Histaminergic neurotransmission in aging and Alzheimer's disease: A review of therapeutic opportunities and gaps.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorderfeaturing a brain accumulation of extracellular ß-amyloidplaques (Aß) and intracellular neurofibrillary tautangles (NFTs). Although cognitive decline is a disease-defining symptom of AD, sleep dysfunction, a common symptom often preceding cognitive decline, hasrecently gained more attention as a core AD symptom. Polysomnography and othersleep measures show sleep fragmentation with shortening of N3 sleep togetherwith excessive daytime sleepiness (EDS) and sundowning as the main findings in AD patients. The latter reflects dysfunction of the wake-promoting neurons (WPNs), including histaminergic neurons (HAN) located in thetuberomammillary nucleus (TMN) of the posterior hypothalamus, which projectunmyelinated axons to various parts of the brain. Histamine's role in cognitionand arousal is broadly recognized. Selective targeting of histaminergic subtype-3 and 4 receptors show therapeutic potential in rodent models of AD andaging. Method: Based on PubMed, Scopus, and google scholar databases search, this review summarizes the current knowledge on the histaminergic system in AD and aging, its therapeutic potential in AD, and highlight areas where moreresearch is needed. Results: Animal studies have demonstrated that pharmacological manipulation of histaminergic receptors or histamine supplementation improves cognition in AD models. However, measurements of HA or HA metabolite levels in the human brainand CSF present contradictory reports due to either lack of power or controls for known confounders. Discussion: Systemic studies including broad age, sex, neuropathological diagnosis, and disease stage are warranted to fill the gap in our current understanding of the histaminergic neurotransmitter/neuromodulator system in humans, especially age-related changes, and therapeuticpotential of histamine in AD-related dysfunction.

Comparative Efficacy and Safety of Multiple Wake-Promoting Agents for the Treatment of Excessive Daytime Sleepiness in Narcolepsy: A Network Meta-Analysis.

Purpose: Narcolepsy is a rare debilitating disorder for which multiple novel pharmacological options have been approved as treatment for the past few years. The current study systematically updates the comparative efficacy and detailed safety analysis of approved wake-promoting agents in narcolepsy. Methods: Randomized controlled trials (RCTs) were searched for diagnosed narcolepsy with approved interventions. Efficacy outcomes included the Maintenance of Wakefulness Test (MWT), Epworth Sleepiness Scale (ESS), Clinical Global Impression of Change (CGI-C), and Patient Global Impression of Change (PGI-C). Safety outcomes including overall adverse event (AE) risk were measured. The study was registered at PROSPERO (CRD 42022334915). Results: The final analysis included 17 RCTs with five drug treatments: modafinil/armodafinil, sodium oxybate, pitolisant, solriamfetol, and lower-sodium oxybate (LXB). For efficacy measures, interventions included in each outcome were effective compared with placebo. Furthermore, the magnitude of solriamfetol effect on MWT (9.11 minutes; 95% CI=7.05-11.16), ESS (-4.79; 95% CI=-6.56 to -3.01), and PGI-C (9.39; 95% CI= 2.37-37.19), and LXB effect on CGI-C (9.67; 95% CI=2.73-34.26) was greater than that of other treatments included in each outcome compared with placebo. For safety measures, all interventions had an acceptable safety profile with LXB having least risk for overall AEs (0.56; 95% CI=0.20-1.53), serious AEs (0.33; 95% CI=0.09-1.20), AEs leading to treatment discontinuation (0.11; 95% CI=0.01-2.04), and all-cause discontinuation (0.04; 95% CI=0.00-0.67) compared to placebo. Placebo had the lowest risk for exploratory AEs. Conclusion: All approved interventions were effective in controlling the symptoms of narcolepsy at varying degrees with an acceptable safety profile.

[Xingnao Kaiqiao acupuncture on promoting wake-up of consciousness disorder in children with early severe traumatic brain injury].

