedonistic, and future time perspectives. Complementarily, a sample of 376 U.S. entrepreneurs provided evidence that their present-hedonistic and future time perspectives impacted their alertness; we found mixed support for the relationship between past-positive time perspective and entrepreneurial alertness. A replication analysis with 764 U.K. entrepreneurs corroborated support for our hypotheses. [ABSTRACT FROM AUTHOR]

Every year, many people lose their lives because of road accidents. It is evident from statistics that drowsiness is one of the main causes of a large number of car accidents. In our research, we wish to solve this major problem by measuring the drowsiness level of the human brain while driving. The study aims to develop a novel technique to detect different alertness levels (i.e., awake, moderately drowsy, and maximally drowsy) of a person while driving. A hybrid model using a stacked autoencoder and hyperbolic tangent Long Short‐Term Memory (TLSTM) network with attention mechanism is designed for this purpose. The designed model uses different biopotential signals, such as electroencephalography (EEG), facial electromyography (EMG), and different biomarkers, such as pulse rate, respiration rate galvanic skin response, and head movement to detect a person's alertness level. Here, the stacked autoencoder model is used for automated feature extraction. TLSTM is used to predict a person's alertness level using stacked autoencoder network‐extracted features. The proposed model can classify awake, moderately drowsy, and maximally drowsy states of a person with accuracies of 99%, 98.3%, and 98.6%, respectively. The novel contributions of the paper includes (i) incorporation of an attention mechanism into the TLSTM network of the proposed hybrid model to focus on the emphatic states to enhance classification accuracy, and (ii) utilization of EEG, facial EMG, pulse rate, respiration rate, galvanic skin reaction, and head movement pattern to assess a person's alertness level. [ABSTRACT FROM AUTHOR]

An essential aspect of motor learning is generalizing procedural knowledge to facilitate skill acquisition across diverse conditions. Here, we examined the development of generalized motor learning during initial practice-dependent learning, and how distinct components of learning are consolidated over longer timescales during wakefulness or sleep. In the first experiment, a group of young healthy volunteers engaged in a novel motor sequence task over 36h in a two-arm experimental design (either morning-evening-morning, or evening-morning-evening) aimed at controlling for circadian confounders. The findings unveiled an immediate, rapid generalization of sequential learning, accompanied by an additional long-timescale performance gain. Sleep modulated accuracy, but not speed, above and beyond equivalent wake intervals. To further elucidate the role of sleep across ages and under neurodegenerative disorders, a second experiment utilized the same task in a group of early-stage, drug-naïve individuals with Parkinson’s disease and in healthy individuals of comparable age. Participants with Parkinson’s disease exhibited comparable performance to their healthy age-matched group with the exception of reduced performance in recalling motor sequences, revealing a disease-related cognitive shortfall. In line with the results found in young subjects, both groups exhibited improved accuracy, but not speed, following a night of sleep. This result emphasizes the role of sleep in skill acquisition and provides a potential framework for deeper investigation of the intricate relationship between sleep, aging, Parkinson’s disease, and motor learning. [ABSTRACT FROM AUTHOR]

Background: Insomnia is more prevalent in individuals with Autism Spectrum Disorder (ASD), can worsen core-symptoms and reduces quality of life of both individuals and caregivers. Although ASD is four times more prevalent in males than females, less is known about sex specific sleep differences in autistic individuals. Recent ASD studies suggest that sleep problems may be more severe in females, which aligns with the sex bias seen in insomnia for the general population. We have previously shown that male mice with a mutation in the high confidence ASD gene Shank3, Shank3∆C, recapitulate most aspects of the ASD insomnia phenotype. The objective of the present study was to leverage the Shank3∆C model to investigate sex-specific effects in sleep using polysomnography. Methods: Adult male and female Shank3∆C and wildtype (WT) littermates were first recorded for 24 h of baseline recordings. Subsequently, they were sleep deprived (SD) for five hours via gentle handling and allowed 19 h of recovery sleep to characterize the homeostatic response to SD. Vigilance states (rapid eye movement (REM) sleep, non-rapid eye movement (NREM) sleep and wake) were assigned by manual inspection using SleepSign. Data processing, statistical analysis and visualization were conducted using MATLAB. Results: Sex and genotype effects were found during baseline sleep and after SD. At baseline, male Shank3∆C mice sleep less during the dark period (active phase) while female Shank3∆C mice sleep less during the light period (rest phase) and sleep more during the dark period. Both male and female Shank3∆C mice show reduced spectral power in NREM sleep. We detect a significant effect of sex and genotype in sleep onset latency and homeostatic sleep pressure (sleepiness). In addition, while male Shank3∆C mice fail to increase sleep time following SD as seen in WT, female Shank3∆C mice decrease sleep time. Conclusions: Overall, our study demonstrates sex differences in sleep architecture and homeostatic response to SD in adult Shank3∆C mice. Thus, our study demonstrates an interaction between sex and genotype in Shank3∆C mice and supports the use of the Shank3∆C model to better understand mechanisms contributing to the sex differences in insomnia in ASD in clinical populations. Plain language summary: Sleep problems are common in people with Autism Spectrum Disorder (ASD) and can make their condition worse, impacting both their lives and those of their caregivers. Historically ASD has been diagnosed more often in males and much less is known about the female phenotype. However, recent studies suggest that sleep problems may be more severe in autistic females. We previously shown that the ASD mouse model, Shank3∆C, display an autism like sleep phenotype. Using this model, we examine sex specific deficits in sleep. We investigated canonical measures of sleep during undisturbed conditions (sleep architecture) and after sleep deprivation (sleep homeostasis). Our findings revealed that male Shank3∆C mice slept less during their active period while female Shank3∆C mice slept less during their rest period and more during their active period. In addition, both male and female Shank3∆C mice displayed lower sleep quality. After sleep deprivation, both male and female Shank3∆C mice took longer to fall asleep despite accumulation of sleep pressure, however, differences in sleep time after sleep deprivation differed based on sex. In healthy controls, sleep time increases after sleep deprivation. Male Shank3∆C mice showed no such increase in sleep time, while female Shank3∆C mice slept even less. Our results suggest sex specific differences in two hallmark measures of sleep, architecture and sleep homeostasis in this ASD model. These results highlight the importance of awareness of sex specific differences when studying sleep in ASD as well as eventual treatment or interventions. Highlights: At baseline, Shank3∆C mice have a time-of-day dependent reduction in sleep time. Male Shank3∆C mice had reduced sleep during the active phase, while female mice had reduced sleep during the rest phase but increased sleep during the active phase. Shank3∆C mice have a reduction of EEG spectral power during non-rapid eye movement sleep, suggesting reduced sleep synchrony or quality. Both male and female Shank3∆C mice show an impaired response to sleep deprivation. While male Shank3∆C mice fail to increase sleep time after sleep deprivation, female Shank3∆C mice decrease sleep time after sleep deprivation. After sleep deprivation, both male and female Shank3∆C mutant mice have a delayed sleep onset despite accumulation of sleep pressure similar to wildtype animals. [ABSTRACT FROM AUTHOR]

