Competitive dynamics underlie cognitive improvements during sleep.

We provide evidence that human sleep is a competitive arena in which cognitive domains vie for limited resources. Using pharmacology and effective connectivity analysis, we demonstrate that long-term memory and working memory are served by distinct offline neural mechanisms that are mutually antagonistic. Specifically, we administered zolpidem to increase central sigma activity and demonstrated targeted suppression of autonomic vagal activity. With effective connectivity, we determined the central activity has greater causal influence over autonomic activity, and the magnitude of this influence during sleep produced a behavioral trade-off between offline long-term and working memory processing. These findings suggest a sleep switch mechanism that toggles between central sigma-dependent long-term memory and autonomic vagal-dependent working memory processing.

Opioids cause dissociated states of consciousness in C57BL/6J mice.

The electroencephalogram (EEG) provides an objective, neural correlate of consciousness. Opioid receptors modulate mammalian neuronal excitability, and this fact was used to characterize how opioids administered to mice alter EEG power and states of consciousness. The present study tested the hypothesis that antinociceptive doses of fentanyl, morphine, or buprenorphine differentially alter the EEG and states of sleep and wakefulness in adult, male C57BL/6J mice. Mice were anesthetized and implanted with telemeters that enabled wireless recordings of cortical EEG and electromyogram (EMG). After surgical recovery, EEG and EMG were used to objectively score states of consciousness as wakefulness, rapid eye movement (REM) sleep, or non-REM (NREM) sleep. Measures of EEG power (dB) were quantified as δ (0.5-4 Hz), θ (4-8 Hz), α (8-13 Hz), σ (12-15 Hz), ß (13-30 Hz), and γ (30-60 Hz). Compared with saline (control), fentanyl and morphine decreased NREM sleep, morphine eliminated REM sleep, and buprenorphine eliminated NREM sleep and REM sleep. Opioids significantly and differentially disrupted the temporal organization of sleep/wake states, altered specific EEG frequency bands, and caused dissociated states of consciousness. The results are discussed relative to the fact that opioids, pain, and sleep modulate interacting states of consciousness.NEW & NOTEWORTHY This study discovered that antinociceptive doses of fentanyl, morphine, and buprenorphine significantly and differentially disrupt EEG-defined states of consciousness in C57BL/6J mice. These data are noteworthy because: 1) buprenorphine is commonly used in medication-assisted therapy for opioid addiction, and 2) there is evidence that disordered sleep can promote addiction relapse. The results contribute to community phenotyping efforts by making publicly available all descriptive and inferential statistics from this study (Supplemental Tables S1-S8).

Chronic Toxoplasma gondii infection and sleep-wake alterations in mice.

AIM: Toxoplasma gondii (Tg) is an intracellular parasite infecting more than a third of the human population. Yet, the impact of Tg infection on sleep, a highly sensitive index of brain functions, remains unknown. We designed an experimental mouse model of chronic Tg infection to assess the effects on sleep-wake states. METHODS: Mice were infected using cysts of the type II Prugniaud strain. We performed chronic sleep-wake recordings and monitoring as well as EEG power spectral density analysis in order to assess the quantitative and qualitative changes of sleep-wake states. Pharmacological approach was combined to evaluate the direct impact of the infection and inflammation caused by Tg. RESULTS: Infected mouse exhibited chronic sleep-wake alterations over months, characterized by a marked increase (>20%) in time spent awake and in cortical EEG θ power density of all sleep-wake states. Meanwhile, slow-wave sleep decreased significantly. These effects were alleviated by an anti-inflammatory treatment using corticosteroid dexamethasone. CONCLUSION: We demonstrated for the first time the direct consequences of Tg infection on sleep-wake states. The persistently increased wakefulness and reduced sleep fit with the parasite's strategy to enhance dissemination through host predation and are of significance in understanding the neurodegenerative and neuropsychiatric disorders reported in infected patients.

Effects of propofol on sleep architecture and sleep-wake systems in rats.