OBJECTIVE: To observe the awakening effect and safety of Xingnao Kaiqiao (regaining consciousness and opening orifices) acupuncture on consciousness disorder in children with early severe traumatic brain injury (STBI) based on western medicine treatment. METHODS: A total of 62 children with STBI were randomly divided into an observation group (31 cases,1 case dropped off) and a control group (31 cases, 1 case dropped off). The control group was treated with routine rehabilitation therapy (6 times a week for 30 days), and intravenous drip of cattle encephalon glycoside and ignotin injection (once a day for 28 days). On the basis of the treatment in the control group, the observation group was treated with Xingnao Kaiqiao acupuncture at Neiguan (PC 6), Shuigou (GV 26), Yintang (GV 24+), Baihui (GV 20), Sanyinjiao (SP 6), Zusanli (ST 36), etc., and supplementary acupoints according to clinical symptoms, once a day, 6 times a week for 30 days. The scores of Glasgow coma scale (GCS), coma recovery scale-revised (CRS-R) and modified Barthel index (MBI) were observed before treatment and 10, 20 and 30 d into treatment. Electroencephalogram (EEG) grading before and after treatment was observed in the two groups, and safety was evaluated. RESULTS: After 10, 20 and 30 days of treatment, the scores of GCS, CRS-R and MBI in the two groups were increased compared before treatment (P<0.05), and those in the observation group were higher than the control group (P<0.05). After treatment, EEG grading of both groups was improved compared with that before treatment (P<0.05), and the observation group was better than the control group (P<0.05). There were no adverse events or adverse reactions in the two groups during treatment. CONCLUSION: On the basis of western medicine treatment, Xingnao Kaiqiao acupuncture plays a remarkable role in wakening the early STBI children, can improve the level of consciousness disorder and daily living ability, and it is safe and effective.

Symptom Severity and Treatment Satisfaction in Patients with Idiopathic Hypersomnia: The Real World Idiopathic Hypersomnia Outcomes Study (ARISE).

Objective: Idiopathic hypersomnia is a debilitating sleep disorder characterized by excessive daytime sleepiness, sleep inertia, and prolonged sleep duration. The patient burden of idiopathic hypersomnia is poorly understood. The Real World Idiopathic Hypersomnia Outcomes Study (ARISE) evaluated symptoms and treatment effectiveness/satisfaction in participants with idiopathic hypersomnia. Methods: ARISE was a United States-based virtual cross-sectional survey. Participants were adults 21-65 years of age with idiopathic hypersomnia recruited from social media, the Hypersomnia Foundation website, and a patient panel. Self-assessments included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Treatment Satisfaction Questionnaire for Medication, version II (TSQM-vII), and additional treatment questions. Data were analyzed for all participants and for subgroups with/without long sleep time (LST; ≥11 hours in 24 hours). Results: Of 75 participants enrolled, most were female (81.3%). The mean (SD) age was 34.1 (10.7) years and 49% had LST. Most participants took off-label prescription medications (89.3%) and/or used other measures (93.3%) to manage their symptoms. The mean (SD) ESS score was 14.5 (3.5) and the mean IHSS score was 35.2 (7.6). Treatment satisfaction was low (mean [SD] TSQM-vII score: overall, 61.9 [21.2]; with LST, 57.9 [21.4]; without LST, 66.7 [20.3]), primarily driven by dissatisfaction with treatment effectiveness. The most common classes of prescription medications used were stimulants (61.3%), wake-promoting agents (28.0%), and antidepressants (18.7%); non-prescription measures used to manage symptoms included caffeine (73.3%), planned naps (34.7%), and individual accommodations (32.0%). Conclusion: Overall, participants with idiopathic hypersomnia, with or without LST, had substantial symptom burden despite most of the study population taking off-label medications and using nonprescription measures to manage symptoms.

