Microglial TNFα controls daily changes in synaptic GABAARs and sleep slow waves.

Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNFα. We demonstrate that sleep induces microglia-dependent synaptic enrichment of GABAARs in a manner dependent on microglial TNFα and P2RX7. We further show that microglia-specific depletion of TNFα alters slow waves during NREM sleep and blunt memory consolidation in sleep-dependent learning tasks. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of synaptic GABAARs, sculpt sleep slow waves, and support memory consolidation.

Effects of gabapentin on slow-wave sleep period in critically ill adult patients: A randomized controlled trial.

Sleep deprivation is a prevalent problem in critically ill patients, which leads to delayed recovery and delirium. Slow-wave sleep (SWS) is essential to energy restoration, tissue repair, and immune system strengthening. This study aimed to investigate the effects of gabapentin on SWS in critically ill patients. We performed a prospective open-label randomized controlled study to compare SWS and the clinical outcomes of gabapentin versus a control intervention in critically ill adult patients admitted to the intensive care unit (ICU) within 24 h. The patients' characteristics and sleep-related outcomes were recorded. The sleep-related outcomes, namely, bispectral analysis (BIS), the Richards-Campbell Sleep Questionnaire (RCSQ), and insulin-like growth factor-1 (IGF-1) levels, were evaluated. Furthermore, clinical outcomes and safety were assessed. Sixty patients from 348 cases were eligible for randomization. On day 3 of the study, patients in the gabapentin group had significantly increased SWS (66.79 vs. 0.00 min; p < 0.001), total sleep time (TST) (331.39 vs. 46.16 min; p = 0.001), RCSQ score (55.05 ± 20.18 vs. 32.80 ± 15.31; p < 0.001), and IGF-1 concentrations (84.33 ± 12.40 vs. 44.00 ± 10.20 ng/mL, p < 0.001) compared with the control group. Improvements in clinical outcomes, such as delirium, ICU-free days, and mechanical ventilator-free days, were observed; however, these differences did not reach statistically significant. Gabapentin at bedtime increased SWS, TST, and IGF-1 concentrations in critically ill patients. This regimen might be beneficial to critically ill patients for improving their sleep quality.

Propofol enhancement of slow wave sleep to target the nexus of geriatric depression and cognitive dysfunction: protocol for a phase I open label trial.

INTRODUCTION: Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series. METHODS AND ANALYSIS: SWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2-6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion. ETHICS AND DISSEMINATION: The study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial. TRIAL REGISTRATION NUMBER: NCT04680910.

REM Sleep Preserves Affective Response to Social Stress-Experimental Study.

Sleep's contribution to affective regulation is insufficiently understood. Previous human research has focused on memorizing or rating affective pictures and less on physiological affective responsivity. This may result in overlapping definitions of affective and declarative memories and inconsistent deductions for how rapid eye movement sleep (REMS) and slow-wave sleep (SWS) are involved. Literature associates REMS theta (4-8 Hz) activity with emotional memory processing, but its contribution to social stress habituation is unknown. Applying selective sleep stage suppression and oscillatory analyses, we investigated how sleep modulated affective adaptation toward social stress and retention of neutral declarative memories. Native Finnish participants (N = 29; age, M = 25.8 years) were allocated to REMS or SWS suppression conditions. We measured physiological (skin conductance response, SCR) and subjective stress response and declarative memory retrieval thrice: before laboratory night, the next morning, and after 3 d. Linear mixed models were applied to test the effects of condition and sleep parameters on emotional responsivity and memory retrieval. Greater overnight increase in SCR toward the stressor emerged after suppressed SWS (intact REMS) relative to suppressed REMS (20.1% vs 6.1%; p = 0.016). The overnight SCR increase was positively associated with accumulated REMS theta energy irrespective of the condition (r = 0.601; p = 0.002). Subjectively rated affective response and declarative memory recall were comparable between the conditions. The contributions of REMS and SWS to habituation of social stress are distinct. REMS theta activity proposedly facilitates the consolidation of autonomic affective responses. Declarative memory consolidation may not have greater dependence on intact SWS relative to intact REMS.

Alpha anteriorization and theta posteriorization during deep sleep.