Previous studies have shown that the synchronization of electroencephalogram (EEG) signals is found during propofol-induced general anesthesia, which is similar to that of slow-wave sleep (SWS). However, a complete understanding is lacking in terms of the characteristics of EEG changes in rats after propofol administration and whether propofol acts through natural sleep circuits. Here, we examined the characteristics of EEG patterns induced by intraperitoneal injection of propofol in rats. We found that high (10 mg/kg) and medium (5 mg/kg) doses of propofol induced a cortical EEG of low-frequency, high-amplitude activity with rare electromyographic activity and markedly shortened sleep latency. The high dose of propofol increased deep slow-wave sleep (SWS2) to 4 h, as well as the number of large SWS2 bouts (>480 s), their mean duration and the peak of the power density curve in the delta range of 0.75-3.25 Hz. After the medium dose of propofol, the total number of wakefulness, light slow-wave sleep (SWS1) and SWS2 episodes increased, whereas the mean duration of wakefulness decreased. The high dose of propofol significantly increased c-fos expression in the ventrolateral preoptic nucleus (VLPO) sleep center and decreased the number of c-fos-immunoreactive neurons in wake-related systems including the tuberomammillary nucleus (TMN), perifornical nucleus (PeF), lateral hypothalamic nucleus (LH), ventrolateral periaqueductal gray (vPAG) and supramammillary region (SuM). These results indicated that the high dose of propofol produced high-quality sleep by increasing SWS2, whereas the medium dose produced fragmented and low-quality sleep by disrupting the continuity of wakefulness. Furthermore, sleep-promoting effects of propofol are correlated with activation of the VLPO cluster and inhibition of the TMN, PeF, LH, vPAG and SuM.

Paradoxical anesthesia: Sleep-like EEG during anesthesia induced by mesopontine microinjection of GABAergic agents.

General anesthetic agents are thought to induce loss-of-consciousness (LOC) and enable pain-free surgery by acting on the endogenous brain circuitry responsible for sleep-wake cycling. In clinical use, the entire CNS is exposed to anesthetic molecules with LOC and amnesia usually attributed to synaptic suppression in the cerebral cortex and immobility and analgesia to agent action in the spinal cord and brainstem. This model of patch-wise suppression has been challenged, however, by the observation that all functional components of anesthesia can be induced by focal delivery of minute quantities of GABAergic agonists to the brainstem mesopontine tegmental anesthesia area (MPTA). We compared spectral features of the cortical electroencephalogram (EEG) in rats during systemic anesthesia and anesthesia induced by MPTA microinjection. Systemic administration of (GABAergic) pentobarbital yielded the sustained, δ-band dominant EEG signature familiar in clinical anesthesia. In contrast, anesthesia induced by MPTA microinjection (pentobarbital or muscimol) featured epochs of δ-band EEG alternating with the wake-like EEG, the pattern typical of natural non-rapid-eye-movement (NREM) and REM sleep. The rats were not sleeping, however, as they remained immobile, atonic and unresponsive to noxious pinch. Recalling the paradoxical wake-like quality the EEG during REM sleep, we refer to this state as "paradoxical anesthesia". GABAergic anesthetics appear to co-opt both cortical and spinal components of the sleep network via dedicated axonal pathways driven by MPTA neurons. Direct drug exposure of cortical and spinal neurons is not necessary, and is probably responsible for off-target side-effects of systemic administration including monotonous δ-band EEG, hypothermia and respiratory depression. SIGNIFICANCE STATEMENT: The concept that GABAergic general anesthetic agents induce loss-of-consciousness by substituting for an endogenous neurotransmitter, thereby co-opting neural circuitry responsible for sleep-wake transitions, has gained considerable traction. However, the electroencephalographic (EEG) signatures of sleep and anesthesia differ fundamentally. We show that when the anesthetic state is generated by focal delivery of GABAergics into the mesopontine tegmental anesthesia area (MPTA) the resulting EEG repeatedly transitions between delta-wave-dominant and wake-like patterns much as in REM-NREM sleep. This suggests that systemic (clinical) anesthetic delivery, which indiscriminately floods the entire cerebrum with powerful inhibitory agents, obscures the sleep-like EEG signature associated with the less adulterated form of anesthesia obtained when the drugs are applied selectively to loci where the effective neurotransmitter substitution actually occurs.

