Cannabinoids and sleep-wake cycle: The potential role of serotonin.

Cannabis sativa (Marijuana) has a long history as a medicinal plant and Δ9-tetrahydrocannabinol (Δ9-THC) is the most active component in this plant. Cannabinoids are interesting compounds with various modulatory effects on physiological processes and cognitive functions. The use of cannabinoids is a double-edged sword, because they induce both adverse and therapeutic properties. One of the most important roles of cannabinoids is modulating sleep-wake cycle. Sleep, its cycle, and its mechanism are highly unknown. Also, the effects of cannabinoids on sleep-wake cycle are so inconsistent. Thus, understanding the role of cannabinoids in modulating sleep-wake cycle is a critical scientific goal. Cannabinoids interact with many neurotransmitter systems. In this review article, we chose serotonin due to its important role in regulating sleep-wake cycle. We found that the interaction between cannabinoids and serotonergic signaling especially in the dorsal raphe is extensive, unknown, and controversial.

Cervical transcutaneous vagal nerve stimulation (ctVNS) improves human cognitive performance under sleep deprivation stress.

Fatigue is a pervasive public health and safety issue. Common fatigue countermeasures include caffeine or other chemical stimulants. These can be effective in limited circumstances but other non-pharmacological fatigue countermeasures such as non-invasive electrical neuromodulation have shown promise. It is reasonable to suspect that other types of non-invasive neuromodulation may be similarly effective or perhaps even superior. The objective of this research was to evaluate the efficacy of cervical transcutaneous vagal nerve stimulation (ctVNS) to mitigate the negative effects of fatigue on cognition and mood. Two groups (active or sham stimulation) of twenty participants in each group completed 34 h of sustained wakefulness. The ctVNS group performed significantly better on arousal, multi-tasking, and reported significantly lower fatigue ratings compared to sham for the duration of the study. CtVNS could be a powerful fatigue countermeasure tool that is easy to administer, long-lasting, and has fewer side-effects compared to common pharmacological interventions.

Characterization of pharmaco-EEG fingerprint and sleep-wake profiles of Lavandula angustifolia Mill. essential oil inhalation and diazepam administration in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Lavandula angustifolia Mill. Essential oil (Lavender EO) has a long history of medicinal use and is particularly claimed to possess anxiolytic and sedative properties. Lavender EO aromatherapy has been used to reduce distress and improve insomnia naturally. Increasing evidence appeared to show similarities between the effects of lavender EO and the anxiolytic drugs, benzodiazepines. However, its effects on sleep-wake and electrical brain patterns in comparison to that of the standard anxiolytic, diazepam, remained to be explored. AIM OF THE STUDY: The aim of this work was to investigate electroencephalography (EEG) profiles and sleep-pattern elicited by lavender EO inhalation compared to that of diazepam, a standard anxiolytic drug in in vivo rat model. MATERIALS AND METHODS: Adult male Wistar rats were anesthetized for electrode implantation on the frontal and parietal skulls. EEG signals were recorded for 180 min following intraperitoneal injection of diazepam (10 mg/kg) or during continuous inhalation of lavender EO (200 µL) or distilled water (control). Fast Fourier transform was used for the analyses of EEG power spectra and sleep-wake parameters. RESULTS: During a 30-60 min period, diazepam and lavender EO significantly increased frontal powers of 0.78-45.31 and 7.03-18.36 Hz, respectively. Both treatments also increased parietal powers with lower magnitudes of significant change. Significant increases in some frequency ranges remained until a 60-90 min period. Sleep-wake analyses also revealed that diazepam significantly reduced time spent in wake, increased time spent in non-rapid eye movement (NREM), increased episode duration of NREM, decreased numbers of wake episode and decreased rapid eye movement (REM) sleep latency. On the other hand, lavender EO only significantly decreased wake episodes and latency to REM sleep. Lavender EO inhalation reduced numbers of wake episode but maintain normal time spent in wake, NREM and REM sleeps. CONCLUSIONS: These findings might suggest beneficial and distinct anxiolytic-like effects of lavender EO for sleep enhancing purposes.

Coffee effectively attenuates impaired attention in ADORA2A C/C-allele carriers during chronic sleep restriction.