The paper introduces a parametric resonance model for characterizing some features of the brain's electrical activity. This activity is assumed to be a fundamental aspect of brain functionality underpinning functions from basic sensory processing to complex cognitive operations such as memory, reasoning, and emotion. A pivotal element of the proposed parametric model is neuron synchronization which is crucial for generating detectable brain waves. The analysis of the frequency content of brain waves, categorized as delta (0÷4 Hz), theta (4÷7 Hz), alpha (8÷12 Hz), beta (13÷30 Hz), and gamma (30÷100 Hz) reveals, notably, that the mean frequency of each of these brain wave classes is, in sequence, approximately the double of that of the previous one. Based on this observation, the proposed parametric resonance model suggests a cascade of amplification effects. Following the proposed model, in the transition from wakefulness to sleep, the brain wave bands are energized at double frequency by higher frequency neighboring bands; on the contrary, in the sleep to awake transition, brain waves are energized at a half frequency by their lower frequency neighbor waves. Finally, the trend of increasing amplitude values from higher to lower frequencies lends empirical support to the parametric resonant brain model validity. [ABSTRACT FROM AUTHOR]

Anesthesia modifies sensory representations in the thalamo-cortical circuit but is considered to have a milder impact on peripheral sensory processing. Here, tracking the same neurons across wakefulness and isoflurane or ketamine medetomidine anesthesia, we show that the amplitude and sign of single neuron responses to sounds are massively modified by anesthesia in the cochlear nucleus of the brainstem, the first relay of the auditory system. The reorganization of activity is so profound that decoding of sound representation under anesthesia is not possible based on awake activity. However, population-level parameters, such as average tuning strength and population decoding accuracy, are weakly affected by anesthesia, explaining why its effect has previously gone unnoticed when comparing independently sampled neurons. Together, our results indicate that the functional organization of the auditory brainstem largely depends on the network state and is ill-defined under anesthesia. This demonstrates a remarkable sensitivity of an early sensory stage to anesthesia, which is bound to disrupt downstream processing. [ABSTRACT FROM AUTHOR]

The brain is a complex non-equilibrium system capable of expressing many different dynamics as well as the transitions between them. We hypothesized that the level of non-equilibrium can serve as a signature of a given brain state, which was quantified using the arrow of time (the level of irreversibility). Using this thermodynamic framework, the irreversibility of emergent cortical activity was quantified from local field potential recordings in male Lister-hooded rats at different anesthesia levels and during the sleep-wake cycle. This measure was carried out on five distinct brain states: slow-wave sleep, awake, deep anesthesia–slow waves, light anesthesia–slow waves, and microarousals. Low levels of irreversibility were associated with synchronous activity found both in deep anesthesia and slow-wave sleep states, suggesting that slow waves were the state closest to the thermodynamic equilibrium (maximum symmetry), thus requiring minimum energy. Higher levels of irreversibility were found when brain dynamics became more asynchronous, for example, in wakefulness. These changes were also reflected in the hierarchy of cortical dynamics across different cortical areas. The neural dynamics associated with different brain states were characterized by different degrees of irreversibility and hierarchy, also acting as markers of brain state transitions. This could open new routes to monitoring, controlling, and even changing brain states in health and disease. [ABSTRACT FROM AUTHOR]