Melatonin effects on EEG activity during non-rapid eye movement sleep in mild-to-moderate Alzheimer´s disease: a pilot study.

INTRODUCTION: There is evidence to suggest that melatonin diminishes non-rapid eye movement sleep (NREMS) latency in patients with Alzheimer´s disease (AD). However, melatonin's effects on cortical activity during NREMS in AD have not been studied. The objective of this research was to analyze the effects of melatonin on cortical activity during the stages of NREMS in 8 mild-to-moderate AD patients that received 5-mg of fast-release melatonin. METHODS: During a single-blind, placebo-controlled crossover study, polysomnographic recordings were obtained from C3-A1, C4-A2, F7-T3, F8-T4, F3-F4 and O1-O2. Also, the relative power (RP) and EEG coherences of the delta, theta, alpha1, alpha2, beta1, beta2 and gamma bands were calculated during NREMS-1, NREMS-2 and NREMS-3. These sleep latencies and all EEG data were then compared between the placebo and melatonin conditions. RESULTS: During NREMS-2, a significant RP increase was observed in the theta band of the left-central hemisphere. During NREMS-3, significant RP decreases in the beta bands were recorded in the right-central hemisphere, compared to the placebo group. After melatonin administration, significant decreases of EEG coherences in the beta2, beta1 and gamma bands were observed in the right hemisphere during NREMS-3. DISCUSSION: We conclude that short NREMS onset related to melatonin intake in AD patients is associated with a significant RP increase in the theta band and a decrease in RP and EEG coherences in the beta and gamma bands during NREMS-3. These results suggest that the GABAergic pathways are preserved in mild-to-moderate AD.

Melatonin ameliorates the sleep disorder induced by surgery under sevoflurane anaesthesia in aged mice.

Post-operative sleep disorders induce adverse effects on patients, especially the elderly, which may be associated with surgery and inhalational anaesthetics. Melatonin is a neuroendocrine regulator of the sleep-wake cycle. In this study, we analysed the alterations of post-operative sleep in aged melatonin-deficient (C57BL/6J) mice, and investigated if exogenous melatonin could facilitate entrainment of circadian rhythm after laparotomy under sevoflurane anaesthesia. The results showed that laparotomy under sevoflurane anaesthesia had a greater influence on post-operative sleep than sevoflurane alone. Laparotomy under anaesthesia led to circadian rhythm shifting forward, altered EEG power density and delta power of NREM sleep, and lengthened REM and NREM sleep latencies. In the light phase, the number of waking episodes tended to decline, and wake episode duration elevated. However, these indicators presented the opposite tendency during the dark phase. Melatonin showed significant efficacy for ameliorating the sleep disorder and restoring physiological sleep, and most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist.

Depth of sedation during drug induced sedation endoscopy monitored by BiSpectral Index® and Cerebral State Index®.

PURPOSE: Drug induced sedation endoscopy (DISE) is performed to investigate patterns and sites of obstruction in patients with sleep-disordered breathing (SDB). During DISE the patients are sedated to obtain a muscular relaxation of the upper airway which mimics the relaxation during natural sleep. Different sleep stages are intended to be simulated by drug induced sedation, and it is helpful to measure the depth of sedation. The BiSpectral Index® (BIS) is often used for this procedure. Besides the BIS, other means of sedation depth monitoring exist in anaesthesiology but have not yet been investigated with respect to DISE. Monitoring of the Cerebral State Index® (CSI) is one of these methods. The aim of the study was to compare the BIS and CSI for sedation depth monitoring during DISE. METHODS: Sixty patients underwent DISE monitored by the BIS and CSI in parallel. The BIS and CSI values were compared using the Bland-Altman analysis. RESULTS: The BIS and CSI values differed during the course of sedation during DISE by a mean of - 6.07. At light sedation (BIS 60-80), lower values by 10 scale points of CSI compared with BIS were detectable. At deeper sedation levels (BIS 40-50), the CSI turned to present equal and even higher values compared with the BIS. CONCLUSION: Sedation depth measurement during DISE can be performed by the BIS or CSI, but the differences should be interpreted carefully as comparable data for sleep stages in natural sleep are available only for BIS.