Many people consume coffee to attenuate increased sleepiness and impaired vigilance and attention due to insufficient sleep. We investigated in genetically caffeine sensitive men and women whether 'real world' coffee consumption during a simulated busy work week counteracts disabling consequences of chronically restricted sleep. We subjected homozygous C-allele carriers of ADORA2A (gene encoding adenosine A2A receptors) to five nights of only 5 h time-in-bed. We administered regular coffee (n = 12; 200 mg caffeine at breakfast and 100 mg caffeine after lunch) and decaffeinated coffee (n = 14) in double-blind fashion on all days following sleep restriction. At regular intervals four times each day, participants rated their sleepiness and performed the psychomotor vigilance test, the visual search task, and the visuo-spatial and letter n-back tasks. At bedtime, we quantified caffeine and the major caffeine metabolites paraxanthine, theobromine and theophylline in saliva. The two groups did not differ in age, body-mass-index, sex-ratio, chronotype and mood states. Subjective sleepiness increased in both groups across consecutive sleep restriction days and did not differ. By contrast, regular coffee counteracted the impact of repeated sleep loss on sustained and selective attention, as well as executive control when compared to decaffeinated coffee. The coffee also induced initial or transient benefits on different aspects of baseline performance during insufficient sleep. All differences between the groups disappeared after the recovery night and the cessation of coffee administration. The data suggest that 'real world' coffee consumption can efficiently attenuate sleep restriction-induced impairments in vigilance and attention in genetically caffeine sensitive individuals. German Clinical Trial Registry: # DRSK00014379.

The Effect of Coffee and Caffeine Consumption on Patients with Multiple Sclerosis-Related Fatigue.

Background: Coffee and caffeine are considered to have beneficial effects in patients with multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) that can lead to disability and chronic fatigue. Methods: In the present study the preference in terms of coffee and caffeine consumption in patients with MS was assessed. In total the opinions of 124 MS patients were explored with a questionnaire, which was developed to investigate the consumption behavior and associated beneficial and harmful effects of coffee and caffeine concerning symptoms of fatigue. Results: Our study showed that 37.1% of the included patients experience severe symptoms of fatigue. In our cohort, fatigue was not related to age, type of diagnosis or duration of the disease. The effects of coffee did not differ between MS patients with and without fatigue. Very few side effects linked to coffee consumption were reported, and we could demonstrate that coffee consumption had no negative impact on quality of sleep. A positive effect on everyday life was observed particularly among patients with a mid-level expanded disability status scale (EDSS). The strongest effects of coffee consumption were observed regarding a better ability to concentrate while fulfilling tasks, an expanded attention span and a better structured daily routine. Conclusions: Since coffee showed no severe side effects and in the absence of an effective fatigue therapy, coffee consumption might be a therapeutic approach for selected patients with MS-related fatigue.

Putative TAAR5 agonist alpha-NETA affects event-related potentials in oddball paradigm in awake mice.

Trace amines have been reported to be neuromodulators of monoaminergic systems. Trace amines receptor 5 (TAAR5) is expressed in several regions of mice central nervous system, such as amygdala, arcuate nucleus and ventromedial hypothalamus, but very limited information is available on its functional role. The purpose of this study is to examine the effect of TAAR5 agonist alpha-NETA on the generation of mismatch negativity (MMN) analogue in C57BL/6 mice. Event-related potentials have been recorded from awake mice in oddball paradigms before and after the alpha-NETA administration. Alpha-NETA has been found to decrease N40 MMN-like difference, which resulted from the increased response to standard stimuli. An opposite effect has been found for the P80 component: the amplitude increased in response both to standard and deviant stimuli. A significant increase in N40 peak latency after the alpha-NETA administration has been found. This may suggest a reduced speed of information processing similar to the increase in P50 and N100 components latencies in schizophrenia patients. These results provide new evidence for a role of TAAR5 in cognitive processes.

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.

Melatonin inhibits GABAergic neurons in the hypothalamus consistent with a reduction in wakefulness.

Although melatonin is necessary for circadian regulation of sleep, the mechanisms underlying this effect of melatonin are still unclear. In the present study, we showed that melatonin suppressed the activity of GABAergic neurons in the lateral hypothalamus, which has been reported to play a crucial role in maintaining wakefulness. The inhibitory effect of the melatonin was mediated by activation of melatonin 1 receptors and depended on the inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels. At behavioral levels, infusion of melatonin into the lateral hypothalamus significantly decreased the locomotor and exploratory activities and increased the time of immobility in open filed. Additionally, using electroencephalogram (EEG) and electromyogram (EMG) recordings, we found that infusion of melatonin into the lateral hypothalamus decreased the time spent in wakefulness and increased the amount of sleep. Overall, these results suggest that melatonin inhibits GABAergic neurons in the lateral hypothalamus via melatonin 1 receptor-dependent inhibition of the HCN channels, which is consistent with a decrease in wakefulness. These findings provide a new mechanism underlying the hypnotic effect of the melatonin.

