Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture.

Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that lactate is the primary energy substrate for sustaining neuronal activity in multiple brain regions, its role in regulating sleep/wake architecture is not fully understood. Here we investigated the involvement of astrocytic lactate supply in maintaining consolidated wakefulness by downregulating, in a cell-specific manner, the expression of monocarboxylate transporters (MCTs) in the lateral hypothalamus of transgenic mice. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to wake-promoting orexin neurons, impairing wakefulness stability. Additionally, we show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexin neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability.

Memory's gatekeeper: The role of PFC in the encoding of congruent events.

Theoretical models conventionally portray the consolidation of memories as a slow process that unfolds during sleep. According to the classical Complementary Learning Systems theory, the hippocampus (HPC) rapidly changes its connectivity during wakefulness to encode ongoing events and create memory ensembles that are later transferred to the prefrontal cortex (PFC) during sleep. However, recent experimental studies challenge this notion by showing that new information consistent with prior knowledge can be rapidly consolidated in PFC during wakefulness and that PFC lesions disrupt the encoding of congruent events in the HPC. The contributions of the PFC to memory encoding have therefore largely been overlooked. Moreover, most theoretical frameworks assume random and uncorrelated patterns representing memories, disregarding the correlations between our experiences. To address these shortcomings, we developed a HPC-PFC network model that simulates interactions between the HPC and PFC during the encoding of a memory (awake stage), and subsequent consolidation (sleeping stage) to examine the contributions of each region to the consolidation of novel and congruent memories. Our results show that the PFC network uses stored memory "schemas" consolidated during previous experiences to identify inputs that evoke congruent patterns of activity, quickly integrate it into its network, and gate which components are encoded in the HPC. More specifically, the PFC uses GABAergic long-range projections to inhibit HPC neurons representing input components correlated with a previously stored memory "schema," eliciting sparse hippocampal activity during exposure to congruent events, as it has been experimentally observed.

Restoration of sleep-wake behavior following short photoperiod exposure in ventral subicular lesioned male Wistar rats: A 24-h sleep-wake electroencephalographical study.

The ventral subiculum regulates emotion, stress responses, and spatial and social cognition. In our previous studies, we have demonstrated anxiety- and depression-like symptoms, deficits in spatial and social cognition in ventral subicular lesioned (VSL) rats, and restoration of affective and cognitive behaviors following photoperiod manipulation (short photoperiod regime, SPR; 6:18 LD cycle). In the present study, we have studied the impact of VSL on sleep-wake behavioral patterns and the effect of SPR on sleep-wakefulness behavior. Adult male Wistar rats subjected to VSL demonstrated decreased wake duration and enhanced total sleep time due to increased non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). Power spectral analysis indicated increased delta activity during NREMS and decreased sigma band power during all vigilance states. Light is one of the strongest entrainers of the circadian rhythm, and its manipulation may have various physiological and functional consequences. We investigated the effect of 21-day exposure to SPR on sleep-wakefulness (S-W) behavior in VSL rats. We observed that SPR exposure restored S-W behavior in VSL rats, resulting in an increase in wake duration and a significant increase in theta power during wake and REMS. This study highlights the crucial role of the ventral subiculum in maintaining normal sleep-wakefulness patterns and highlights the effectiveness of photoperiod manipulation as a non-pharmacological treatment for reversing sleep disturbances reported in mood and neuropsychiatric disorders like Alzheimer's disease, bipolar disorder, and major depressive disorder, which also involve alterations in circadian rhythm.

Effects of an OX2R agonist on migration and removal of tau from mouse brain.