Oral Dexmedetomidine Promotes Non-rapid Eye Movement Stage 2 Sleep in Humans.

BACKGROUND: The administration of dexmedetomidine is limited to highly monitored care settings because it is only available for use in humans as intravenous medication. An oral formulation of dexmedetomidine may broaden its use to all care settings. The authors investigated the effect of a capsule-based solid oral dosage formulation of dexmedetomidine on sleep polysomnography. METHODS: The authors performed a single-site, placebo-controlled, randomized, crossover, double-blind phase II study of a solid oral dosage formulation of dexmedetomidine (700 mcg; n = 15). The primary outcome was polysomnography sleep quality. Secondary outcomes included performance on the motor sequence task and psychomotor vigilance task administered to each subject at night and in the morning to assess motor memory consolidation and psychomotor function, respectively. Sleep questionnaires were also administered. RESULTS: Oral dexmedetomidine increased the duration of non-rapid eye movement (non-REM) stage 2 sleep by 63 (95% CI, 19 to 107) min (P = 0.010) and decreased the duration of rapid eye movement (REM) sleep by 42 (5 to 78) min (P = 0.031). Overnight motor sequence task performance improved after placebo sleep (7.9%; P = 0.003) but not after oral dexmedetomidine-induced sleep (-0.8%; P = 0.900). In exploratory analyses, we found a positive correlation between spindle density during non-REM stage 2 sleep and improvement in the overnight test performance (Spearman rho = 0.57; P = 0.028; n = 15) for placebo but not oral dexmedetomidine (Spearman rho = 0.04; P = 0.899; n = 15). Group differences in overnight motor sequence task performance, psychomotor vigilance task metrics, and sleep questionnaires did not meet the threshold for statistical significance. CONCLUSIONS: These results demonstrate that the nighttime administration of a solid oral dosage formulation of dexmedetomidine is associated with increased non-REM 2 sleep and decreased REM sleep. Spindle density during dexmedetomidine sleep was not associated with overnight improvement in the motor sequence task.

Chronic alcohol exposure reduces acetylated histones in the sleep-wake regulatory brain regions to cause insomnia during withdrawal.

BACKGROUND: Alcohol use disorder (AUD) develops after chronic and heavy use of alcohol. Insomnia, a hallmark of AUD, plays a crucial role in the development of AUD. However, the causal mechanisms are unknown. Since chronic alcohol reduces acetylated histones and disrupts the epigenome, we hypothesized that chronic alcohol exposure will reduce acetylated histones in wake-promoting regions of the brain to cause insomnia during alcohol withdrawal. METHODS: Adult male C57BL/6J mice, surgically instrumented for electrophysiological monitoring of sleep-wakefulness, were exposed to chronic alcohol (6.8%) consumption using Lieber-DeCarli liquid diet. Three experiments were performed. First, the effect of chronic alcohol consumption was examined on sleep-wakefulness during 7 days of withdrawal. Second, the expression of acetylated histones, H3 lysine 14 (AcH3K14), was examined in two major sleep-wake regulatory brain regions: basal forebrain (BF) and lateral hypothalamus (LH) of the brain by using western blotting. Next, blockade of histone deacetylase, via systemic administration of TSA was examined on alcohol-induced changes in sleep-wakefulness. RESULTS: Alcoholic mice displayed a significant reduction in the quality and quantity of NREM sleep coupled with a significant increase in wakefulness that lasted for several days during alcohol withdrawal. In addition, alcoholic mice displayed a significant reduction in the expression of AcH3K14 in both BF and LH. Systemic administration of TSA significantly attenuated insomnia and improved the quality and quantity of sleep during alcohol withdrawal. CONCLUSIONS: Based on our results, we suggest that a causal relationship exists between reduced histone acetylation and insomnia during alcohol withdrawal.