Brain states (wake, sleep, general anesthesia, etc.) are profoundly associated with the spatiotemporal dynamics of brain oscillations. Previous studies showed that the EEG alpha power shifted from the occipital cortex to the frontal cortex (alpha anteriorization) after being induced into a state of general anesthesia via propofol. The sleep research literature suggests that slow waves and sleep spindles are generated locally and propagated gradually to different brain regions. Since sleep and general anesthesia are conceptualized under the same framework of consciousness, the present study examines whether alpha anteriorization similarly occurs during sleep and how the EEG power in other frequency bands changes during different sleep stages. The results from the analysis of three polysomnography datasets of 234 participants show consistent alpha anteriorization during the sleep stages N2 and N3, beta anteriorization during stage REM, and theta posteriorization during stages N2 and N3. Although it is known that the neural circuits responsible for sleep are not exactly the same for general anesthesia, the findings of alpha anteriorization in this study suggest that, at macro level, the circuits for alpha oscillations are organized in the similar cortical areas. The spatial shifts of EEG power in different frequency bands during sleep may offer meaningful neurophysiological markers for the level of consciousness.

Comparing targeted memory reactivation during slow wave sleep and sleep stage 2.

Sleep facilitates declarative memory consolidation, which is assumed to rely on the reactivation of newly encoded memories orchestrated by the temporal interplay of slow oscillations (SO), fast spindles and ripples. SO as well as the number of spindles coupled to SO are more frequent during slow wave sleep (SWS) compared to lighter sleep stage 2 (S2). But, it is unclear whether memory reactivation is more effective during SWS than during S2. To test this question, we applied Targeted Memory Reactivation (TMR) in a declarative memory design by presenting learning-associated sound cues during SWS vs. S2 in a counterbalanced within-subject design. Contrary to our hypothesis, memory performance was not significantly better when cues were presented during SWS. Event-related potential (ERP) amplitudes were significantly higher for cues presented during SWS than S2, and the density of SO and SO-spindle complexes was generally higher during SWS than during S2. Whereas SO density increased during and after the TMR period, SO-spindle complexes decreased. None of the parameters were associated with memory performance. These findings suggest that the efficacy of TMR does not depend on whether it is administered during SWS or S2, despite differential processing of memory cues in these sleep stages.

Modulate the impact of the drowsiness on the resting state functional connectivity.

This research explores different methodologies to modulate the effects of drowsiness on functional connectivity (FC) during resting-state functional magnetic resonance imaging (RS-fMRI). The study utilized a cohort of students (MRi-Share) and classified individuals into drowsy, alert, and mixed/undetermined states based on observed respiratory oscillations. We analyzed the FC group difference between drowsy and alert individuals after five different processing methods: the reference method, two based on physiological and a global signal regression of the BOLD time series signal, and two based on Gaussian standardizations of the FC distribution. According to the reference method, drowsy individuals exhibit higher cortico-cortical FC than alert individuals. First, we demonstrated that each method reduced the differences between drowsy and alert states. The second result is that the global signal regression was quantitively the most effective, minimizing significant FC differences to only 3.3% of the total FCs. However, one should consider the risks of overcorrection often associated with this methodology. Therefore, choosing a less aggressive form of regression, such as the physiological method or Gaussian-based approaches, might be a more cautious approach. Third and last, using the Gaussian-based methods, cortico-subcortical and intra-default mode network (DMN) FCs were significantly greater in alert than drowsy subjects. These findings bear resemblance to the anticipated patterns during the onset of sleep, where the cortex isolates itself to assist in transitioning into deeper slow wave sleep phases, simultaneously disconnecting the DMN.

Episodic long-term memory formation during slow-wave sleep.

We are unresponsive during slow-wave sleep but continue monitoring external events for survival. Our brain wakens us when danger is imminent. If events are non-threatening, our brain might store them for later consideration to improve decision-making. To test this hypothesis, we examined whether novel vocabulary consisting of simultaneously played pseudowords and translation words are encoded/stored during sleep, and which neural-electrical events facilitate encoding/storage. An algorithm for brain-state-dependent stimulation selectively targeted word pairs to slow-wave peaks or troughs. Retrieval tests were given 12 and 36 hr later. These tests required decisions regarding the semantic category of previously sleep-played pseudowords. The sleep-played vocabulary influenced awake decision-making 36 hr later, if targeted to troughs. The words' linguistic processing raised neural complexity. The words' semantic-associative encoding was supported by increased theta power during the ensuing peak. Fast-spindle power ramped up during a second peak likely aiding consolidation. Hence, new vocabulary played during slow-wave sleep was stored and influenced decision-making days later.

Neuroligin-2 shapes individual slow waves during slow-wave sleep and the response to sleep deprivation in mice.