Can the Orexin Antagonist Suvorexant Preserve the Ability to Awaken to Auditory Stimuli While Improving Sleep?

STUDY OBJECTIVES: The safety profile of the dual orexin receptor antagonists (DORAs) are currently unknown with regard to nocturnal responsivity among people with insomnia. We compared the auditory awakening thresholds (AATs) of the DORA suvorexant (10 and 20 mg) versus placebo in 12 individuals with DSM-5 insomnia. METHODS: The study used a double-blind, placebo-controlled, three-way crossover design. Participants were randomly assigned to a treatment sequence that included placebo, suvorexant 10 mg, and suvorexant 20 mg. At the time of maximum drug concentration, auditory tones were played during stable stage N2 sleep. Tones increased by 5-decibel (db) increments until the participant awakened. The db at awakening was recorded as the AAT and compared between conditions. The proportion of awakenings higher than 85 db was also compared between conditions. Finally, sensitivity analyses were also conducted using surrounding thresholds (80 db and 90 db). RESULTS: The mean AAT did not differ significantly between either dose of suvorexant compared to placebo. Moreover, the proportions of individuals who remained asleep at the AAT 85 db cutoff did not differ across conditions. In addition, wake after sleep onset decreased and total sleep time increased in the suvorexant 20 mg condition compared to placebo. CONCLUSIONS: Suvorexant (10 and 20 mg) preserved the ability to respond to nocturnal stimuli, whereas the 20-mg dose improved the sleep of people with insomnia. This suggests that DORAs such as suvorexant can effectively treat insomnia while allowing patients to awaken to nocturnal stimuli in the environment. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: A Phase IV 3-Way Double-blind, Randomized, Crossover Study to Compare the Awakening Threshold Effects (Responsivity) of Belsomra 10 mg and 20 mg to Placebo in Non-elderly Insomniacs; Identifier NCT03312517; URL: https://clinicaltrials.gov/ct2/show/NCT03312517. CITATION: Drake CL, Kalmbach DA, Cheng P, Roth T, Tran KM, Cuamatzi-Castelan A, Atkinson R, SinghM, Tonnu CV, Fellman-Couture C. Can the orexin antagonist suvorexant preserve the ability to awaken to auditory stimuli while improving sleep? J Clin Sleep Med. 2019;15(9):1285-1291.

Effects of Xingnaojing Injection on Adenosinergic Transmission and Orexin Signaling in Lateral Hypothalamus of Ethanol-Induced Coma Rats.

Acute alcohol exposure induces unconscious condition such as coma whose main physical manifestation is the loss of righting reflex (LORR). Xingnaojing Injection (XNJI), which came from Chinese classic formula An Gong Niu Huang Pill, is widely used for consciousness disorders in China, such as coma. Although XNJI efficiently shortened the duration of LORR induced by acute ethanol, it remains unknown how XNJI acts on ethanol-induced coma (EIC). We performed experiments to examine the effects of XNJI on orexin and adenosine (AD) signaling in the lateral hypothalamic area (LHA) in EIC rats. Results showed that XNJI reduced the duration of LORR, which implied that XNJI promotes recovery form coma. Microdialysis data indicated that acute ethanol significantly increased AD release in the LHA but had no effect on orexin A levels. The qPCR results displayed a significant reduction in the Orexin-1 receptors (OX1R) expression with a concomitant increase in the A1 receptor (A1R) and equilibrative nucleoside transporter type 1 (ENT1) expression in EIC rats. In contrast, XNJI reduced the extracellular AD levels but orexin A levels remained unaffected. XNJI also counteracted the downregulation of the OX1R expression and upregulation of A1R and ENT1 expression caused by EIC. As for ADK expression, XNJI but not ethanol, displayed an upregulation in the LHA in EIC rats. Based on these results, we suggest that XNJI promotes arousal by inhibiting adenosine neurotransmission via reducing AD level and the expression of A1R and ENT1.

Pinelliae Rhizoma Praeparatum Cum Alumine Extract: Sedative and Hypnotic Effects in Mice and Component Compounds.

