Search

Histamine, a neurotransmitter, plays a predominant role in maintaining wakefulness. Further, our previous studies showed that histamine N-methyltransferase (HNMT), a histamine-metabolising enzyme, is important for regulating brain histamine concentration. However, the effects of pharmacological HNMT inhibition on mouse behaviour, including the sleep-wake cycle and cataplexy, in a mouse model of narcolepsy have not yet been investigated. In the present study, we investigated the effects of metoprine, an HNMT inhibitor with high blood-brain barrier permeability, in wild-type (WT) and orexin-deficient (OxKO) narcoleptic mice. Metoprine increased brain histamine concentration in a time- and dose-dependent manner without affecting peripheral histamine concentrations. Behavioural tests showed that metoprine increased locomotor activity in both novel and familiar environments, but did not alter anxiety-like behaviour. Sleep analysis showed that metoprine increased wakefulness and decreased non-rapid eye movement (NREM) sleep through the activation of the histamine H1 receptor (H1R) in WT mice. In contrast, the reduction of rapid eye movement (REM) sleep by metoprine occurred independent of H1R. In OxKO mice, metoprine was found to prolong wakefulness and robustly suppress cataplexy. In addition, metoprine has a greater therapeutic effect on cataplexy than pitolisant, which induces histamine release in the brain, and has been approved for patients with narcolepsy. These data demonstrate that HNMT inhibition has a strong effect on wakefulness, demonstrating therapeutic potential against cataplexy in narcolepsy., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Wearable sleep-tracking technology is of growing use in the sleep and circadian fields, including for applications across other disciplines, inclusive of a variety of disease states. Patients increasingly present sleep data derived from their wearable devices to their providers and the ever-increasing availability of commercial devices and new-generation research/clinical tools has led to the wide adoption of wearables in research, which has become even more relevant given the discontinuation of the Philips Respironics Actiwatch. Standards for evaluating the performance of wearable sleep-tracking devices have been introduced and the available evidence suggests that consumer-grade devices exceed the performance of traditional actigraphy in assessing sleep as defined by polysomnogram. However, clear limitations exist, for example, the misclassification of wakefulness during the sleep period, problems with sleep tracking outside of the main sleep bout or nighttime period, artifacts, and unclear translation of performance to individuals with certain characteristics or comorbidities. This is of particular relevance when person-specific factors (like skin color or obesity) negatively impact sensor performance with the potential downstream impact of augmenting already existing healthcare disparities. However, wearable sleep-tracking technology holds great promise for our field, given features distinct from traditional actigraphy such as measurement of autonomic parameters, estimation of circadian features, and the potential to integrate other self-reported, objective, and passively recorded health indicators. Scientists face numerous decision points and barriers when incorporating traditional actigraphy, consumer-grade multi-sensor devices, or contemporary research/clinical-grade sleep trackers into their research. Considerations include wearable device capabilities and performance, target population and goals of the study, wearable device outputs and availability of raw and aggregate data, and data extraction, processing, and analysis. Given the difficulties in the implementation and utilization of wearable sleep-tracking technology in real-world research and clinical settings, the following State of the Science review requested by the Sleep Research Society aims to address the following questions. What data can wearable sleep-tracking devices provide? How accurate are these data? What should be taken into account when incorporating wearable sleep-tracking devices into research? These outstanding questions and surrounding considerations motivated this work, outlining practical recommendations for using wearable technology in sleep and circadian research., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objectives: Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnea (OSA). Traditional polysomnographic (PSG) measures only partially explain EDS in OSA. This study analyzed traditional and novel PSG characteristics of two different measures of EDS among patients with OSA., Methods: Sleepiness was assessed using the Epworth Sleepiness Scale (>10 points defined as "risk of dozing") and a measure of general sleepiness (feeling sleepy ≥ 3 times/week defined as "feeling sleepy"). Four sleepiness phenotypes were identified: "non-sleepy," "risk of dozing only," "feeling sleepy only," and "both at risk of dozing and feeling sleepy.", Results: Altogether, 2083 patients with OSA (69% male) with an apnea-hypopnea index (AHI) ≥ 5 events/hour were studied; 46% were "non-sleepy," 26% at "risk of dozing only," 7% were "feeling sleepy only," and 21% reported both. The two phenotypes at "risk of dozing" had higher AHI, more severe hypoxemia (as measured by oxygen desaturation index, minimum and average oxygen saturation [SpO2], time spent < 90% SpO2, and hypoxic impacts) and they spent less time awake, had shorter sleep