Melatonin recovers sleep phase delayed by MK-801 through the melatonin MT2 receptor- Ca2+ -CaMKII-CREB pathway in the ventrolateral preoptic nucleus.

Melatonin (MLT) is widely used to treat sleep disorders although the underlying mechanism is still elusive. In mice, using wheel-running detection, we found that exogenous MLT could completely recover the period length prolonged by N-methyl-D-aspartate receptor (NMDAR) impairment due to the injection of the NMDAR antagonist MK-801, a preclinical model of psychosis. The analysis of the possible underlying mechanisms indicated that MLT could regulate the homeostatic state in the ventrolateral preoptic nucleus (VLPO) instead of the circadian process in the suprachiasmatic nucleus (SCN). In addition, our data showed that MK-801 decreased Ca2+ -related CaMKII expression and CREB phosphorylation levels in the VLPO, and MLT could rescue these intracellular impairments but not NMDAR expression levels. Accordingly, Gcamp6 AAV virus was injected in-vivo to further monitor intracellular Ca2+ levels in the VLPO, and MLT demonstrated a unique ability to increase Ca2+ fluorescence compared with MK-801-injected mice. Additionally, using the selective melatonin MT2 receptor antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT), we discovered that the pharmacological effects of MLT upon NMDAR impairments were mediated by melatonin MT2 receptors. Using electroencephalography/electromyography (EEG/EMG) recordings, we observed that the latency to the first nonrapid eye movement (NREM) sleep episode was delayed by MK-801, and MLT was able to recover this delay. In conclusion, exogenous MLT by acting upon melatonin MT2 receptors rescues sleep phase delayed by NMDAR impairment via increasing intracellular Ca2+ signaling in the VLPO, suggesting a regulatory role of the neurohormone on the homeostatic system.

Sleep and pain management: a review.

There is a complex interplay between sleep disturbance and patients in pain. There is an increasing appreciation of the direct effects of analgesic drugs and sleep quality. This review provides an overview of the effects of different analgesic drugs and their effects on phases of sleep. The effects of different pain conditions and their direct effects on sleep physiology are also discussed. A structured search of the scientific literature using MEDLINE and PubMed databases. Original human and animal studies were included. A multi-search term strategy was employed. An appreciation of the physiological effects of these drugs will allow a more considered prescription of them to better manage sleep disturbance.

The retinoid X receptor: a nuclear receptor that modulates the sleep-wake cycle in rats.

RATIONALE: The nuclear receptor retinoid X receptor (RXR) belongs to a nuclear receptor superfamily that modulates diverse functions via homodimerization with itself or several other nuclear receptors, including PPARα. While the activation of PPARα by natural or synthetic agonists regulates the sleep-wake cycle, the role of RXR in the sleep modulation is unknown. OBJECTIVES: We investigated the effects of bexarotene (Bexa, a RXR agonist) or UVI 3003 (UVI, a RXR antagonist) on sleep, sleep homeostasis, levels of neurochemical related to sleep modulation, and c-Fos and NeuN expression. METHODS: The sleep-wake cycle and sleep homeostasis were analyzed after application of Bexa or UVI. Moreover, we also evaluated whether Bexa or UVI could induce effects on dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine contents, collected from either the nucleus accumbens or basal forebrain. In addition, c-Fos and NeuN expression in the hypothalamus was determined after Bexa or UVI treatments. RESULTS: Systemic application of Bexa (1 mM, i.p.) attenuated slow-wave sleep and rapid eye movement sleep. In addition, Bexa increased the levels of dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine sampled from either the nucleus accumbens or basal forebrain. Moreover, Bexa blocked the sleep rebound period after total sleep deprivation, increased in the hypothalamus the expression of c-Fos, and decreased NeuN activity. Remarkably, UVI 3003 (1 mM, i.p.) induced opposite effects in sleep, sleep homeostasis, neurochemicals levels, and c-Fos and NeuN activity. CONCLUSIONS: The administration of RXR agonist or antagonist significantly impaired the sleep-wake cycle and exerted effects on the levels of neurochemicals related to sleep modulation. Moreover, Bexa or UVI administration significantly affected c-Fos and NeuN expression in the hypothalamus. Our findings highlight the neurobiological role of RXR on sleep modulation.