Pinelliae Rhizoma Praeparatum Cum Alumine (PRPCA) is useful for eliminating dampness and phlegm in clinical settings, targeting the main mechanisms of insomnia as defined in traditional Chinese medicine. However, little is known regarding the sedative and hypnotic effects of PRPCA. In the present study, we examined the sedative effects of PRPCA via a locomotor activity test and aimed to determine the most appropriate concentration of PRPCA for achieving these effects. The strongest sedative effects were observed at a PRPCA concentration of 0.45 g/ml. In addition, we investigated the hypnotic effects of PRPCA and its role in promoting sleep via sleep monitoring and vigilance state analysis. PRPCA increased rapid eye movement (REM) sleep and non-REM (NREM) sleep while decreasing wakefulness. In addition, PRPCA decreased the number of bouts of wakefulness (16-32 s and 32-64 s) and increased the number of bouts of NREM sleep (128-256 s). Furthermore, we identified a total of 32 component compounds via chromatography and mass spectrometry. Hence, the current work provides valuable information regarding the sedative and hypnotic effects of PRPCA and its regulatory mechanisms in promoting sleep.

Ethanol Induces Sedation and Hypnosis via Inhibiting Histamine Release in Mice.

Ethanol is one of the most highly abused psychoactive compounds worldwide and induces sedation and hypnosis. The histaminergic system is involved in the regulation of sleep/wake function and is a crucial player in promoting wakefulness. To explore the role and mechanism of the histaminergic system in ethanol-induced sedation and hypnosis, we recorded locomotor activity (LMA) and electroencephalography (EEG)/electromyography (EMG) in mice using an infrared ray passive sensor recording system and an EEG/EMG recording system, respectively, after administration of ethanol. In vivo microdialysis coupled with high performance liquid chromatography and fluorometry technology were used to detect histamine release in the mouse frontal cortex (FrCx). The results revealed that ethanol significantly suppressed LMA of histamine receptor 1 (H1R)-knockout (KO) and wild-type (WT) mice in the range of 1.5-2.5 g/kg, but suppression was remarkably stronger in WT mice than in H1R-KO mice. At 2.0 and 2.5 g/kg, ethanol remarkably increased non-rapid eye movement sleep and decreased wakefulness, respectively. Neurochemistry experimental data indicated that ethanol inhibited histamine release in the FrCx in a dose-dependent manner. These findings suggest that ethanol induces sedation and hypnosis via inhibiting histamine release in mice.

Chronic Suppression of Hypothalamic Cell Proliferation and Neurogenesis Induces Aging-Like Changes in Sleep-Wake Organization in Young Mice.

Aging is associated with sleep-wake disruption, dampening of circadian amplitudes, and a reduced homeostatic sleep response. Aging is also associated with a decline in hypothalamic cell proliferation. We hypothesized that the aging-related decline in cell-proliferation contributes to the dysfunction of preoptic-hypothalamic sleep-wake and circadian systems and consequent sleep-wake disruption. We determined if cytosine-ß-D-arabinofuranoside (AraC), an antimitotic agent known to suppress hypothalamic cell proliferation and neurogenesis, causes sleep-wake instability in young mice. The sleep-wake profiles were compared during baseline, during 4 weeks of artificial cerebrospinal fluid (aCSF) + 5-bromo-2'-deoxyuridine (BrdU) or AraC+BrdU infusion into the lateral ventricle, and 8 weeks after treatments. The sleep-wake architecture after AraC treatment was further compared with sleep-wake profiles in aged mice. Compared to aCSF+BrdU, 4 weeks of AraC+BrdU infusion significantly decreased (-96%) the number of BrdU+ cells around the third ventricular wall and adjacent preoptic-hypothalamic area and produced a) sleep disruption during the light phase with decreases in non-rapid eye movement (nonREM) (-9%) and REM sleep (-21%) amounts, and increased numbers of shorter (<2 min; 142 versus 98 episodes/12 h) and decreased numbers of longer (>5 min; 19 versus 26 episodes/12 h) nonREM sleep episodes; and b) wake disruption during the dark phase, with increased numbers of shorter (138 versus 91 episodes/12 h) and decreased numbers of longer active waking (17 versus 24 episodes/12 h) episodes. AraC-treated mice also exhibited lower delta activity within nonREM recovery sleep. The sleep-wake architecture of AraC-treated mice was similar to that observed in aged mice. These findings are consistent with a hypothesis that a decrease in hypothalamic cell proliferation/neurogenesis is detrimental to sleep-wake and circadian systems and may underlie sleep-wake disturbance in aging.

Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function.

Insomnia is one of the most common sleep problems with an estimated prevalence of 10%-15% in the general population. Although adenosine A2A receptor (A2AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A2AR signaling, however, may be an alternative strategy for treating insomnia, because adenosine levels in the brain accumulate during wakefulness. In the present study, we found that 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid, denoted A2AR positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the A2AR and induced slow wave sleep (SWS) without affecting body temperature in wild-type male mice after intraperitoneal administration, whereas the SWS-inducing effect of this benzoic acid derivative was abolished in A2AR KO mice. In contrast to the A2AR agonist CGS 21680, the A2AR PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing A2AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A2ARs could help people with insomnia to fall asleep.

Melatonin protects embryonic development and maintains sleep/wake behaviors from the deleterious effects of fluorene-9-bisphenol in zebrafish (Danio rerio).

Environmental endocrine chemicals have various adverse effects on the development of vertebrates. Fluorene-9-bisphenol (BHPF), a substitute of bisphenol A (BPA), is widely used in commercial production. The effects of BHPF on development and behavior are unclear. Melatonin plays a protective role under many unfavorable conditions. In this study, we investigated the effects of BHPF on the development and behaviors of zebrafish and whether melatonin reverses effects induced by BHPF. Zebrafish embryos were exposed to 0.1, 10, or 1000 nmol/L BHPF with or without 1 µmol/L melatonin from 2 hours postfertilization to 6 days postfertilization. The results showed that 0.1 and 10 nmol/L BHPF had little effect on development. High-dose BHPF (1000 nmol/L) delayed the development, increased mortality and surface tension of embryonic chorions, caused aberrant expression of the key genes (ntl, shh, krox20, pax2, cmlc2) in early development detected by in situ hybridization, and damaged the CaP motor neurons, which were associated with locomotion ability detected by immunofluorescence. Melatonin addition reversed or weakened these adverse effects of BHPF on development, and melatonin alone increased surface tension as the effects of high-dose BHPF. However, all groups of BHPF exposure triggered insomnia-like behaviors, with increased waking activity and decreased rest behaviors. BHPF acted on the hypocretin (hcrt) system and upregulated the expression of sleep/wake regulators such as hcrt, hcrt receptor (hcrtr), arylalkylamine N-acetyltransferase-2 (aanat2). Melatonin recovered the alternation of sleep/wake behaviors induced by BHPF and restored abnormal gene expression to normal levels. This study showed that high-dose BHPF had adverse effects on early development and induced behavioral alternations. However, melatonin prevented BHPF-induced aberrant development and sleep/wake behaviors.

Rongchang and Xifeng capsules suppress pentylenetetrazole-induced seizures and change rest/wake behavior in zebrafish larvae.

OBJECTIVE: To evaluate the effects of Rongchang capsule and Xifeng capsule on pentylenetetrazole- induced epilepsy in zebrafish larvae and to explore the possible mechanisms behind their actions. METHODS: We utilized a trajectory tracking system to monitor seizures in zebrafish larva to confirm that certain concentrations of Rongchang capsule and Xifeng capsule produce antiepileptic effects. c-fos expression was assessed by quantitative reverse transcription-polymerase chain reaction to validate the efficacy of the capsules. Rest/wake behavior and correlation analysis predicted the targets of Rongchang capsule and Xifeng capsule. RESULTS: Larval movement times and total distances traveled by zebrafish larvae experiencing pentylenetetrazole (PTZ)-induced seizures were decreased by valproate treatment. Rongchang (500 µg/mL) and Xifeng (200 µg/mL) rescued the epileptic behaviors and down-regulated c-fos expression in the brains of larvae, which indicated antiepileptic effects. The rest/wake behavioral profiles showed that Rongchang and Xifeng differentially decreased rest time at night and increased larval locomotor activities during the day. Based on correlation between the actions of the two capsules and known compounds, we predicted that they might change rest/wake behaviors by affecting serotonin, GABAergic and histamine signaling pathways. CONCLUSION: The efficacy of Rongchang capsule and Xifeng capsule in alleviating epilepsy-like behaviors and molecular responses was confirmed. Our study provides insight into the capsules' effect on epilepsy.