Background: This narrative review was written by an expert panel to the members of the jury to help in the development of clinical practice guidelines on oxygen therapy. Results: According to the expert panel, acute hypoxemic respiratory failure was defined as PaO2 < 60 mm Hg or SpO2 < 90% on room air, or PaO2/FiO2 ≤ 300 mm Hg. Supplemental oxygen should be administered according to the monitoring of SpO2, with the aim at maintaining SpO2 above 92% and below 98%. Noninvasive respiratory supports are generally reserved for the most hypoxemic patients with the aim of relieving dyspnea. High-flow nasal cannula oxygen (HFNC) seems superior to conventional oxygen therapy (COT) as a means of avoiding intubation and may therefore be should probably be used as a first-line noninvasive respiratory support in patients requiring more than 6 L/min of oxygen or PaO2/FiO2 ≤ 200 mm Hg and a respiratory rate above 25 breaths/minute or clinical signs of respiratory distress, but with no benefits on mortality. Continuous positive airway pressure (CPAP) cannot currently be recommended as a first-line noninvasive respiratory support, since its beneficial effects on intubation remain uncertain. Despite older studies favoring noninvasive ventilation (NIV) over COT, recent clinical trials fail to show beneficial effects with NIV compared to HFNC. Therefore, there is no evidence to support the use of NIV or CPAP as first-line treatment if HFNC is available. Clinical trials do not support the hypothesis that noninvasive respiratory supports may lead to late intubation. The potential benefits of awake prone positioning on the risk of intubation in patients with COVID-19 cannot be extrapolated to patients with another etiology. Conclusions: Whereas oxygen supplementation should be initiated for patients with acute hypoxemic respiratory failure defined as PaO2 below 60 mm Hg or SpO2 < 90% on room air, HFNC should be the first-line noninvasive respiratory support in patients with PaO2/FiO2 ≤ 200 mm Hg with increased respiratory rate. Further studies are needed to assess the potential benefits of CPAP, NIV through a helmet and awake prone position in patients with acute hypoxemic respiratory failure not related to COVID-19. [ABSTRACT FROM AUTHOR]

Summary Wakefulness and sleep have often been treated as distinct and global brain states. However, an emerging body of evidence on the local regulation of sleep stages challenges this conventional view. Apart from unihemispheric sleep, the current data that support local variations of neural oscillations during sleep are focused on the homeostatic regulation of local sleep, i.e., the role preceding awake activity. Here, to examine local differences in brain activity during natural sleep, we recorded the electroencephalogram and the local field potential across multiple sites within the avian pallium of zebra finches without perturbing the previous awake state. We scored the sleep stages independently in each pallial site and found that the sleep stages are not pallium‐wide phenomena but rather deviate widely across electrode sites. Importantly, deeper electrode sites had a dominant role in defining the temporal aspects of sleep state congruence. Altogether, these findings show that local regulation of sleep oscillations also occurs in the avian brain without prior awake recruitment of specific pallial circuits and in the absence of mammalian cortical neural architecture. [ABSTRACT FROM AUTHOR]

The Raphe Pallidus (RPa) is a brainstem nucleus containing sympathetic premotor neurons that control thermogenesis and modulate cardiovascular function. It receives inputs from various hypothalamic areas, including the Lateral Hypothalamus (LH), a heterogeneous region intricately involved in several autonomic and behavioral functions. A key subpopulation of neurons in the LH expresses orexin/hypocretin, a neuropeptide which is crucially involved in the regulation of the wake-sleep states and feeding behavior. The RPa receives orexinergic projections from the LH and orexinergic signalling in the RPa has been shown to enhance thermogenesis in the anaesthetized rat, but only in the presence of an already existing thermogenic drive, without significantly affecting cardiovascular function. The present work was aimed at exploring the effects on thermoregulation and autonomic function and the possible role in the modulation of the wake-sleep states and feeding behavior of orexin injection in the RPa in the free-behaving rat. In order to assess the influence of an already present thermogenic drive on orexinergic signalling in the RPa, animals were studied at three different ambient temperatures (Ta, 10°C, 24°C, and 32°C). We found that orexin injection into the RPa variably affected the wake-sleep states, autonomic functions, motor activity, and feeding behavior, at the different Tas. In particular, in the first post-injection hour, we observed an increase in wakefulness, which was large at Ta 24°C and Ta 10°C and rather mild at Ta 32°C. Deep brain temperature was increased by orexin injection at Ta 10°C, but not at either Ta 24°C or Ta 32°C. Moreover, an increase in mean arterial blood pressure occurred at Ta 24°C, which was probably masked by the high baseline levels at Ta 10°C and was completely absent at Ta 32°C. Finally, an enhancement in feeding behavior was observed at Ta 24°C and 10°C only. In accordance with what observed in anaesthetized rats, orexinergic signalling in the RPa seems to be ineffective in the absence of any thermogenic drive. Moreover, the effects observed on the wake-sleep states and feeding behavior introduce the RPa as a novel player in the central neural network promoting wakefulness and feeding. [ABSTRACT FROM AUTHOR]