Inactivation of the Ventral Pallidum by GABAA Receptor Agonist Promotes Non-rapid Eye Movement Sleep in Rats.

GABA, the most abundant inhibitory neurotransmitter in the brain, is closely linked with sleep and wakefulness. As the largest area input to the ventral pallidum (VP), the nucleus accumbens (NAc) has been confirmed to play a pivotal role in promoting non-rapid eye movement (NREM) sleep through inhibitory projections from NAc adenosine A2A receptor-expressing neurons to VP GABAergic neurons which mostly express GABAA receptors. Although these studies demonstrate the possible role of VP GABAergic neurons in sleep-wake regulation, whether and how its modulate sleep-wake cycle is not completely clear. In our study, pharmacological manipulations were implemented in freely moving rats and then the EEG and the EMG were recorded to monitor the sleep-wake states. We found that microinjection of muscimol, a GABAA receptor agonist, into the VP increased NREM sleep in both light and dark period. Microinjection of bicuculline, a GABAA receptor antagonist, into the VP increased wakefulness in the light period. Collectively, our data identify the important role of VP GABAA receptor-expressing neurons in NREM sleep of rats which may help improve the understanding of the pathological sleep disorders.

Wake-Promoting and EEG Spectral Effects of Modafinil After Acute or Chronic Administration in the R6/2 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is characterised by progressive symptoms including cognitive deficits and sleep/wake disturbances reflected in an abnormal electroencephalography (EEG). Modafinil, a wake-promoting and cognitive-enhancing drug, has been considered as a treatment for HD. We used HD (R6/2) mice to investigate the potential for using modafinil to treat sleep-wake disturbance in HD. R6/2 mice show sleep-wake and EEG changes similar to those seen in HD patients, with increased rapid eye movement sleep (REMS), decreased wakefulness/increased non-REMS (NREMS), and pathological changes in EEG spectra, particularly an increase in gamma power. We recorded EEG from R6/2 and wild-type mice treated with modafinil acutely (with single doses between 25 and 100 mg/kg; at 12 and 16 weeks of age), or chronically (64 mg/kg modafinil/day from 6 to 15 weeks). Acutely, modafinil increased wakefulness in R6/2 mice and restored NREMS to wild-type levels at 12 weeks. It also suppressed the pathologically increased REMS. This was accompanied by decreased delta power, increased peak frequency of theta, and increased gamma power. At 16 weeks, acute modafinil also restored wakefulness and NREMS to wild-type levels. However, whilst REMS decreased, it did not return to normal levels. By contrast, in the chronic treatment group, modafinil-induced wakefulness was maintained at 15 weeks (after 9 weeks of treatment). Interestingly, chronic modafinil also caused widespread suppression of power across the EEG spectra, including a reduction in gamma that increases pathologically in R6/2 mice. The complex EEG effects of modafinil in R6/2 mice should provide a baseline for further studies to investigate the translatability of these result to clinical practice.

Local field potential power spectra and locomotor activity following treatment with pseudoephedrine in mice.