latency, and higher heart rate response to arousals than "non-sleepy" and "feeling sleepy only" phenotypes. While statistically significant, effect sizes were small. Sleep stages, frequency of arousals, wake after sleep onset and limb movement did not differ between sleepiness phenotypes after adjusting for confounders., Conclusions: In a large international group of patients with OSA, PSG characteristics were weakly associated with EDS. The physiological measures differed among individuals characterized as "risk of dozing" or "non-sleepy," while "feeling sleepy only" did not differ from "non-sleepy" individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objectives: To investigate whether neurobehavioral impairments are exacerbated during successive cycles of sleep restriction and recovery in young adults, and whether a variable short sleep schedule can mitigate these impairments relative to a stable one., Methods: Fifty-two healthy young adults (25 males, aged: 21-28) were randomly assigned to the stable short sleep group, the variable short sleep group, or the control group in this laboratory-based study. They underwent two baseline nights of 8-hour time-in-bed (TIB), followed by two cycles of "weekday" sleep opportunity manipulation and "weekend" recovery (8-hour TIB). During each manipulation period, the stable short sleep and the control groups received 6- and 8-hour TIBs each night respectively, while the variable short sleep group received 8-hour, 4-hour, 8-hour, 4-hour, and 6-hour TIBs from the first to the fifth night. Neurobehavioral functions were assessed five times each day., Results: The stable short sleep group showed faster vigilance deterioration in the second week of sleep restriction as compared to the first. This effect was not observed in the variable short sleep group. Subjective alertness and practice-based improvement in processing speed were attenuated in both short sleep groups., Conclusions: In young adults, more variable short sleep schedules incorporating days of prophylactic or recovery sleep might mitigate compounding vigilance deficits resulting from recurrent cycles of sleep restriction. However, processing speed and subjective sleepiness were still impaired in both short sleep schedules. Getting sufficient sleep consistently is the only way to ensure optimal neurobehavioral functioning., Clinical Trial: Performance, Mood, and Brain and Metabolic Functions During Different Sleep Schedules (STAVAR), https://www.clinicaltrials.gov/study/NCT04731662, NCT04731662., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neurological and neurodevelopmental conditions are a major public health concern for which new therapies are urgently needed. The development of effective therapies relies on the precise mapping of the neural substrates causally involved in behaviour generation. Direct electrical stimulation (DES) performed during cognitive and neurological monitoring in awake surgery is currently considered the gold standard for the causal mapping of brain functions. However, DES is limited by the focal nature of the stimulation sites, hampering a real holistic exploration of human brain functions at the network level. We used 4137 DES points derived from 612 glioma patients in combination with human connectome data-resting-state functional MRI, n = 1000 and diffusion weighted imaging, n = 284-to provide a multimodal description of the causal macroscale functional networks subtending 12 distinct behavioural domains. To probe the validity of our procedure, we (i) compared the network topographies of healthy and clinical populations; (ii) tested the predictive capacity of DES-derived networks; (iii) quantified the coupling between structural and functional connectivity; and (iv) built a multivariate model able to quantify single subject deviations from a normative population. Lastly, we probed the translational potential of DES-derived functional networks by testing their specificity and sensitivity in identifying critical neuromodulation targets and neural substrates associated with postoperative language deficits. The combination of DES and human connectome data resulted in an average 29.4-fold increase in whole brain coverage compared to DES alone. DES-derived functional networks are predictive of future stimulation points (97.8% accuracy) and strongly supported by the anatomical connectivity of subcortical stimulations. We did not observe any significant topographical differences between the patients and the healthy population at both group and single subject level. Showcasing concrete clinical applications, we found that DES-derived functional networks overlap with effective neuromodulation targets across several functional domains, show a high degree of specificity when tested with the intracranial stimulation points of a different stimulation technique and can be used effectively to characterize postoperative behavioural deficits. The integration of DES with the human connectome fundamentally advances the quality of the functional mapping provided by DES or functional imaging alone. DES-derived functional networks can reliably predict future stimulation points, have a strong correspondence with the underlying white matter and can be used for patient specific functional mapping. Possible applications range from psychiatry and neurology to neuropsychology, neurosurgery and neurorehabilitation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Individuals and society are dependent on transportation. Individuals move about