Objective: This study aims to present a case of persistent mycetoma caused by Scedosporium boydii and undertake a systematic literature overview to elucidate the clinical characteristics and antifungal treatment exhibited by such patients. Methods: We report the case of a 24-year-old female who sustained a Scedosporium boydii infection in her right foot over a decade ago following a nail puncture. Concurrently, a comprehensive literature overview was conducted on PubMed, focusing on documented cases of Scedosporium boydii infections with the intent of extracting relevant clinical data. Results: Our analysis revealed that post-transplantation, trauma, near drowning, corticosteroid administration, and prior surgical history were the main risk factors for Scedosporium boydii infection. Prevalent infection sites included skin/bone tissues, the central nervous system, and ocular regions. Among the 49 patients identified, 24 received itraconazole therapy and 25 received voriconazole, with no significant difference in patient outcomes (P = 0.158). Of these, 12 patients experienced treatment failure. Notably, prolonged antifungal treatment duration was identified as a protective factor against mortality in Scedosporium boydii infections [P = 0.022, OR(95%CI): 0.972(0.949–0.996)]. Conversely, a history of post-transplantation emerged as a potential risk factor for mortality[P = 0.046, OR(95%CI): 7.017(1.034–47.636)]. Conclusion: While uncommon, Scedosporium boydii infections carry a significant burden of morbidity and adverse outcomes. Heightened clinical vigilance is warranted in individuals presenting with risk factors for this pathogen. Timely and effective antifungal intervention is crucial, with both voriconazole and itraconazole demonstrating positive treatment outcomes for Scedosporium boydii infection. Therefore, prioritizing these antifungal agents should be considered a key therapeutic strategy in the management of this patient population. [ABSTRACT FROM AUTHOR]

Negligence of public transport drivers due to drowsiness poses risks not only to their own lives but also to the lives of passengers. The designed journey tracker system alerts the drivers and activates potential penalties. A custom EfficientNet model architecture, based on EfficientNet design principles, is built and trained using the Media Research Lab (MRL) eye dataset. Reflections in frames are filtered out to ensure accurate detections. A 10 min initial period is utilized to understand the driver's baseline behavior, enhancing the reliability of drowsiness detections. Input from drivers is considered to determine the frame rate for more precise real-time monitoring. Only the eye regions of individual drivers are captured to maintain privacy and ethical standards, fostering driver comfort. Hyperparameter tuning and testing of different activation functions during model training aim to strike a balance between model complexity, performance and computational cost. Obtained an accuracy rate of 95% and results demonstrate that the "swish" activation function outperforms ReLU, sigmoid and tanh activation functions in extracting hierarchical features. Additionally, models trained from scratch exhibit superior performance compared to pretrained models. This system promotes safer public transportation and enhances professionalism by monitoring driver alertness. The system detects closed eyes and performs a cross-reference using personalization data and pupil detection to trigger appropriate alerts and impose penalties. [ABSTRACT FROM AUTHOR]

Background/Objectives: A well-established association exists between the development of hypertension and sleep quality. The connection between self-reported sleep quality and the onset of hypertension is particularly significant in populations with metabolic deterioration, such as in Mexico. Methods: The Tlalpan 2020 Cohort was analyzed to explore this association. Clinical and anthropometric characteristics, along with the Medical Outcomes Study Sleep Scale (MOS-SS), were compared between participants who developed hypertension and those who did not over a follow-up period of 30.8 months. The potential role of poor sleep quality in the development of hypertension was assessed. Results: Among 1520 participants, 12% developed hypertension. These individuals had higher anthropometric and laboratory values and reported poorer sleep quality. An elevated sleep problems index was associated with a 50% higher relative risk of developing hypertension (OR: 1.5; 95% CI: 1.087 to 2.069). Additionally, self-reported snoring was associated with hypertension onset (36.3 vs. 43.3; p = 0.019). Conclusions: Poor sleep quality and respiratory disturbances during sleep increase the risk of developing hypertension. Furthermore, hypertension was associated with snoring, highlighting the importance of early interventions to improve sleep quality. [ABSTRACT FROM AUTHOR]

Consciousness, defined as being aware of and responsive to one's surroundings, is characteristic of normal waking life and typically is lost during sleep and general anaesthesia. The traditional view of consciousness as a global brain state has evolved toward a more sophisticated interplay between global and local states, with the presence of local sleep in the awake brain and local wakefulness in the sleeping brain. However, this interplay is not clear for general anaesthesia, where loss of consciousness was recently suggested to be associated with a global state of brain‐wide synchrony that selectively involves layer 5 cortical pyramidal neurons across sensory, motor and associative areas. According to this global view, local wakefulness of layer 5 cortex should be incompatible with deep anaesthesia, a hypothesis that deserves to be scrutinised with causal manipulations. Here, we show that unilateral chemogenetic activation of layer 5 pyramidal neurons in the sensorimotor cortex of isoflurane‐anaesthetised mice induces a local state transition from slow‐wave activity to tonic firing in the transfected hemisphere. This wakefulness‐like activity dramatically disrupts layer 5 interhemispheric synchrony with mirror‐image locations in the contralateral hemisphere, but does not reduce the level of unconsciousness under deep anaesthesia, nor in the transitions to/from anaesthesia. Global layer 5 synchrony may thus be a sufficient condition for anaesthesia‐induced unconsciousness, but is not a necessary one, at least under isoflurane anaesthesia. Local wakefulness‐like activity of layer 5 cortex can be induced and maintained under deep anaesthesia, encouraging further investigation into the local vs. global aspects of anaesthesia‐induced unconsciousness. Key points: The neural correlates of consciousness have evolved from global brain states to a nuanced interplay between global and local states, evident in terms of local sleep in awake brains and local wakefulness in sleeping brains.The concept of local wakefulness remains unclear for general anaesthesia, where the loss of consciousness has been recently suggested to involve brain‐wide synchrony of layer 5 cortical neurons.We found that local wakefulness‐like activity of layer 5 cortical can be chemogenetically induced in anaesthetised mice without affecting the depth of anaesthesia or the transitions to and from unconsciousness.Global layer 5 synchrony may thus be a sufficient but not necessary feature for the unconsciousness induced by general anaesthesia.Local wakefulness‐like activity of layer 5 neurons is compatible with general anaesthesia, thus promoting further investigation into the local vs. global aspects of anaesthesia‐induced unconsciousness. [ABSTRACT FROM AUTHOR]