BACKGROUND: Sleep disturbances are a common comorbidity to most neurodevelopmental disorders and tend to worsen disease symptomatology. It is thus crucial to understand mechanisms underlying sleep disturbances to improve patients' quality of life. Neuroligin-2 (NLGN2) is a synaptic adhesion protein regulating GABAergic transmission. It has been linked to autism spectrum disorders and schizophrenia in humans, and deregulations of its expression were shown to cause epileptic-like hypersynchronized cerebral activity in rodents. Importantly, the absence of Nlgn2 (knockout: KO) was previously shown to alter sleep-wake duration and quality in mice, notably increasing slow-wave sleep (SWS) delta activity (1-4 Hz) and altering its 24-h dynamics. This type of brain oscillation is involved in memory consolidation, and is also a marker of homeostatic sleep pressure. Sleep deprivation (SD) is notably known to impair cognition and the physiological response to sleep loss involves GABAergic transmission. METHODS: Using electrocorticographic (ECoG) recordings, we here first aimed to verify how individual slow wave (SW; 0.5-4 Hz) density and properties (e.g., amplitude, slope, frequency) contribute to the higher SWS delta activity and altered 24-h dynamics observed in Nlgn2 KO mice. We further investigated the response of these animals to SD. Finally, we tested whether sleep loss affects the gene expression of Nlgn2 and related GABAergic transcripts in the cerebral cortex of wild-type mice using RNA sequencing. RESULTS: Our results show that Nlgn2 KO mice have both greater SW amplitude and density, and that SW density is the main property contributing to the altered 24-h dynamics. We also found the absence of Nlgn2 to accelerate paradoxical sleep recovery following SD, together with profound alterations in ECoG activity across vigilance states. Sleep loss, however, did not modify the 24-h distribution of the hypersynchronized ECoG events observed in these mice. Finally, RNA sequencing confirmed an overall decrease in cortical expression of Nlgn2 and related GABAergic transcripts following SD in wild-type mice. CONCLUSIONS: This work brings further insight into potential mechanisms of sleep duration and quality deregulation in neurodevelopmental disorders, notably involving NLGN2 and GABAergic neurotransmission.

Optochemical control of slow-wave sleep in the nucleus accumbens of male mice by a photoactivatable allosteric modulator of adenosine A2A receptors.

Optochemistry, an emerging pharmacologic approach in which light is used to selectively activate or deactivate molecules, has the potential to alleviate symptoms, cure diseases, and improve quality of life while preventing uncontrolled drug effects. The development of in-vivo applications for optochemistry to render brain cells photoresponsive without relying on genetic engineering has been progressing slowly. The nucleus accumbens (NAc) is a region for the regulation of slow-wave sleep (SWS) through the integration of motivational stimuli. Adenosine emerges as a promising candidate molecule for activating indirect pathway neurons of the NAc expressing adenosine A2A receptors (A2ARs) to induce SWS. Here, we developed a brain-permeable positive allosteric modulator of A2ARs (A2AR PAM) that can be rapidly photoactivated with visible light (λ > 400 nm) and used it optoallosterically to induce SWS in the NAc of freely behaving male mice by increasing the activity of extracellular adenosine derived from astrocytic and neuronal activity.

Extracting Stress-Related EEG Patterns From Pre-Sleep EEG for Forecasting Slow-Wave Sleep Deficiency.

Sleep is vital to our daily activity. Lack of proper sleep can impair functionality and overall health. While stress is known for its detrimental impact on sleep quality, the precise effect of pre-sleep stress on subsequent sleep structure remains unknown. This study introduced a novel approach to study the pre-sleep stress effect on sleep structure, specifically slow-wave sleep (SWS) deficiency. To achieve this, we selected forehead resting EEG immediately before and upon sleep onset to extract stress-related neurological markers through power spectra and entropy analysis. These markers include beta/delta correlation, alpha asymmetry, fuzzy entropy (FuzzEn) and spectral entropy (SpEn). Fifteen subjects were included in this study. Our results showed that subjects lacking SWS often exhibited signs of stress in EEG, such as an increased beta/delta correlation, higher alpha asymmetry, and increased FuzzEn in frontal EEG. Conversely, individuals with ample SWS displayed a weak beta/delta correlation and reduced FuzzEn. Finally, we employed several supervised learning models and found that the selected neurological markers can predict subsequent SWS deficiency. Our investigation demonstrated that the classifiers could effectively predict varying levels of slow-wave sleep (SWS) from pre-sleep EEG segments, achieving a mean balanced accuracy surpassing 0.75. The SMOTE-Tomek resampling method could improve the performance to 0.77. This study suggests that stress-related neurological markers derived from pre-sleep EEG can effectively predict SWS deficiency. Such information can be integrated with existing sleep-improving techniques to provide a personalized sleep forecasting and improvement solution.