Xingnao Kaiqiao acupuncture on promoting wake-up of consciousness disorder in children with early severe traumatic brain injury / 中国针灸

OBJECTIVE@#To observe the awakening effect and safety of Xingnao Kaiqiao (regaining consciousness and opening orifices) acupuncture on consciousness disorder in children with early severe traumatic brain injury (STBI) based on western medicine treatment.@*METHODS@#A total of 62 children with STBI were randomly divided into an observation group (31 cases,1 case dropped off) and a control group (31 cases, 1 case dropped off). The control group was treated with routine rehabilitation therapy (6 times a week for 30 days), and intravenous drip of cattle encephalon glycoside and ignotin injection (once a day for 28 days). On the basis of the treatment in the control group, the observation group was treated with Xingnao Kaiqiao acupuncture at Neiguan (PC 6), Shuigou (GV 26), Yintang (GV 24+), Baihui (GV 20), Sanyinjiao (SP 6), Zusanli (ST 36), etc., and supplementary acupoints according to clinical symptoms, once a day, 6 times a week for 30 days. The scores of Glasgow coma scale (GCS), coma recovery scale-revised (CRS-R) and modified Barthel index (MBI) were observed before treatment and 10, 20 and 30 d into treatment. Electroencephalogram (EEG) grading before and after treatment was observed in the two groups, and safety was evaluated.@*RESULTS@#After 10, 20 and 30 days of treatment, the scores of GCS, CRS-R and MBI in the two groups were increased compared before treatment (P<0.05), and those in the observation group were higher than the control group (P<0.05). After treatment, EEG grading of both groups was improved compared with that before treatment (P<0.05), and the observation group was better than the control group (P<0.05). There were no adverse events or adverse reactions in the two groups during treatment.@*CONCLUSION@#On the basis of western medicine treatment, Xingnao Kaiqiao acupuncture plays a remarkable role in wakening the early STBI children, can improve the level of consciousness disorder and daily living ability, and it is safe and effective.

Factors affecting postoperative short-term improvement of consciousness level in patients with prolonged disorders of consciousness after severe traumatic brain injury / 中华创伤杂志

Objective:To investigate the factors affecting postoperative short-term improvement of consciousness level in patients with prolonged disorders of consciousness after severe traumatic brain injury (sTBI).Methods:A case-control study was conducted to analyze the clinical data of 55 patients with prolonged disorders of consciousness after sTBI admitted to Beijing Tiantan Hospital Affiliated to Capital Medical University and Seventh Medical Center of PLA General Hospital from September 2021 to September 2022. There were 33 males and 22 females, with the age range of 13-68 years [(43.0±15.5)years]. All patients were assessed for the consciousness level using the coma recovery scale-revision (CRS-R) preoperatively and within 48 hours postoperatively. A total of 33 patients were observed in vegetative state and 22 in minimally conscious state preoperatively. The consciousness level was found to be improved in 26 patients (consciousness- improved group), but not improved in the remaining 29 patients (consciousness-unimproved group). Indicators were documented including gender, age, cause of injury, Glasgow coma score (GCS) on admission, course of injury, preoperative consciousness level, operation mode, operation time, intraoperative fluid replenishment, intraoperative urine volume, intraoperative bleeding volume, American Society of Anesthesiologists grade, analgesic regimen and sedation maintenance drugs. A univariate analysis was conducted first to assess those indicators′ correlation with postoperative short-term improvement of consciousness level in patients with prolonged disorders of consciousness after sTBI. Multivariate Logistic regression analysis was then used to determine the independent risk factors for their postoperative short-term improvement of consciousness level.Results:Univariate analysis showed that GCS on admission, course of injury, preoperative consciousness level and analgesic regimen were correlated with short-term improvement of postoperative consciousness level in patients with prolonged disorders of consciousness after sTBI (all P<0.05), whereas gender, age, cause of injury, operation mode, operation time, intraoperative fluid replenishment, intraoperative urine volume, intraoperative bleeding volume, American Society of Anesthesiologists grade and sedation maintenance drugs showed no relation to the improvement of postoperative consciousness level (all P>0.05). Multivariate Logistic regression analysis showed that the GCS ≥7 points on admission ( OR=0.06, 95% CI 0.01, 0.36, P<0.01), preoperative minimally conscious state ( OR=0.09, 95% CI 0.02, 0.40, P<0.01) and intraoperative use of Sufentanil combined with Remifentanil ( OR=0.07, 95% CI 0.01, 0.43, P<0.01) were significantly correlated with postoperative improvement of consciousness level. Conclusion:The GCS on admission (≥7 points), preoperative minimally conscious state and intraoperative use of Sufentanil combined with Remifentanil are independent risk factors affecting short-term postoperative improvement of consciousness level in patients with prolonged disorders of consciousness after sTBI.