The efficacy of pseudoephedrine (PSE) as a nasal decongestant has been well­demonstrated; however, PSE is strictly prescribed as a control substance due to its controversial psychostimulant effects. Although standard stimulatory drugs increase exploratory behavior and stimulate the dopamine system, the exact effects of PSE on locomotion and electrical activity in the striatum have not been determined. This study aimed to examine and compare the locomotor activities, local field potential (LFP) and sleep­wake patterns produced by PSE and morphine, which is a standard drug used to promote psychomotor activity. Male Swiss albino mice were anesthetized and implanted with an intracranial electrode into the striatum. Animals were divided into four groups, which received either saline, PSE or morphine. Locomotor activity and LFP signals were continuously monitored following pseudoephedrine or morphine treatment. One­way ANOVA revealed that locomotor count was significantly increased by morphine, but not PSE. Frequency analyses of LFP signals using fast Fourier transform also revealed significant increases in spectral powers of low­ and high­gamma waves following treatment with morphine, but not PSE. Sleep­wake analysis also confirmed significant increases in waking and decreases in both non­rapid eye movement and rapid eye movement sleep following morphine treatment. Sleep­wakefulness did not appear to be disturbed by PSE treatment. These findings indicate that acute PSE administration, even at high doses, does not have psychostimulatory effects and may be relatively safe for the treatment of non­chronic nasal congestion.

"Sleep Surge": The impact of sleep onset and offset on epileptiform discharges in idiopathic generalized epilepsies.

OBJECTIVE: To investigate the impact of sleep onset and offset on the rate of epileptiform discharges (ED) in idiopathic generalized epilepsies (IGE). METHODS: We studied the temporal distribution of EDs with mixed-effects Poisson regression modeling in a cohort of patients diagnosed with IGE who underwent 24-hour ambulatory electroencephalography (EEG) recordings. We defined the mean number discharges per hour per subject as the mean ED rate. The association between each hour and the mean ED rate was quantified with incidence rate ratio (IRR) as the metric. We calculated the IRR of each hourly block for the total cohort in relation to sleep onset and offset. Finally, we admitted secondary risk factors into our Poisson regression model and quantified changes in IRR in order to investigate the impact of those variables on the outcome. The secondary risk factors included: epilepsy syndrome, duration of seizure freedom, duration of epilepsy, number of antiepileptic drugs (AED), type of AED, and age. RESULTS: A total of 39 patients with a mean age of 29.1 y (SD = 10.1) were studied. The distribution of ED rate demonstrated a highly significant abrupt increase in the first hour after sleep onset (IRR = 3.96; p < 0.001). On the contrary, the ED rate significantly dropped in the second hour after the sleep offset compared with the last hour block before sleep offset (IRR = 0.39; p < 0.001). None of the secondary risk factors demonstrated any significant impact on this pattern. CONCLUSIONS: Sleep onset is a very significant trigger for the generation of EDs in IGE. SIGNIFICANCE: Our results support the hypothesis that there is a "critical zone of vigilance" in the sleep-wake boundary from which generalized EDs are more likely to emerge.

Intraperitoneal injection of ginkgolide B, a major active compound of Ginkgo biloba, dose-dependently increases the amount of wake and decreases non-rapid eye movement sleep in C57BL/6 mice.

The terpene lactones of Ginkgo biloba extract, namely ginkgolides (A, B, and C) and bilobalide, possess antioxidant, anti-inflammatory, and neuroprotective effects. They are widely prescribed for the treatment of cerebral dysfunctions and neurological impairments. In addition, they demonstrate antagonistic action at the gamma-aminobutyric acid type A and glycine receptors, which are members of the ligand-gated ion channel superfamily. In the present study, the effects of ginkgolides (A, B, and C) and bilobalide on sleep in C57BL/6 mice were investigated. Ginkgolide B was found to dose-dependently increase the amount of wake and decrease that of non-rapid eye movement sleep without changes in the electroencephalography power density of each sleep/wake stage, core body temperature and locomotor activity for the first 6 h after intraperitoneal injection. Of note, the amount of wake after injection of 5 mg/kg of ginkgolide B showed a significant increase (14.9 %) compared with that of vehicle (P = 0.005). In contrast, there were no significant differences in the amount of sleep, core body temperature, and locomotor activity in the mice injected with ginkgolide A and C. Bilobalide briefly induced a decrease in locomotor activity but did not exert significant effects on the amounts of sleep and wake. The modes of action of the wake-enhancing effects of ginkgolide B are unknown. However, it may act through the antagonism of gamma-aminobutyric acid type A and glycine receptors because it is established that these inhibitory amino acids mediate sleep and sleep-related physiology. It is of interest to further evaluate the stimulant and awaking actions of ginkgolide B on the central nervous system in clinical and basic research studies.