Pathological proteins including tau are produced in neurons and released into interstitial fluid (ISF) in a neural activity-dependent manner during wakefulness. Pathological proteins in ISF can be removed from the brain via the glymphatic pathway during nighttime. Thus, in individuals with Alzheimer's disease (AD) that have dysregulated sleep/wake rhythm, application of orexin receptor 2 (OX2R) agonists during daytime could recover the efflux of pathological proteins to ISF and indirectly promote the glymphatic pathway by improving the quality of nighttime sleep after proper daytime arousal, resulting in increased removal of these proteins from the brain. We investigated this hypothesis using OX-201, a novel OX2R-selective agonist with a 50% effective concentration of 8.0 nM. Diurnal rhythm of tau release into hippocampal ISF correlated well with neuronal activity and wakefulness in wild-type mice. In both wild-type and human P301S tau transgenic mice, OX-201 induced wakefulness and promoted tau release into hippocampal ISF. Human P301S tau transgenic mice, tested under our conditions, showed longer wakefulness time, which differs from individuals with AD. OX-201 treatment over 2 months did not alter hippocampal tau levels. Although further studies are required, at a minimum OX2R agonists may not exacerbate tau accumulation in individuals with tauopathy, including AD.

Derivative Method to Detect Sleep and Awake States through Heart Rate Variability Analysis Using Machine Learning Algorithms.

Sleep disorders can have harmful consequences in both the short and long term. They can lead to attention deficits, as well as cardiac, neurological and behavioral repercussions. One of the most widely used methods for assessing sleep disorders is polysomnography (PSG). A major challenge associated with this method is all the cables needed to connect the recording devices, making the examination more intrusive and usually requiring a clinical environment. This can have potential consequences on the test results and their accuracy. One simple way to assess the state of the central nervous system (CNS), a well-known indicator of sleep disorder, could be the use of a portable medical device. With this in mind, we implemented a simple model using both the RR interval (RRI) and its second derivative to accurately predict the awake and napping states of a subject using a feature classification model. For training and validation, we used a database providing measurements from nine healthy young adults (six men and three women), in which heart rate variability (HRV) associated with light-on, light-off, sleep onset and sleep offset events. Results show that using a 30 min RRI time series window suffices for this lightweight model to accurately predict whether the patient was awake or napping.

Sleep-wake changes and incident depressive symptoms in midlife women.

Our study aimed to investigate the relationship between sleep-wake changes and depressive symptoms events among midlife women. We enrolled 1579 women aged 44-56 years who had no clinically relevant depressive symptoms at baseline. Depressive symptoms were assessed at each visit using the Center for Epidemiologic Studies Depression scale. At the third and fourth follow-up visits, women reported their sleep habits. The sleep midpoint was defined as the time to fall asleep plus one-half of the sleep duration. Sleep-wake changes were determined by the difference in the midpoint of sleep between the third and fourth visits, which were 1 year apart. The median follow-up time was 7 years (range 1-7 years). Cox proportional hazard models were fitted to calculate hazard ratios and 95% confidence intervals for the incidence of depressive symptoms associated with sleep-wake changes. After adjusting for potential confounding factors, the hazard ratio (95% confidence interval) of depressive symptoms for severe sleep midpoint changes was 1.51 (1.12, 2.05) compared with mild sleep midpoint changes. This relationship remained statistically significant and changed little when additionally controlling for sleep duration, sleep quality, insomnia symptoms, use of sleep medications, use of nervous medications, glucose, insulin, lipids, dietary energy intake, and C-reactive protein. Our findings indicate that exposure to long-term severe sleep-wake changes increases the risk of depressive symptoms in midlife women.

EEG-fMRI in awake rat and whole-brain simulations show decreased brain responsiveness to sensory stimulations during absence seizures.

In patients suffering absence epilepsy, recurring seizures can significantly decrease their quality of life and lead to yet untreatable comorbidities. Absence seizures are characterized by spike-and-wave discharges on the electroencephalogram associated with a transient alteration of consciousness. However, it is still unknown how the brain responds to external stimuli during and outside of seizures. This study aimed to investigate responsiveness to visual and somatosensory stimulation in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established rat model for absence epilepsy. Animals were imaged under non-curarized awake state using a quiet, zero echo time, functional magnetic resonance imaging (fMRI) sequence. Sensory stimulations were applied during interictal and ictal periods. Whole-brain hemodynamic responses were compared between these two states. Additionally, a mean-field simulation model was used to explain the changes of neural responsiveness to visual stimulation between states. During a seizure, whole-brain responses to both sensory stimulations were suppressed and spatially hindered. In the cortex, hemodynamic responses were negatively polarized during seizures, despite the application of a stimulus. The mean-field simulation revealed restricted propagation of activity due to stimulation and agreed well with fMRI findings. Results suggest that sensory processing is hindered or even suppressed by the occurrence of an absence seizure, potentially contributing to decreased responsiveness during this absence epileptic process.