Hippocampal ripples coincide with "up-state" and spindles in retrosplenial cortex.

During NREM sleep, hippocampal sharp-wave ripple (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, a set of distributed networks organized around retrosplenial cortex (RS-network) interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in this RS-network are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the RS-network and spindles, we combined cortical wide-field voltage imaging, Electrocorticography, and hippocampal LFP recordings in anesthetized and sleeping mice. Here, we show that, during SWR, "up-states" and spindles reliably co-occur in a cortical subnetwork centered around the retrosplenial cortex. Furthermore, retrosplenial transient activations and spindles predict slow gamma oscillations in CA1 during SWRs. Together, our results suggest that retrosplenial-hippocampal interaction may be a critical pathway of information exchange between the cortex and hippocampus.

[Recent studies about the underlying cerebral mechanism of the fearfull arousals from slow wave sleep].

We consider the disorders of arousal and sleep-related hypermotor epilepsy as genetic twin-conditions, one without, one with epilepsy. They share an augmented arousal-activity during NREM sleep with sleep-wake dissociations, culminating in sleep terrors and sleep-related hypermotor seizures with similar symptoms. The known mutations underlying the two spectra are different, but there are multifold population-genetic-, family- and even individual (the two conditions occurring in the same person) overlaps supporting common genetic roots. In the episodes of disorders of arousal, the anterior cingulate, anterior insular and pre-frontal cortices (shown to be involved in fear- and emotion processing) are activated within a sleeping brain. These regions overlap with the seizure-onset zones of successfully operated sleep-related hypermotor seizures, and notably, belong to the salience network being consistent with its hubs. The arousal-relatedness and the similar fearful disorientation occurring in sleep terrors and hypermotor seizures, make them alike the acute stress-responses emerging from sleep; triggered by false alarms. An acute stress-response can easily mobilize the hypothalamo-pituitary-adrenal axis (preparing fight-flight responses in wakefulness); through its direct pathways to and from the salience network. This hypothesis has never been studied.

Sleep-slow oscillation-spindle coupling precedes spindle-ripple coupling during development.

STUDY OBJECTIVES: Sleep supports systems memory consolidation through the precise temporal coordination of specific oscillatory events during slow-wave sleep, i.e. the neocortical slow oscillations (SOs), thalamic spindles, and hippocampal ripples. Beneficial effects of sleep on memory are also observed in infants, although the contributing regions, especially hippocampus and frontal cortex, are immature. Here, we examined in rats the development of these oscillatory events and their coupling during early life. METHODS: EEG and hippocampal local field potentials were recorded during sleep in male rats at postnatal days (PD)26 and 32, roughly corresponding to early (1-2 years) and late (9-10 years) human childhood, and in a group of adult rats (14-18 weeks, corresponding to ~22-29 years in humans). RESULTS: SO and spindle amplitudes generally increased from PD26 to PD32. In parallel, frontocortical EEG spindles increased in density and frequency, while changes in hippocampal ripples remained nonsignificant. The proportion of SOs co-occurring with spindles also increased from PD26 to PD32. Whereas parietal cortical spindles were phase-locked to the depolarizing SO-upstate already at PD26, over frontal cortex SO-spindle phase-locking emerged not until PD32. Co-occurrence of hippocampal ripples with spindles was higher during childhood than in adult rats, but significant phase-locking of ripples to the excitable spindle troughs was observed only in adult rats. CONCLUSIONS: Results indicate a protracted development of synchronized thalamocortical processing specifically in frontocortical networks (i.e. frontal SO-spindle coupling). However, synchronization within thalamocortical networks generally precedes synchronization of thalamocortical with hippocampal processing as reflected by the delayed occurrence of spindle-ripple phase-coupling.

The effect of slow wave sleep deprivation on mood in adolescents with depressive symptoms: A pilot study.