their world for work, school, healthcare, social activities, religious and athletic events, and so much more. Society requires the movement of goods, food, medicine, etc. for basic needs, commerce, cultural and political exchanges, and all of its dynamic, complex elements. To meet these critical daily demands, the transportation system operates globally and around the clock. Regardless of their role, a basic requirement for the individuals operating the transportation system is that they are awake and at optimal alertness. This applies to individuals driving their own cars, riding a bike or motorcycle, as well as pilots of commercial aircraft, train engineers, long-haul truck drivers, and air traffic controllers. Alert operators are a basic requirement for a safe and effective transportation system. Decades of scientific and operational research have demonstrated that the 24/7 scheduling demands on operators and passengers of our transportation system create sleep and circadian disruptions that reduce alertness and performance and cause serious safety problems. These challenges underly the longstanding interest in transportation safety by the sleep and circadian scientific community. An area currently offering perhaps the most significant opportunities and challenges in transportation safety involves vehicle technology innovations. This paper provides an overview of these latest innovations with a focus on sleep-relevant issues and opportunities. Drowsy driving is discussed, along with fatigue management in round-the-clock transportation operations. Examples of cases where technology innovations could improve or complicate sleep issues are discussed, and ongoing sleep challenges and new safety opportunities are considered., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Executive functions are high-level cognitive processes involving abilities such as working memory/updating, set-shifting and inhibition. These complex cognitive functions are enabled by interactions among widely distributed cognitive networks, supported by white matter tracts. Executive impairment is frequent in neurological conditions affecting white matter; however, whether specific tracts are crucial for normal executive functions is unclear. We review causal and correlation evidence from studies that used direct electrical stimulation during awake surgery for gliomas, voxel-based and tract-based lesion-symptom mapping, and diffusion tensor imaging to explore associations between the integrity of white matter tracts and executive functions in healthy and impaired adults. The corpus callosum was consistently associated with all executive processes, notably its anterior segments. Both causal and correlation evidence showed prominent support of the superior longitudinal fasciculus to executive functions, notably to working memory. More specifically, strong evidence suggested that the second branch of the superior longitudinal fasciculus is crucial for all executive functions, especially for flexibility. Global results showed left lateralization for verbal tasks and right lateralization for executive tasks with visual demands. The frontal aslant tract potentially supports executive functions, however, additional evidence is needed to clarify whether its involvement in executive tasks goes beyond the control of language. Converging evidence indicates that a right-lateralized network of tracts connecting cortical and subcortical grey matter regions supports the performance of tasks assessing response inhibition, some suggesting a role for the right anterior thalamic radiation. Finally, correlation evidence suggests a role for the cingulum bundle in executive functions, especially in tasks assessing inhibition. We discuss these findings in light of current knowledge about the functional role of these tracts, descriptions of the brain networks supporting executive functions and clinical implications for individuals with brain tumours., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Humans continuously alternate between online attention to the current environment and offline attention to internally generated thought and imagery. This may be a fundamental feature of the waking brain, but remains poorly understood. Here, we took a data-driven approach to defining online and offline states of wakefulness, using machine learning methods applied to measures of sensory responsiveness, subjective report, electroencephalogram (EEG), and pupil diameter. We tested the effect of cognitive load on the structure and prevalence of online and offline states, hypothesizing that time spent offline would increase as cognitive load of an ongoing task decreased. We also expected that alternation between online and offline states would persist even in the absence of a cognitive task. As in prior studies, we arrived at a three-state model comprised of one online state and two offline states. As predicted, when cognitive load was high, more time was spent online. Also as predicted, the same three states were present even when participants were not performing a task. These observations confirm our method is successful at isolating seconds-long periods of offline time. Varying cognitive load may be a useful way to manipulate time spent in at least one of these offline states in future experimental studies., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motor learning involves acquiring new movement sequences and adapting motor commands to novel conditions. Labile motor memories, acquired through sequence