Cortical parvalbumin neurons are responsible for homeostatic sleep rebound through CaMKII activation.

The homeostatic regulation of sleep is characterized by rebound sleep after prolonged wakefulness, but the molecular and cellular mechanisms underlying this regulation are still unknown. In this study, we show that Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent activity control of parvalbumin (PV)-expressing cortical neurons is involved in homeostatic regulation of sleep in male mice. Prolonged wakefulness enhances cortical PV-neuron activity. Chemogenetic suppression or activation of cortical PV neurons inhibits or induces rebound sleep, implying that rebound sleep is dependent on increased activity of cortical PV neurons. Furthermore, we discovered that CaMKII kinase activity boosts the activity of cortical PV neurons, and that kinase activity is important for homeostatic sleep rebound. Here, we propose that CaMKII-dependent PV-neuron activity represents negative feedback inhibition of cortical neural excitability, which serves as the distributive cortical circuits for sleep homeostatic regulation.

Awake fiberoptic intubation of a patient with severe multiple trauma in prone position: a case report.

BACKGROUND: Fiberoptic-guided intubation is considered as "gold standard" of difficult airway management. Management of the airway in prone position in patients with severe trauma presenting with penetrating waist and hip injury poses a major challenge to the anesthesiologist. CASE PRESENTATION: A man presented with severe multiple trauma and hemorrhagic shock as a result of an industrial accident with several deformed steel bars penetrating the left lower waist and hip. It was decided to schedule an exploratory laparotomy following extracting the deformed steel bars. Successful administration of awake fiberoptic nasotracheal intubation, performed in a prone position under airway blocks and appropriate sedation, allowed for the procedure. The exploratory laparotomy revealed damage to multiple organs, which were repaired sequentially during a 7-hour surgical operation. The patient's recovery was uneventful, and he was discharged from the hospital one month after the surgery. CONCLUSIONS: Awake fiberoptic nasotracheal intubation, along with airway blocks and appropriate sedation, can be a viable option in patients with severe multiple trauma in the prone position.

Model integration of circadian- and sleep-wake-driven contributions to rhythmic gene expression reveals distinct regulatory principles.

Analyses of gene-expression dynamics in research on circadian rhythms and sleep homeostasis often describe these two processes using separate models. Rhythmically expressed genes are, however, likely to be influenced by both processes. We implemented a driven, damped harmonic oscillator model to estimate the contribution of circadian- and sleep-wake-driven influences on gene expression. The model reliably captured a wide range of dynamics in cortex, liver, and blood transcriptomes taken from mice and humans under various experimental conditions. Sleep-wake-driven factors outweighed circadian factors in driving gene expression in the cortex, whereas the opposite was observed in the liver and blood. Because of tissue- and gene-specific responses, sleep deprivation led to a long-lasting intra- and inter-tissue desynchronization. The model showed that recovery sleep contributed to these long-lasting changes. The results demonstrate that the analyses of the daily rhythms in gene expression must take the complex interactions between circadian and sleep-wake influences into account. A record of this paper's transparent peer review process is included in the supplemental information.

Functional changes in sleep-related arousal after ketamine administration in individuals with treatment-resistant depression.

The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine's effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine's temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine's antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.

Automatic Sleep Stage Classification Using Nasal Pressure Decoding Based on a Multi-Kernel Convolutional BiLSTM Network.