High‐frequency oscillatory activity in cognition‐related neural circuits during wakefulness consistently induces the growth of dendritic spines and axonal terminals. Although these structural changes are essential for cognitive functions, it is hypothesized that if these newly expanded structures fail to establish functional connections, they may become superfluous. Sleep is believed to facilitate the reduction of such redundant structures to maintain neural homeostasis. However, the mechanisms underlying this pruning process during sleep remain poorly understood. In this study, that melatonin type 3 receptors (MT3Rs) are selectively expressed in the stellate neurons of the medial entorhinal cortex (MEC) is demonstrated, an area where high melatonin levels are detected during sleep. Activation of MT3Rs during sleep initiates the shrinkage of dendritic spines in stellate neurons by downregulating neural network activity and dephosphorylating synaptic proteins in the MEC. This process is disrupted when MT3R expression is knocked down or when MT3Rs are blocked during sleep. Notably, interference with MT3Rs in the MEC during sleep impairs the acquisition of spatial memory but does not affect object memory acquisition following sleep. These findings reveal novel molecular mechanisms involving melatonin and MT3Rs in the regulation of dendritic spine shrinkage during sleep, which is crucial for the acquisition and consolidation of spatial memory. [ABSTRACT FROM AUTHOR]

Introduction: Light is a key factor in moderating human alertness, both subjective and objective. However, the methodology applies in research on the effects of exposure to light of different wavelengths and intensities on objective and subjective alertness varies greatly and evidence on objective alertness in particular is still inconclusive. Thus, the present, highly standardized within-subject laboratory study on N = 44 healthy males explored how LED light of different intensities (dim vs. bright light) and wavelengths (red vs. blue) affected objective (reaction time/RT) as well as subjective (sleepiness) alertness in the morning after wake-up. Methods: Participants spent two separate nights in the laboratory and were exposed to either one of the two light intensities or colors for 60 min after wake-up. Additionally, they indicated their sleepiness on the Karolinska Sleepiness Scale and participated in an auditory RT task before and after light intervention. It was hypothesized that both bright and blue light would lead to greater subjective and objective alertness when compared to dim and red light, respectively. Results: Results indicated that average RTs were longer for participants in the bright light condition (p = 0.004, f2 = 0.07) and that RTs decreased post-light exposure irrespective of light being dim or bright (p = 0.026, f2 = 0.07). However, dim versus bright light and RT did not interact (p = 0.758, f2 = 0.07). Chronotype was a significant covariate in the interaction of dim versus bright light and subjective sleepiness (p = 0.008, f2 = 0.22). There was no difference in RTs when comparing exposure to red or blue light (p = 0.488, f2 = 0.01). Findings on subjective sleepiness and light of different wavelengths revealed that sleepiness was reduced after light exposure (p = 0.007, f2 = 0.06), although the wavelength of light did not appear to play a role in this effect (p = 0.817, f2 = 0.06). Conclusion: Hence, neither of the hypotheses could be confirmed. However, they indicated that evening types might benefit from exposure to bright light regarding sleepiness, but not morning types. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by memory impairments and distinct histopathological features such as amyloid-beta (Aβ) accumulations. Alzheimer's patients experience sleep disturbances at early stages of the disease. APPswe/PS1dE9 (APP) mice exhibit sleep disruptions, including reductions in non-rapid eye movement (NREM) sleep, that contribute to their disease progression. In addition, astrocytic calcium transients associated with a sleep-dependent brain rhythm, slow oscillations prevalent during NREM sleep, are disrupted in APP mice. However, at present it is unclear whether restoration of circuit function by targeting astrocytic activity could improve sleep in APP mice. To that end, APP mice expressing channelrhodopsin-2 (ChR2) targeted to astrocytes underwent optogenetic stimulation at the slow oscillation frequency. Optogenetic stimulation of astrocytes significantly increased NREM sleep duration but not duration of rapid eye movement (REM) sleep. Optogenetic treatment increased delta power and reduced sleep fragmentation in APP mice. Thus, optogenetic activation of astrocytes increased sleep quantity and improved sleep quality in an AD mouse model. Astrocytic activity provides a novel therapeutic avenue to pursue for enhancing sleep and slowing AD progression. [ABSTRACT FROM AUTHOR]

Hallucinations can have rather heterogeneous aetiology and presentation. This inspired the concept of different subtypes based on symptom profiles, especially in the field of auditory hallucinations. As many people experience hallucinations in more than one sensory modality, it seems important to investigate potential hallucination subtypes across different sensory modalities. We assessed the content of hallucinations as part of a large survey among the general Dutch population (n = 10,448) using the Questionnaire for Psychotic Experiences. Based on their descriptions, thematic categories were created in a data-driven cluster analysis. 2594 participants who experienced hallucinations over the past week that contained at least 2 different thematic categories were selected. Clustering of their hallucination content was performed with the HDBSCAN method. We identified 4 clusters, i.e., subtypes, which can be typified as 1. hallucinations of foul odors, 2. complex visual scenes, 3. a vast variety of rather common hallucinations possibly related to heightened alertness, and 4. possibly bereavement hallucinations. The bereavement subtype showed an increase in emotional loneliness and the presence of delusions. Our findings suggest that the content of hallucinations can be informative, especially when investigated across sensory modalities. Such subtypes may help to better understand their underlying mechanisms. [ABSTRACT FROM AUTHOR]