learning and dynamic adaptation, undergo a consolidation process during wakefulness after initial training. This process stabilizes the new memories, leading to long-term memory formation. However, it remains unclear if the consolidation processes underlying sequence learning and dynamic adaptation are independent and if distinct neural regions underpin memory consolidation associated with sequence learning and dynamic adaptation. Here, we first demonstrated that the initially labile memories formed during sequence learning and dynamic adaptation were stabilized against interference through time-dependent consolidation processes occurring during wakefulness. Furthermore, we found that sequence learning memory was not disrupted when immediately followed by dynamic adaptation and vice versa, indicating distinct mechanisms for sequence learning and dynamic adaptation consolidation. Finally, by applying patterned transcranial magnetic stimulation to selectively disrupt the activity in the primary motor (M1) or sensory (S1) cortices immediately after sequence learning or dynamic adaptation, we found that sequence learning consolidation depended on M1 but not S1, while dynamic adaptation consolidation relied on S1 but not M1. For the first time in a single experimental framework, this study revealed distinct neural underpinnings for sequence learning and dynamic adaptation consolidation during wakefulness, with significant implications for motor skill enhancement and rehabilitation., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Imaging awake animals is quickly gaining traction in neuroscience as it offers a means to eliminate the confounding effects of anesthesia, difficulties of inter-species translation (when humans are typically imaged while awake), and the inability to investigate the full range of brain and behavioral states in unconscious animals. In this systematic review, we focus on the development of awake mouse blood oxygen level dependent functional magnetic resonance imaging (fMRI). Mice are widely used in research due to their fast-breeding cycle, genetic malleability, and low cost. Functional MRI yields whole-brain coverage and can be performed on both humans and animal models making it an ideal modality for comparing study findings across species. We provide an analysis of 30 articles (years 2011-2022) identified through a systematic literature search. Our conclusions include that head-posts are favorable, acclimation training for 10-14 d is likely ample under certain conditions, stress has been poorly characterized, and more standardization is needed to accelerate progress. For context, an overview of awake rat fMRI studies is also included. We make recommendations that will benefit a wide range of neuroscience applications., (© The Author(s) 2023. Published by Oxford University Press.)

Developing neurophysiological tools to predict WHO tumor grade can empower the treating teams for a better surgical decision-making process. A total of 38 patients with supratentorial diffuse gliomas underwent an asleep-awake-sedated craniotomies for tumor removal with intraoperative neuromonitoring. The resting motor threshold was calculated for different train stimulation paradigms during awake and asleep phases. Receiver operating characteristic analysis and Bayesian regression models were performed to analyze the prediction of tumor grading based on the resting motor threshold differences. Significant positive spearman correlations were observed between resting motor threshold excitability difference and WHO tumor grade for train stimulation paradigms of 5 (R = 0.54, P = 0.00063), 4 (R = 0.49, P = 0.002), 3 (R = 0.51, P = 0.001), and 2 pulses (R = 0.54, P = 0.0007). Kruskal-Wallis analysis of the median revealed a positive significant difference between the median of excitability difference and WHO tumor grade in all paradigms. Receiver operating characteristic analysis showed 3 mA difference as the best predictor of high-grade glioma across different patterns of motor pathway stimulation. Bayesian regression found that an excitability difference above 3 mA would indicate a 75.8% probability of a glioma being high grade. Our results suggest that cortical motor excitability difference between the asleep and awake phases in glioma surgery could correlate with tumor grade., (© The Author(s) 2023. Published by Oxford University Press.)

Study Objectives: This study investigated the differences in melatonin circadian timing and output, sleep characteristics, and cognitive function in myopic and non-myopic (or emmetropic) children, aged 8-15 years., Methods: Twenty-six myopes (refractive error [mean ± standard error mean] -2.06 ± 0.23 diopters) and 19 emmetropes (-0.06 ± 0.04 diopters), aged 11.74 ± 2.31 years were recruited. Circadian timing was assessed using salivary dim-light melatonin onset (DLMO), collected half-hourly for 7 hours, beginning 5 hours before and finishing 2 hours after individual average sleep onset in a sleep laboratory. Nocturnal melatonin output was assessed via aMT6s levels from urine voids collected from 05:30 pm to 8:00 am the following morning. Actigraphy-derived objective sleep timing were acquired for a week prior to the sleep laboratory visit. Cognitive assessments of sustained attention (using psychomotor vigilance task [PVT]) and working memory (using digit spans) were performed on the night of sleep laboratory., Results: Myopic children (9:07 pm ± 14 minutes) exhibited a DLMO phase-delay of 1 hour 8 minutes compared to