Sleep quality is an essential parameter of a healthy human life, while sleep disorders such as sleep apnea are abundant. In the investigation of sleep and its malfunction, the gold-standard is polysomnography, which utilizes an extensive range of variables for sleep stage classification. However, undergoing full polysomnography, which requires many sensors that are directly connected to the heaviness of the setup and the discomfort of sleep, brings a significant burden. In this study, sleep stage classification was performed using the single dimension of nasal pressure, dramatically decreasing the complexity of the process. In turn, such improvements could increase the much needed clinical applicability. Specifically, we propose a deep learning structure consisting of multi-kernel convolutional neural networks and bidirectional long short-term memory for sleep stage classification. Sleep stages of 25 healthy subjects were classified into 3-class (wake, rapid eye movement (REM), and non-REM) and 4-class (wake, REM, light, and deep sleep) based on nasal pressure. Following a leave-one-subject-out cross-validation, in the 3-class the accuracy was 0.704, the F1-score was 0.490, and the kappa value was 0.283 for the overall metrics. In the 4-class, the accuracy was 0.604, the F1-score was 0.349, and the kappa value was 0.217 for the overall metrics. This was higher than the four comparative models, including the class-wise F1-score. This result demonstrates the possibility of a sleep stage classification model only using easily applicable and highly practical nasal pressure recordings. This is also likely to be used with interventions that could help treat sleep-related diseases.

Awake craniotomy with English and British sign language mapping in a patient with a left temporal glioblastoma reveals discordant speech-sign language maps.

The aim of this case study was to describe differences in English and British Sign Language (BSL) communication caused by a left temporal tumour resulting in discordant presentation of symptoms, intraoperative stimulation mapping during awake craniotomy and post-operative language abilities. We report the first case of a hearing child of deaf adults, who acquired BSL with English as a second language. The patient presented with English word finding difficulty, phonemic paraphasias, and reading and writing challenges, with BSL preserved. Intraoperatively, object naming and semantic fluency tasks were performed in English and BSL, revealing differential language maps for each modality. Post-operative assessment confirmed mild dysphasia for English with BSL preserved. These findings suggest that in hearing people who acquire a signed language as a first language, topographical organisation may differ to that of a second, spoken, language.

Anesthetized animal experiments for neuroscience research.

Brain research has progressed with anesthetized animal experiments for a long time. Recent progress in research techniques allows us to measure neuronal activity in awake animals combined with behavioral tasks. The trends became more prominent in the last decade. This new research style triggers the paradigm shift in the research of brain science, and new insights into brain function have been revealed. It is reasonable to consider that awake animal experiments are more ideal for understanding naturalistic brain function than anesthetized ones. However, the anesthetized animal experiment still has advantages in some experiments. To take advantage of the anesthetized animal experiments, it is important to understand the mechanism of anesthesia and carefully handle the obtained data. In this minireview, we will shortly summarize the molecular mechanism of anesthesia in animal experiments, a recent understanding of the neuronal activities in a sensory system in the anesthetized animal brain, and consider the advantages and disadvantages of the anesthetized and awake animal experiments. This discussion will help us to use both research conditions in the proper manner.

Claustrum neurons projecting to the anterior cingulate restrict engagement during sleep and behavior.

The claustrum has been linked to attention and sleep. We hypothesized that this reflects a shared function, determining responsiveness to stimuli, which spans the axis of engagement. To test this hypothesis, we recorded claustrum population dynamics from male mice during both sleep and an attentional task ('ENGAGE'). Heightened activity in claustrum neurons projecting to the anterior cingulate cortex (ACCp) corresponded to reduced sensory responsiveness during sleep. Similarly, in the ENGAGE task, heightened ACCp activity correlated with disengagement and behavioral lapses, while low ACCp activity correlated with hyper-engagement and impulsive errors. Chemogenetic elevation of ACCp activity reduced both awakenings during sleep and impulsive errors in the ENGAGE task. Furthermore, mice employing an exploration strategy in the task showed a stronger correlation between ACCp activity and performance compared to mice employing an exploitation strategy which reduced task complexity. Our results implicate ACCp claustrum neurons in restricting engagement during sleep and goal-directed behavior.

The influence of wakefulness fluctuations on brain networks involved in centrotemporal spike occurrence.