Sleep, constituting approximately one‐third of the human lifespan, is a crucial physiological process essential for physical and mental well‐being. Normal sleep consists of an orderly progression through wakefulness, non‐rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep, all of which are tightly regulated. Melatonin, often referred to as the "hormone of sleep," plays a pivotal role as a regulator of the sleep/wake cycle and exerts its effects through high‐affinity G‐protein coupled receptors known as MT1 and MT2. Selective modulation of these receptors presents a promising therapeutic avenue for sleep disorders. This review examines research on the multifaceted role of melatonin in sleep regulation, focusing on selective ligands targeting MT1 and MT2 receptors, as well as studies involving MT1 and MT2 knockout mice. Contrary to common beliefs, growing evidence suggests that melatonin, through MT1 and MT2 receptors, might not only influence circadian aspects of sleep but likely, also modulate the homeostatic process of sleep and sleep architecture, or could be the molecule linking the homeostatic and circadian regulation of sleep. Furthermore, the distinct brain localization of MT1 and MT2 receptors, with MT1 receptors primarily regulating REM sleep and MT2 receptors regulating NREM sleep, is discussed. Collectively, sleep regulation extends beyond the circulating levels and circadian peak of melatonin; it also critically involves the expression, molecular activation, and regulatory functions of MT1 and MT2 receptors across various brain regions and nuclei involved in the regulation of sleep. This research underscores the importance of ongoing investigation into the selective roles of MT1 and MT2 receptors in sleep. Such research efforts are expected to pave the way for the development of targeted MT1 or MT2 receptors ligands, thereby optimizing therapeutic interventions for sleep disorders. [ABSTRACT FROM AUTHOR]

Sleep/wake cycles intricately shape physiological activities including cognitive brain functions, yet the precise molecular orchestrators of sleep remain elusive. Notably, the clinical impact of benzodiazepine drugs underscores the pivotal role of GABAergic neurotransmission in sleep regulation. However, the specific contributions of distinct GABAA receptor subtypes and their principal scaffolding protein, gephyrin, in sleep dynamics remain unclear. The evolving role of synaptic phospho‐proteome alterations at excitatory and inhibitory synapses suggests a potential avenue for modulating gephyrin and, consequently, GABAARs for sleep through on‐demand kinase recruitment. Our study unveils the distinctive roles of two prevalent GABAA receptor subtypes, α1‐ and α2‐GABAARs, in influencing sleep duration and electrical sleep activity. Notably, the absence of α1‐GABAARs emerges as central in sleep regulation, manifesting significant alterations in both non‐rapid eye movement (NREM) and rapid eye movement (REM) sleep during dark or active phases, accompanied by altered electroencephalogram (EEG) patterns across various frequencies. Gephyrin proteomics analysis reveals sleep/wake‐dependent interactions with a repertoire of known and novel kinases. Crucially, we identify the regulation of gephyrin interaction with ERK1/2, and phosphorylations at serines 268 and 270 are dictated by sleep/wake cycles. Employing AAV‐eGFP‐gephyrin or its phospho‐null variant (S268A/S270A), we disrupt sleep either globally or locally to demonstrate gephyrin phosphorylation as a sleep regulator. In summary, our findings support the local cortical sleep hypothesis and we unveil a molecular mechanism operating at GABAergic synapses, providing critical insights into the intricate regulation of sleep. [ABSTRACT FROM AUTHOR]

Background: Limited research has examined the association between moderate to vigorous physical activity (MVPA), sedentary behavior (SB), and sleep-related outcomes in cancer survivors. Therefore, this study aimed to examine these associations using a nationally representative sample of US adults. Methods: Data from the 2005–2018 National Health and Nutrition Examination Survey (NHANES) were analyzed. A total of 3229 adults with cancer histories were included. Physical activity was measured through accelerometry, and questions on daily activities, sedentary time, and sleep were collected during the household interview. Weighted multivariable analyses were conducted after accounting for the complex sampling design of the NHANES dataset. Results: After adjustments, physical activity and SB outcomes were associated with several self-reported sleep-related parameters. Increases in minutes of self-reported MVPA and SB were associated with a decreased likelihood of reporting ≥ 8 h of sleep (OR = 0.92, 95% CI = 0.86, 0.99 and OR = 0.88, 95% CI = 0.82, 0.95). Converse associations were found between device-measured MVPA and SB with the likelihood of reporting often/always feeling overly sleepy during the day (OR = 0.86, 95% CI = 0.75 and OR = 1.13, 95% CI = 1.05, respectively). However, an increased likelihood of waking up too early in the morning (OR = 1.22, 95% CI = 1.04) was observed with increases in minutes of device-measured MVPA. Conclusions: A sensible strategy to decrease the frequency of sedentary breaks and increase minutes of physical activity throughout the day may reduce sleep complaints reported in cancer survivors. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is considered one of the major causes of sleep disorders and psychological disorders in individuals. Brain asymmetry (BA) demonstrates individual hemispheric activity and psychological disorders. This study aimed to explore the characteristics of BA and psychology in OSA. Enrolment of patients for sleep assessment at the Sleep Medicine Center. Clinical characteristics, handedness, and psychological scales were prospectively collected from subjects. Subsequently, EEG power in alpha, beta, and theta bilaterally was calculated for the rest and sleep phases. A total of 152 OSA and 21 non-OSA subjects were included in the study. In the frontal, central and occipital regions, OSA exhibited increased interhemispheric asymmetry with increasing apnea-hypopnea index (AHI) during rest and sleep. Simultaneously, the results showed that greater activity in the right hemisphere was positively associated with anxiety and extraversion, while inversely with positive and lie scale. In addition, the results show that OSA contributes to abnormal BA fluctuations during sleep. Our results suggest that sleep disorders associated with apnea-hypopnea and arousal may contribute to increased BA during sleep. Such changes may persist into wakefulness with psychological traits. • The association between sleep apnea and brain asymmetry. • Pathological mechanisms involved in OSA psychological disorders. • The correlation of brain asymmetry during sleep and wakefulness. [ABSTRACT FROM AUTHOR]