emmetropes (7:59 pm ± 13 minutes), p = 0.002. aMT6s melatonin levels were significantly lower among myopes (18.70 ± 2.38) than emmetropes (32.35 ± 6.93, p = 0.001). Myopes also exhibited significantly delayed sleep onset, delayed wake-up time, poor and reduced sleep, and more evening-type diurnal preference than emmetropes (all p < 0.05). Finally, myopes showed a slower reaction time in the PVT (p < 0.05), but not digit span tasks at night., Conclusions: These findings suggest a potential association between circadian rhythm dysfunction and myopia in children., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objectives: Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2)., Methods: Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5 g, week 1; 6 g, weeks 2-3; 7.5 g, weeks 4-8; and 9 g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups., Results: The modified intent-to-treat population comprised 190 participants (NT1, n = 145; NT2, n = 45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, p < .001) and NT2 (6 and 9 g, p < .05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, p < .001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (p < .001), nocturnal arousals (p < .05), and ESS scores (p ≤ .001) were reported for NT1 with directional improvements for NT2., Conclusions: Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Declines in the capacity to sustain attention to repetitive, monotonous tasks is a phenomenon known as vigilance decrement (Endsley M, Kiris E. The out-of-the-loop performance problem and level of control in automation. 1995. Hum Factors. 37:32-64). This review compares cognitive theories with psycho-physiological models of vigilance decrement, and a gap is identified in mapping between the 2. That is, theories of vigilance decrement refer to "cognitive" resources; by contrast, psychophysiological models of the cerebral systems associated with attention explain performance functions according to neurochemical resources. A map does not currently exist in the literature that bridges the gap between cognitive theories of vigilance decrement and psychophysiological models of the human attention system. The link between "cognitive resource" theories of vigilance decrement and the psychophysiological models of attention performance is a gap in the literature that this review fills. This comprehensive review provides an expanded psychophysiological understanding of vigilance decrement that could help inform the management of declines in sustained attention capacity in operational settings. In addition, elucidating the link between cognitive theories of vigilance decrement and psychophysiological models of the human attention system might be used to treat and better understand pathologies such as attention-deficit hyperactivity disorder., (© The Author(s) 2023. Published by Oxford University Press.)

The prevalence of artificial light exposure has enabled us to be active any time of the day or night, leading to the need for high alertness outside of traditional daytime hours. To address this need, we developed a personalized sleep intervention framework that analyzes real-world sleep-wake patterns obtained from wearable devices to maximize alertness during specific target periods. Our framework utilizes a mathematical model that tracks the dynamic sleep pressure and circadian rhythm based on the user's sleep history. In this way, the model accurately predicts real-time alertness, even for shift workers with complex sleep and work schedules (N = 71, t = 13~21 days). This allowed us to discover a new sleep-wake pattern called the adaptive circadian split sleep, which incorporates a main sleep period and a late nap to enable high alertness during both work and non-work periods of shift workers. We further developed a mobile application that integrates this framework to recommend practical, personalized sleep schedules for individual users to maximize their alertness during a targeted activity time based on their desired sleep onset and available sleep duration. This can reduce the risk of errors for those who require high alertness during nontraditional activity times and improve the health and quality of life for those leading shift work-like lifestyles., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objectives: We examined the impact of adding a single-high-melanopic-illuminance task lamp in an otherwise low-melanopic-illuminance environment on alertness, neurobehavioral performance, learning, and mood during an 8-h simulated workday., Methods: Sixteen healthy young adults [mean(±SD) age = 24.2 ± 2.9, 8F] participated in a 3-day inpatient study with two 8-h simulated workdays and were randomized to either ambient fluorescent room light (~30 melanopic EDI lux, 50 lux), or room light supplemented with a light emitting diode task lamp (~250 melanopic EDI lux, 210 lux) in a cross-over design. Alertness, mood, and cognitive performance were assessed throughout the light exposure and compared between conditions using linear mixed models., Results: The primary outcome measure of percentage correct responses on the addition task was significantly improved relative to baseline in the supplemented condition (3.15% ± 1.18%), compared to the ambient conditions (0.93% ± 1.1%; FDR-adj q = 0.005). Additionally, reaction time and attentional failures on the psychomotor vigilance tasks were significantly improved with exposure to supplemented compared to ambient lighting (all, FDR-adj q ≤ 0.030). Furthermore, subjective measures of