OBJECTIVE: Drowsiness has been implicated in the modulation of centro-temporal spikes (CTS) in Self-limited epilepsy with Centro-Temporal Spikes (SeLECTS). Here, we explore this relationship and whether fluctuations in wakefulness influence the brain networks involved in CTS generation. METHODS: Functional MRI (fMRI) and electroencephalography (EEG) was simultaneously acquired in 25 SeLECTS. A multispectral EEG index quantified drowsiness ('EWI': EEG Wakefulness Index). EEG (Pearson Correlation, Cross Correlation, Trend Estimation, Granger Causality) and fMRI (PPI: psychophysiological interactions) analytic approaches were adopted to explore respectively: (a) the relationship between EWI and changes in CTS frequency and (b) the functional connectivity of the networks involved in CTS generation and wakefulness oscillations. EEG analyses were repeated on a sample of routine EEG from the same patient's cohort. RESULTS: No correlation was found between EWI fluctuations and CTS density during the EEG-fMRI recordings, while they showed an anticorrelated trend when drowsiness was followed by proper sleep in routine EEG traces. According to PPI findings, EWI fluctuations modulate the connectivity between the brain networks engaged by CTS and the left frontal operculum. CONCLUSIONS: While CTS frequency per se seems unrelated to drowsiness, wakefulness oscillations modulate the connectivity between CTS generators and key regions of the language circuitry, a cognitive function often impaired in SeLECTS. SIGNIFICANCE: This work advances our understanding of (a) interaction between CTS occurrence and vigilance fluctuations and (b) possible mechanisms responsible for language disruption in SeLECTS.

Mouse brain elastography changes with sleep/wake cycles, aging, and Alzheimer's disease.

Understanding the physiological processes in aging and how neurodegenerative disorders affect cognitive function is a high priority for advancing human health. One specific area of recently enabled research is the in vivo biomechanical state of the brain. This study utilized reverberant optical coherence elastography, a high-resolution elasticity imaging method, to investigate stiffness changes during the sleep/wake cycle, aging, and Alzheimer's disease in murine models. Four-dimensional scans of 44 wildtype mice, 13 mice with deletion of aquaporin-4 water channel, and 12 mice with Alzheimer-related pathology (APP/PS1) demonstrated that (1) cortical tissue became softer (on the order of a 10% decrease in shear wave speed) when young wildtype mice transitioned from wake to anesthetized, yet this effect was lost in aging and with mice overexpressing amyloid-ß or lacking the water channel AQP4. (2) Cortical stiffness increased with age in all mice lines, but wildtype mice exhibited the most prominent changes as a function of aging. The study provides novel insight into the brain's biomechanics, the constraints of fluid flow, and how the state of brain activity affects basic properties of cortical tissues.

Chronic Astrocytic TNFα Production in the Preoptic-Basal Forebrain Causes Aging-like Sleep-Wake Disturbances in Young Mice.

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.

Evaluating the Electroencephalographic Signal Quality of an In-Ear Wearable Device.

Wearable in-ear electroencephalographic (EEG) devices hold significant promise for advancing brain monitoring technologies into everyday applications. However, despite the current availability of several in-ear EEG devices in the market, there remains a critical need for robust validation against established clinical-grade systems. In this study, we carried out a detailed examination of the signal performance of a mobile in-ear EEG device from Naox Technologies. Our investigation had two main goals: firstly, evaluating the hardware circuit's reliability through simulated EEG signal experiments and, secondly, conducting a thorough comparison between the in-ear EEG device and gold-standard EEG monitoring equipment. This comparison assesses correlation coefficients with recognized physiological patterns during wakefulness and sleep, including alpha rhythms, eye artifacts, slow waves, spindles, and sleep stages. Our findings support the feasibility of using this in-ear EEG device for brain activity monitoring, particularly in scenarios requiring enhanced comfort and user-friendliness in various clinical and research settings.

[The role of cerebral activation in the sleep-wake cycle]. / Rol' tserebral'noi aktivatsii v tsikle son­bodrstvovanie.

The development of views on cerebral activation in the wakefulness-sleep cycle, starting with the work of Constantin von Economo, is considered. The emphasis is on the cyclic activation of high-amplitude discharges in sleep, which, with known assumptions, can include K-complexes, as well as patterns of delta-like waves. Considering the participation of the peripheral nervous system in this, the integrative role of cyclic activation of high-amplitude discharges in the organization of the sleep-wake cycle is discussed.