General Anesthesia versus Local Anesthesia for Deep Brain Stimulation in Parkinson's Disease: A Meta-Analysis.

BACKGROUND: Deep brain stimulation (DBS) implantation under general anesthesia (GA) is of great importance for patients with disabling off-medication symptoms or medical comorbidities. However, the relative advantages/disadvantages of routine local anesthesia (LA) surgery versus GA regarding clinical outcomes are controversial, and the safety of DBS implantation under GA is debatable. SUMMARY: We systematically reviewed the literature to compare the efficacy and safety of awake and asleep DBS surgery. We identified cohort studies from the Cochrane library, MEDLINE, and EMBASE (January 1970 to August 2019) by using Review Manager 5.3 software to conduct a meta-analysis following the PRISMA guidelines. Fourteen cohort studies involving 1,523 patients were included. The meta-analysis results showed that there were no significant differences between the GA and LA groups in UPDRSIII score improvement (standard mean difference [SMD] 0.06; 95% CI -0.16 to 0.28; p = 0.60), postoperative LEDD requirement (SMD -0.17; 95% CI -0.44 to 0.12; p = 0.23), or operation time (SMD 0.18; 95% CI -0.31 to 0.67; p = 0.47). Additionally, there was no significant difference in the incidence of adverse events (OR 0.98; 95% CI 0.53-1.80; p = 0.94), including postoperative speech disturbance and intracranial hemorrhage. However, the volume of intracranial air was significantly lower in the GA group than that in the LA group. In a subgroup analysis, there was no significant difference in clinical efficacy between the microelectrode recording (MER) and non-MER groups. We demonstrated equivalent clinical outcomes of DBS surgery between GA and LA in terms of improvement of symptoms and the incidence of adverse events. Key Messages: MER might not be necessary for DBS implantation. For patients who cannot tolerate DBS surgery while being awake, GA should be an appropriate alternative.

Effect of crocetin on quality of sleep: A randomized, double-blind, placebo-controlled, crossover study.

OBJECTIVES: The aim of the present study was to investigate the effect of crocetin on sleep architecture and subjective sleep parameters in healthy adult participants with mild sleep complaints. DESIGN: A randomized, double-blind, placebo-controlled, crossover study with two intervention periods of 14 days each, separated by a 14-day wash-out period. INTERVENTIONS: Thirty participants were randomly assigned to one of two sequence groups. Each group was given crocetin at 7.5 mg/day, or placebo. We measured objective sleep parameters using single-channel electroencephalography and assessed subjective sleep parameters using the Oguri-Shirakawa-Azumi Sleep Inventory, Middle-age and Aged version (OSA-MA). MAIN OUTCOME MEASURES: Differences between crocetin and placebo in an objective sleep parameter (delta power), and OSA-MA scores. RESULTS: Delta power was significantly increased with crocetin compared with placebo. There were no significant differences in the other sleep parameters, including sleep latency, sleep efficiency, total sleep time, and wake after sleep onset. Subjective scores for sleepiness on rising and feeling refreshed were significantly improved with crocetin compared with placebo. CONCLUSIONS: The findings of the present study suggest that crocetin supplementation contributes to sleep maintenance, leading to improved subjective sleep quality.

Chronic Consumption of Fructose Induces Behavioral Alterations by Increasing Orexin and Dopamine Levels in the Rat Brain.

It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleep⁻wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleep⁻wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleep⁻wake cycle.

[Development of a Therapeutic Drug for Narcolepsy].

Narcolepsy-cataplexy is a debilitating disorder characterized by excessive daytime sleepiness and cataplexy, a bilateral loss of muscle tone triggered by positive emotions. The disease is caused by the loss of orexin-producing neurons in the hypothalamus. Currently, only symptom-oriented therapies are available for narcolepsy. We have recently discovered a potent, non-peptide orexin type-2 receptor (OX2R) agonist, YNT-185. We show that peripheral administration of YNT-185 significantly ameliorated the narcolepsy symptoms in a mouse model for narcolepsy. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof -of-concept for mechanistic therapy for narcolepsy-cataplexy using OX2R agonists. Additionally, YNT-185 promoted wakefulness in wild-type mice, suggesting that orexin receptor agonists may be useful for the treatment of excessive daytime sleepiness due to other conditions, such as sleepiness accompanying depression and sleepiness due to side effects of medicines or jet lag/shift work.