sleepiness, alertness, happiness, health, mood, and motivation were also significantly better in the supplemented, compared to ambient conditions (all, FDR-adj q ≤ 0.036). There was no difference in mood disturbance, affect, declarative memory, or motor learning between the conditions (all, FDR-adj q ≥ 0.308)., Conclusions: Our results show that supplementing ambient lighting with a high-melanopic-illuminance task lamp can improve daytime alertness and cognition. Therefore, high-melanopic-illuminance task lighting may be effective when incorporated into existing suboptimal lighting environments., Clinical Trials: NCT04745312. Effect of Lighting Supplementation on Daytime Cognition. https://clinicaltrials.gov/ct2/show/NCT04745312., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context modulates neocortical processing of sensory data. Unexpected visual stimuli elicit large responses in primary visual cortex (V1)-a phenomenon known as deviance detection (DD) at the neural level, or "mismatch negativity" (MMN) when measured with EEG. It remains unclear how visual DD/MMN signals emerge across cortical layers, in temporal relation to the onset of deviant stimuli, and with respect to brain oscillations. Here we employed a visual "oddball" sequence-a classic paradigm for studying aberrant DD/MMN in neuropsychiatric populations-and recorded local field potentials in V1 of awake mice with 16-channel multielectrode arrays. Multiunit activity and current source density profiles showed that although basic adaptation to redundant stimuli was present early (50 ms) in layer 4 responses, DD emerged later (150-230 ms) in supragranular layers (L2/3). This DD signal coincided with increased delta/theta (2-7 Hz) and high-gamma (70-80 Hz) oscillations in L2/3 and decreased beta oscillations (26-36 Hz) in L1. These results clarify the neocortical dynamics elicited during an oddball paradigm at a microcircuit level. They are consistent with a predictive coding framework, which posits that predictive suppression is present in cortical feed-back circuits, which synapse in L1, whereas "prediction errors" engage cortical feed-forward processing streams, which emanate from L2/3., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sodium oxybate (γ-hydroxybutyrate, GHB) is an endogenous GHB/GABAB receptor agonist, clinically used to promote slow-wave sleep and reduce next-day sleepiness in disorders such as narcolepsy and fibromyalgia. The neurobiological signature of these unique therapeutic effects remains elusive. Promising current neuropsychopharmacological approaches to understand the neural underpinnings of specific drug effects address cerebral resting-state functional connectivity (rsFC) patterns and neurometabolic alterations. Hence, we performed a placebo-controlled, double-blind, randomized, cross-over pharmacological magnetic resonance imaging study with a nocturnal administration of GHB, combined with magnetic resonance spectroscopy of GABA and glutamate in the anterior cingulate cortex (ACC). In sum, 16 healthy male volunteers received 50 mg/kg GHB p.o. or placebo at 02:30 a.m. to maximize deep sleep enhancement and multi-modal brain imaging was performed at 09:00 a.m. of the following morning. Independent component analysis of whole-brain rsFC revealed a significant increase of rsFC between the salience network (SN) and the right central executive network (rCEN) after GHB intake compared with placebo. This SN-rCEN coupling was significantly associated with changes in GABA levels in the ACC (pall < 0.05). The observed neural pattern is compatible with a functional switch to a more extrinsic brain state, which may serve as a neurobiological signature of the wake-promoting effects of GHB., (© The Author(s) 2023. Published by Oxford University Press.)

Auditory gating (AG) is an adaptive mechanism for filtering out redundant acoustic stimuli to protect the brain against information overload. AG deficits have been found in many mental illnesses, including schizophrenia (SZ). However, the neural correlates of AG remain poorly understood. Here, we found that the posterior parietal cortex (PPC) shows an intermediate level of AG in auditory thalamocortical circuits, with a laminar profile in which the strongest AG is in the granular layer. Furthermore, AG of the PPC was decreased and increased by optogenetic inactivation of the medial dorsal thalamic nucleus (MD) and auditory cortex (AC), respectively. Optogenetically activating the axons from the MD and AC drove neural activities in the PPC without an obvious AG. These results indicated that AG in the PPC is determined by the integrated signal streams from the MD and AC in a bottom-up manner. We also found that a mouse model of SZ (postnatal administration of noncompetitive N-methyl-d-aspartate receptor antagonist) presented an AG deficit in the PPC, which may be inherited from the dysfunction of MD. Together, our findings reveal a neural circuit underlying the generation of AG in the PPC and its involvement in the AG deficit of SZ., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vigilance-maintaining a prolonged state of preparation to detect and respond to specific yet unpredictable environmental changes-usually decreases across prolonged tasks, causing potentially severe real-life consequences, which could be mitigated through transcranial direct current stimulation (tDCS). The present study aimed at replicating previous mitigatory effects observed with anodal high-definition tDCS (HD-tDCS) over the right posterior