Sleepiness in patients with obstructive sleep apnea (OSA) is associated with accidental and economic burden, as well as cardiovascular risk. Despite OSA treatment, 10–28 % of patients report residual sleepiness. Its determinants, as well as those of objective impaired alertness remain poorly known. In this study, we investigated factors associated with residual subjective sleepiness and objective impaired alertness in patients treated for OSA. Consecutive OSA treated patients referred for maintenance of wakefulness tests (MWT) at a tertiary university center were recruited between 2017 and 2020. Clinical data and polysomnography parameters were compared between patients with vs without subjective sleepiness (Epworth Sleepiness Scale, ESS≥11) and those with vs without impaired alertness (at least one trial with sleep onset on MWT). A multivariate logistic model was used to assess explanatory variables of MWT and ESS results. We included 141 patients, of whom 12.8 % had both subjective sleepiness and objective impaired alertness, 17.7 % objective impaired alertness only and 9.2 % subjective sleepiness only. Self-reported history of car accident/near miss, smoking history and ESS≥11 were significantly associated with objective impaired alertness whereas residual Apnea-hypopnea Index and CPAP use were not. The only significant variable associated with ESS at the time of MWT evaluation was initial ESS. Patients with objective impaired alertness only were more often smokers (52 % vs 19 %, p = 0.01), had a higher body mass index (BMI) (32 vs 29 kg/m2, p = 0.05), and showed lower initial ESS (11 vs 13, p < 0.01). More than one third of OSA treated patients referred for MWT have objective impaired alertness and/or subjective sleepiness. Our findings highlight the need for a comprehensive medical assessment including accident history, subjective sleepiness and comorbidities. Particular attention should be paid to smoking patients with high BMI, who are at risk of impaired alertness with no report of subjective sleepiness. • Up to 40 % of treated OSA patients have residual sleepiness and/or impaired alertness. • Maintenance Wakefulness Test and Epworth sleepiness scale results discrepant in 25 % of treated OSA patients. • Self-reported history of car accident, smoking and ESS≥11 are associated with impaired alertness. • Smoking and high BMI are at risk of impaired alertness without report of sleepiness. [ABSTRACT FROM AUTHOR]

Pre-sleep stress or hyperarousal is a known key etiological component in insomnia disorder. Despite this, physiological alterations during the sleep onset are not well-understood. In particular, insomnia and obstructive sleep apnea (OSA) are highly prevalent co-morbid conditions, where autonomic regulation may be altered. We aimed to characterize heart rate variability (HRV) during sleep onset as a potential measure of pre-sleep hyperarousal. We described the profile of pre-sleep HRV measures and explore autonomic differences in participants with self-reported insomnia disorder (with no OSA, n = 69; with mild OSA, n = 70; with moderate or severe OSA, n = 66), compared to normal sleep controls (n = 123). Heart rate data during the sleep onset process were extracted for HRV analyses. During the sleep onset process, compared to normal sleep controls, participants with insomnia had altered HRV, indicated by higher heart rate (p = 0.004), lower SDNN (p = 0.003), reduced pNN20 (p < 0.001) and pNN50 (p = 0.010) and lower powers (p < 0.001). Participants with insomnia and moderate/severe OSA may have further deteriorated HRV outcomes compared to no/mild OSA patients with insomnia but differences were not significant. Insomnia itself was associated with significantly higher heart rate, lower pNN20, and lower high frequency power even after adjustment for age, gender, BMI and OSA severity. Participants with insomnia had lower vagal activity during the sleep onset period, which may be compounded by OSA, reflected in higher heart rates and lower HRV. These altered heart rate dynamics may serve as a physiological biomarker for insomnia during bedtime wakefulness, or as a potential tool to evaluate the efficacy of behavioral interventions which target bedtime stress. • Altered heart rate dynamics may present in subjects with insomnia even before sleep. • HRV may be a biomarker of hyper-arousal during wakefulness before sleep onset. • Tracking HRV during sleep onset may have value in evaluation/treatments for insomnia. • Bedtime HRV is a target marker for sleep onset difficulty due to hyperarousal/stress. [ABSTRACT FROM AUTHOR]