BACKGROUND: There is an urgent need for safe, rapid-acting treatment strategies for adolescent depression. In depressed adults, slow wave sleep deprivation (SWSD) improved next-day mood without disrupting sleep duration, but SWSD has not been tested in adolescents. In a pilot study, the aim was to assess the effect of SWSD on sleep physiology and mood outcomes (depression, rumination, anhedonia) among adolescents with depressive symptoms. METHODS: Sixteen adolescents (17.44 ± 1.46 yr, 12 female) completed three nights of polysomnographic sleep recording: Baseline, SWSD, and Recovery nights. Acoustic stimulation (tones of random pitch, duration, and volume) suppressed slow wave sleep (SWS) in real-time during SWSD. After each night, depression, rumination, and anhedonia severity were assessed. RESULTS: SWSD successfully suppressed SWS, increased N2, and had minimal impact on Rapid Eye Movement (REM), nocturnal awakenings, and total sleep time. While SWSD did not improve depression or anhedonia severity overall, lower baseline non-REM alpha activity and greater SWS rebound during recovery sleep correlated with SWSD-related reduction in clinician-rated depression severity. Next-day rumination severity decreased after SWSD, with sustained improvements following recovery sleep. However, rumination improvement was not associated with SWS suppression, but rather reduction in total sleep time and REM in exploratory correlation models. LIMITATIONS: Small sample size and large proportion of females. CONCLUSION: SWSD did not improve depression in adolescents overall but a subset with low non-REM alpha activity and intact homeostatic sleep regulation may benefit from this approach. Findings from this pilot study also suggest that partial sleep deprivation may be a beneficial therapeutic strategy for rumination in adolescents.

Memory reactivation in slow wave sleep enhances relational learning in humans.

Sleep boosts the integration of memories, and can thus facilitate relational learning. This benefit may be due to memory reactivation during non-REM sleep. We set out to test this by explicitly cueing reactivation using a technique called targeted memory reactivation (TMR), in which sounds are paired with learned material in wake and then softly played during subsequent sleep, triggering reactivation of the associated memories. We specifically tested whether TMR in slow wave sleep leads to enhancements in inferential thinking in a transitive inference task. Because the Up-phase of the slow oscillation is more responsive to cues than the Down-phase, we also asked whether Up-phase stimulation is more beneficial for such integration. Our data show that TMR during the Up-Phase boosts the ability to make inferences, but only for the most distant inferential leaps. Up-phase stimulation was also associated with detectable memory reinstatement, whereas Down-phase stimulation led to below-chance performance the next morning. Detection of memory reinstatement after Up-state stimulation was negatively correlated with performance on the most difficult inferences the next morning. These findings demonstrate that cueing memory reactivation at specific time points in sleep can benefit difficult relational learning problems.

Selective REM sleep restriction in mice using a device designed for tunable somatosensory stimulation.

BACKGROUND: Sleep perturbation is widely used to investigate the physiological mechanisms that mediate sleep-wake dynamics, and to isolate the specific roles of sleep in health and disease. However, state-of-the-art methods to accomplish sleep perturbation in preclinical models are limited in their throughput, flexibility, and specificity. NEW METHOD: A system was developed to deliver vibro-tactile somatosensory stimulation aimed at controlled, selective sleep perturbation. The frequency and intensity of stimulation can be tuned to target a variety of experimental applications, from sudden arousal to sub-threshold transitions between light and deep stages of NREM sleep. This device was activated in closed-loop to selectively interrupt REM sleep in mice. RESULTS: Vibro-tactile stimulation effectively and selectively interrupted REM sleep - significantly reducing the average REM bout duration relative to matched, unstimulated baseline recordings. As REM sleep was repeatedly interrupted, homeostatic mechanisms prompted a progressively quicker return to REM sleep. These effects were dependent on the parameters of stimulation applied. COMPARISON WITH EXISTING METHODS: Existing sleep perturbation systems often require moving parts within the cage and/or restrictive housing. The system presented is unique in that it interrupts sleep without invading the animal's space. The ability to vary stimulation parameters is a great advantage over existing methods, as it allows for adaptation in response to habituation and/or circadian/homeostatic changes in arousal threshold. CONCLUSIONS: The proposed method of stimulation demonstrates feasibility in affecting mouse sleep within a standard home cage environment, thus limiting environmental stress. Furthermore, the ability to tune frequency and intensity of stimulation allows for graded control over the extent of sleep perturbation, which potentially expands the utility of this technology beyond applications related to sleep.

Impact of single-trial avoidance learning on subsequent sleep.

Both non-rapid eye movement (NonREM) sleep and rapid eye movement (REM) sleep, as well as sleep spindle and ripple oscillations, are important for memory formation. Through cortical EEG recordings of prefrontal cortex and hippocampus during and after an inhibitory avoidance task, we analysed the dynamic changes in the amounts of sleep, spindle and ripple oscillations related to memory formation. The total amount of NonREM sleep was reduced during the first hour after learning. Moreover, significant decrease of the total spindle and ripple counts was observed at the first hour after learning as well. In addition, foot shock alone, with no associated learning, produced little effect on the dynamics of sleep oscillations, indicating that the learning experience is necessary for these changes to occur.