parietal cortex (rPPC) while extending the analyses on electrophysiological measures associated with vigilance. In sum, 60 participants completed the ANTI-Vea task while receiving anodal (1.5 mA, n = 30) or sham (0 mA, n = 30) HD-tDCS over the rPPC for ~ 28 min. EEG recordings were completed before and after stimulation. Anodal HD-tDCS specifically mitigated executive vigilance (EV) and reduced the alpha power increment across time-on-task while increasing the gamma power increment. To further account for the observed behavioral and physiological outcomes, a new index of Alphaparietal/Gammafrontal is proposed. Interestingly, the increment of this Alphaparietal/Gammafrontal Index with time-on-task is associated with a steeper EV decrement in the sham group, which was mitigated by anodal HD-tDCS. We highlight the relevance of replicating mitigatory effects of tDCS and the need to integrate conventional and novel physiological measures to account for how anodal HD-tDCS can be used to modulate cognitive performance., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Study Objectives: To determine how mid-afternoon naps of differing durations benefit memory encoding, vigilance, speed of processing (SOP), mood, and sleepiness; to evaluate if these benefits extend past 3 hr post-awakening and to examine how sleep macrostructure during naps modulate these benefits., Methods: Following short habitual sleep, 32 young adults underwent four experimental conditions in randomized order: wake; naps of 10 min, 30 min, and 60 min duration verified with polysomnography. A 10-min test battery was delivered at a pre-nap baseline, and at 5 min, 30 min, 60 min, and 240 min post-nap. Participants encoded pictures 90 min post-nap and were tested for recognition 210 min later., Results: Naps ranging from 10 to 60 min increased positive mood and alleviated self-reported sleepiness up to 240 min post-nap. Compared to waking, only naps of 30 min improved memory encoding. Improvements in vigilance were moderate, and benefits for SOP were not observed. Sleep inertia was observed for the 30 min to 60 min naps but was resolved within 30 min after waking. We found no significant associations between sleep macrostructure and memory benefits., Conclusions: With short habitual sleep, naps ranging from 10 to 60 min had clear and lasting benefits for positive mood and self-reported sleepiness/alertness. Cognitive improvements were moderate, with only the 30 min nap showing benefits for memory encoding. While there is no clear "winning" nap duration, a 30 min nap appears to have the best trade-off between practicability and benefit., Clinical Trial Id: Effects of Varying Duration of Naps on Cognitive Performance and Memory Encoding, https://www.clinicaltrials.gov/ct2/show/NCT04984824, NCT04984824., (© Sleep Research Society 2023. Published by Oxford University Press on behalf of the Sleep Research Society.)

Cortical feedback has long been considered crucial for the modulation of sensory perception and recognition. However, previous studies have shown varying modulatory effects of the primary auditory cortex (A1) on the auditory response of subcortical neurons, which complicate interpretations regarding the function of A1 in sound perception and recognition. This has been further complicated by studies conducted under different brain states. In the current study, we used cryo-inactivation in A1 to examine the role of corticothalamic feedback on medial geniculate body (MGB) neurons in awake marmosets. The primary effects of A1 inactivation were a frequency-specific decrease in the auditory response of most MGB neurons coupled with an increased spontaneous firing rate, which together resulted in a decrease in the signal-to-noise ratio. In addition, we report for the first time that A1 robustly modulated the long-lasting sustained response of MGB neurons, which changed the frequency tuning after A1 inactivation, e.g. some neurons are sharper with corticofugal feedback and some get broader. Taken together, our results demonstrate that corticothalamic modulation in awake marmosets serves to enhance sensory processing in a manner similar to center-surround models proposed in visual and somatosensory systems, a finding which supports common principles of corticothalamic processing across sensory systems., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The present study assessed the hypothesis that electrophysiological markers of emotional and task stimulus significance can be demonstrated in concert at the level of the individual case. Participants (n = 18, 9 females) viewed low and high-arousing pictures selected from behavior systems of sexual reproduction, disease avoidance, and predator fear. Furthermore, to concurrently manipulate task relevance, participants performed an explicit emotion categorization task with either low or high-arousing pictures alternating as target stimuli in separate experimental blocks. Pooled across behavior systems, event-related components sensitive to emotional significance reached statistical significance in 100% of the tests for the early posterior negativity and in 96% of the tests for the late positive potential. Regarding explicit task relevance, the target P3 effect was significant in 96% of the tests. These findings demonstrate that neural markers of stimulus significance driven by emotional picture content and explicit task demands can be assessed at the individual level. Replicating an effect case-after-case provides strong support for an effect common-to-all