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist with sedative effects on sleep homeostasis. Oxytocin-expressing (OXT) neurons in the paraventricular nucleus (PVN) of the hypothalamus (PVNOXT) regulate sexual reproduction, drinking, sleep-wakefulness, and other instinctive behaviors. To investigate the effect of DEX on the activity and signal transmission of PVNOXT in regulating the sleep-wakefulness cycle. Here, we employed OXT-cre mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in PVNOXT neurons. Combining chemogenetic methods with electroencephalogram (EEG) /electromyogram (EMG) recordings, we found that cannula injection of DEX in PVN significantly increased the duration of non-rapid eye movement (NREM) sleep in mice. Furthermore, the chemogenetic activation of PVNOXT neurons using i.p. injection of clozapine N-oxide (CNO) after cannula injection of DEX to PVN led to a substantial increase in wakefulness. Electrophysiological results showed that DEX decreased the frequency of action potential (AP) and the spontaneous excitatory postsynaptic current (sEPSC) of PVNOXT neurons through α2-adrenoceptors. Therefore, these results identify that DEX promotes sleep and maintains sleep homeostasis by inhibiting PVNOXT neurons through the α2-adrenoceptor. [ABSTRACT FROM AUTHOR]

The antecedents and determinants of entrepreneurial capabilities and competencies remain one of the incontestable questions that drive the exploitation and discovery of effective financial and digital opportunities. In the present paper, we propose a conceptual model based on Kirzner's alertness theory [entrepreneurial alertness] and rely on two factors [entrepreneurial orientation and marketing orientation] as key accelerators of entrepreneurial financial alertness. We assume that entrepreneurial financial alertness (EFA) might have a direct impact on entrepreneurial finance-based digital transformation (EFDT), which in turn, is expected to predict both innovation entrepreneurial finance (IEF) and SMEs' entrepreneurial performance (SMEEP). Structural equation modeling (SEM) was employed using data collected from a purposive sample size of 214 Jordanian entrepreneurs. Our findings largely support the impact of EFA on EFDT. EFDT was also supported having a significant impact on both IEF and SMEEP. Our study has many implications for both researchers and practitioners in the area of entrepreneurial finance-based digital transformation. The study has great added-value by proposing and examining a solid theoretical foundation covering the most influential factors that drive digital entrepreneurial transformation as such transformation stands as an emerging and pressing issue, not fully tackled by prior studies. [ABSTRACT FROM AUTHOR]

Purpose : The aim of this study was to investigate sleep parameters and architecture in patients admitted to the intensive care unit (ICU) on the day of abdominal surgery. Methods : A total of ten patients who underwent laparotomy under general anesthesia at the hepatopancreatobiliary surgery department of a general hospital in Busan, South Korea participated in this observational study. We measured total sleep time (TST), sleep efficiency (SE), wake after sleep onset (WASO), and sleep stages on their first night in the ICU using the WatchPAT300. Furthermore, we used nonparametric statistics to examine differences in postoperative sleep based on sedative administration. Results : The Median (IQR) TST for the participants was 399.50(263.80) minutes; the SE was 75.1 (30.4)%; the WASO rate was 27.8(30.6)%; and the WASO frequency was 5.50(8.50) times. Patients' rapid eye movement (REM) sleep time was 114.31(87.88) minutes, with 55.8(11.9)% of N1, 18.2(5.3)% of N2, and 24.8 (11.7)% of N3 sleep stages. The sedation group had a longer TST (Z=-2.619, p=.008), higher SE (Z=-2.611, p=.008), lower WASO rate (Z=-2.611, p=.008), smaller number of WASOs (Z=-2.627, p=.008), and longer REM sleep (Z=-2.617, p=.008) compared to the non-sedation group. Conclusion : We observed a high rate of light sleep and awakenings during sleep in patients admitted to the ICU after surgery. Moreover, non-sedated patients lacked either deep or REM sleep. Sleep-improving interventions are needed for non-sedated surgical patients who are admitted to the ICU. [ABSTRACT FROM AUTHOR]

Abstract Background Cytokines, known for their pro- and anti-inflammatory roles, are also key regulators of sleep–wake cycles. Classical pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), are associated with increased sleep, particularly slow-wave sleep (SWS), while anti-inflammatory cytokines, like interleukin-10 (IL-10), generally reduce sleep duration. Given the essential role of sleep in memory consolidation, this study aimed to investigate whether interleukin-12 (IL-12), a pro-inflammatory cytokine, could increase sleep duration following a memory acquisition task and subsequently improve memory performance. Male Swiss mice were surgically implanted with electrodes for electrocorticogram (ECoG) and electromyogram (EMG) recordings to track their sleep–wake cycles. After a recovery period, baseline sleep–wake activity was recorded. The mice were then randomly assigned to two groups and treated with either IL-12 (0.5 µg, i.p.) or a phosphate-buffered saline (PBS, i.p.) control, administered immediately before the multiple-trial inhibitory avoidance (MTIA) task, a behavioral test used to assess memory performance. Following the memory acquisition session, sleep–wake activity was immediately recorded for a continuous 24-h period. Results Mice treated with IL-12 exhibited longer latency to cross into the dark compartment during the MTIA test, indicating improved memory retention compared to the control group. Interestingly, this improved performance was associated with prolonged wakefulness, particularly in the first three hours after task acquisition. Conclusion The study shows that IL-12 can improve memory retention through prolonged wake episodes rather than increased sleep. This finding challenges the conventional understanding that sleep is the primary state for memory consolidation, suggesting that under specific conditions, wakefulness may also play a key role in supporting memory processes. Further research is needed to explore the underlying mechanisms of IL-12's cognitive effects.