Phagocytic elimination of synapses by microglia during sleep.

Synaptic strength reduces during sleep, but the underlying mechanisms of this process are unclear. This study showed reduction of synaptic proteins in rat prefrontal cortex (PFC) at AM7 or Zeitgeber Time (ZT0), when the light phase or sleeping period for rats started. At this time point, microglia were weakly activated, displaying larger and more granular somata with increased CD11b expression compared with those at ZT12, as revealed by flow cytometry. Expression of opsonins, such as complements or MFG-E8, matrix metalloproteinases, and microglial markers at ZT0 were increased compared with that at ZT12. Microglia at ZT0 phagocytosed synapses, as revealed by immunohistochemical staining. Immunoblotting detected more synapsin I in the isolated microglia at ZT0 than at ZT12. Complement C3- or MFG-E8-bound synapses were the most abundant at ZT0, some of which were phagocytosed by microglia. Systemic administration of synthetic glucocorticoid dexamethasone reduced microglial size, granularity and CD11b expression at ZT0, resembling microglia at ZT12, and increased synaptic proteins and decreased the sleeping period. Noradrenaline (NA) suppressed glutamate-induced phagocytosis in primary cultured microglia. Systemic administration of the brain monoamine-depleting agent reserpine decreased NA content and synapsin I expression in PFC, and increased expression of microglia markers, C3 and MFG-E8, while increasing the sleeping period. A NA precursor l-threo-dihydroxyphenylserine abolished the reserpine-induced changes. These results suggest that microglia may eliminate presumably weak synapses during every sleep phase. The circadian changes in concentrations of circulating glucocorticoids and brain NA might be correlated with the circadian changes of microglial phenotypes and synaptic strength.

Alcohol use disorder and sleep disturbances: a feed-forward allostatic framework.

The development of alcohol use disorder (AUD) involves binge or heavy drinking to high levels of intoxication that leads to compulsive intake, the loss of control in limiting intake, and a negative emotional state when alcohol is removed. This cascade of events occurs over an extended period within a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three heuristic stages map onto the dysregulation of functional domains of incentive salience/habits, negative emotional states, and executive function, mediated by the basal ganglia, extended amygdala, and frontal cortex, respectively. Sleep disturbances, alterations of sleep architecture, and the development of insomnia are ubiquitous in AUD and also map onto the three stages of the addiction cycle. During the binge/intoxication stage, alcohol intoxication leads to a faster sleep onset, but sleep quality is poor relative to nights when no alcohol is consumed. The reduction of sleep onset latency and increase in wakefulness later in the night may be related to the acute effects of alcohol on GABAergic systems that are associated with sleep regulation and the effects on brain incentive salience systems, such as dopamine. During the withdrawal/negative affect stage, there is a decrease in slow-wave sleep and some limited recovery in REM sleep when individuals with AUD stop drinking. Limited recovery of sleep disturbances is seen in AUD within the first 30 days of abstinence. The effects of withdrawal on sleep may be related to the loss of alcohol as a positive allosteric modulator of GABAA receptors, a decrease in dopamine function, and the overactivation of stress neuromodulators, including hypocretin/orexin, norepinephrine, corticotropin-releasing factor, and cytokines. During the preoccupation/anticipation stage, individuals with AUD who are abstinent long-term present persistent sleep disturbances, including a longer latency to fall asleep, more time awake during the night, a decrease in slow-wave sleep, decreases in delta electroencephalogram power and evoked delta activity, and an increase in REM sleep. Glutamatergic system dysregulation that is observed in AUD is a likely substrate for some of these persistent sleep disturbances. Sleep pathology contributes to AUD pathology, and vice versa, possibly as a feed-forward drive to an unrecognized allostatic load that drives the addiction process.