and may support individual inferences. Contributions of the case-by-case approach to reveal reproducible effects and implications for the development of neural biomarkers for specific affective and cognitive component processes are discussed., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ventromedial prefrontal cortex (vmPFC) processes many critical brain functions, such as decision-making, value-coding, thinking, and emotional arousal/recognition, but whether vmPFC plays a role in sleep-wake promotion circuitry is still unclear. Here, we find that photoactivation of dorsomedial hypothalamus (DMH)-projecting vmPFC neurons, their terminals, or their postsynaptic DMH neurons rapidly switches non-rapid eye movement (NREM) but not rapid eye movement sleep to wakefulness, which is blocked by photoinhibition of DMH outputs in lateral hypothalamus (LHs). Chemoactivation of DMH glutamatergic but not GABAergic neurons innervated by vmPFC promotes wakefulness and suppresses NREM sleep, whereas chemoinhibition of vmPFC projections in DMH produces opposite effects. DMH-projecting vmPFC neurons are inhibited during NREM sleep and activated during wakefulness. Thus, vmPFC neurons innervating DMH likely represent the first identified set of cerebral cortical neurons for promotion of physiological wakefulness and suppression of NREM sleep., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signalling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naïve mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus, a key node of the hypothalamic-pituitary-adrenal stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide delivered in drinking water over 4 days, disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of paraventricular nucleus KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of paraventricular nucleus KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signalling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signalling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objectives: Several factors may contribute to the high prevalence of sleep disturbances occurring in postmenopausal women. However, the contribution of the circadian timing system to their sleep disturbances remains unclear. In the present study, we aim to understand the impact of circadian factors on changes of sleep and alertness occurring after menopause., Methods: Eight healthy postmenopausal women and 12 healthy young women in their mid-follicular phase participated in an ultradian sleep-wake cycle procedure (USW). This protocol consisted of alternating 60-min wake periods and nap opportunities for ≥ 48 h in controlled laboratory conditions. Core body temperature (CBT), salivary melatonin, self-reported alertness, and polysomnographically recorded sleep were measured across this procedure., Results: In both groups, all measures displayed a circadian variation throughout the USW procedure. Compared to young women, postmenopausal women presented lower CBT values, more stage N1 and N2 sleep, and number of arousals. They also showed a reduced amplitude of the circadian variation of melatonin, total sleep time (TST), sleep onset latency (SOL), stage N3 sleep, and alertness levels. Postmenopausal women fell asleep faster and slept more during the biological day and presented higher alertness levels during the biological night than young women., Conclusion: These results support the hypothesis of a weakened circadian signal promoting sleep and wakefulness in older women. Aging processes including hormonal changes may be main contributors to the increased sleep-wake disturbances after menopause., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Previous studies have described synchronic electroencephalographic (EEG) patterns of the background activity that is characteristic of several vigilance states., Study Objectives: To explore whether the background synchronous activity of the amygdala-hippocampal-neocortical circuit is modified during sleep in the delta, theta, alpha, sigma, beta, and gamma bands characteristic of each sleep state., Methods: By simultaneously recording intracranial and noninvasive scalp EEG (10-20 system) in epileptic patients who were candidates for neurosurgery, we explored synchronous activity among the amygdala, hippocampus, and neocortex during wakefulness (W), Non-Rapid Eye Movement (NREM), and Rapid-Eye Movement (REM) sleep., Results: Our findings reveal that hippocampal-cortical synchrony in the sleep spindle frequencies was spread across the cortex and was higher during NREM versus W and REM, whereas the amygdala showed punctual higher synchronization with the temporal lobe. Contrary to expectations, delta synchrony between the amygdala and frontal lobe and between the hippocampus and temporal lobe was higher during REM than NREM. Gamma and alpha showed higher synchrony between limbic structures and the neocortex during wakefulness versus sleep, while synchrony among deep structures showed a mixed pattern. On the one hand, amygdala-hippocampal synchrony resembled cortical activity (i.e. higher gamma and alpha synchrony in W); on the other, it showed its own pattern in slow frequency oscillations., Conclusions: This is the first study to depict diverse patterns of synchronic interaction among the frequency bands during distinct vigilance states in a broad human brain circuit with direct anatomical and functional connections that play a crucial role in emotional processes and memory., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)