Looking back at a life in sleep research-and some thoughts for the future.

In reviewing my studies, some of which are nearing the half century mark, I've described work on sleep-related growth hormone, the effects of hypnotics on the perception of sleep, REM sleep induction in humans by cholinergic drugs, the benzodiazepine receptor, the anatomic sites of action of hypnotics, the endocannabinoid system and sleep, and the relation of anesthesia to sleep. Special mention along the way goes to cases in which drugs produced totally unexpected effects, including methysergide producing opposite effects on growth hormone secretion in sleep and a waking provocative test, the converse actions on sleep of the B-10 benzodiazepine enantiomers, and the promotion of wakefulness by microinjection of the hypnotic triazolam into the dorsal raphe nuclei. This work is placed in the context of what was known at the time, as well as what has been observed in subsequent years. Many of these studies indicate that the medial preoptic area may be a common site for the sleep-promoting action of a wide range of agents including traditional hypnotics, ethanol, propofol and melatonin. In the future it may be worthwhile looking at the beta-carbolines, and also the endocannabinoid system, when exploring drugs with new mechanisms of action for treating sleep/wake disorders. An Addendum to this paper describes memories of working with Frederick Snyder, J. Christian Gillin, Richard Jed Wyatt, and Floyd E. Bloom.

Test-retest reliability of the Epworth Sleepiness Scale in clinical trial settings.

The present analysis examined the test-retest reliability of the Epworth Sleepiness Scale in participants with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea in three clinical trials. Intraclass correlation coefficient estimates for Epworth Sleepiness Scale scores from two solriamfetol 12-week placebo-controlled trials (one narcolepsy, one obstructive sleep apnea) and one long-term open-label extension trial (narcolepsy or obstructive sleep apnea) were calculated using postbaseline time-point pairs for the overall population in each trial, by treatment, and by primary obstructive sleep apnea therapy adherence. In the 12-week narcolepsy trial, intraclass correlation coefficients (95% confidence intervals) were 0.83 (0.79, 0.87) for weeks 4 and 8 (n = 199), 0.87 (0.83, 0.90) for weeks 8 and 12 (n = 196), and 0.81 (0.76, 0.85) for weeks 4 and 12 (n = 196). In the 12-week obstructive sleep apnea trial, intraclass correlation coefficients (95% confidence intervals) were 0.74 (0.69, 0.78) (n = 416), 0.80 (0.76, 0.83) (n = 405), and 0.74 (0.69, 0.78) (n = 405), respectively. In the open-label extension trial, intraclass correlation coefficients (95% confidence intervals) were 0.82 (0.79, 0.85) for weeks 14 and 26/27 (n = 495), 0.85 (0.82, 0.87) for weeks 26/27 and 39/40 (n = 463), and 0.78 (0.74, 0.81) for weeks 14 and 39/40 (n = 463). Placebo/solriamfetol treatment or adherence to primary obstructive sleep apnea therapy did not affect reliability. In conclusion, across three large clinical trials of participants with narcolepsy or obstructive sleep apnea, Epworth Sleepiness Scale scores demonstrated a robust acceptable level of test-retest reliability in evaluating treatment response over time.

Histamine H / 中国药理学通报

Pitolisant is an orally active histamine H

Tau-driven degeneration of sleep- and wake-regulating neurons in Alzheimer's disease.

Disturbances of the sleep/wake cycle in Alzheimer's disease (AD) are common, frequently precede cognitive decline, and tend to worsen with disease progression. Sleep is critical to the maintenance of homeostatic and circadian function, and chronic sleep disturbances have significant cognitive and physical health consequences that likely exacerbate disease severity. Sleep-wake cycles are regulated by neuromodulatory centers located in the brainstem, the hypothalamus, and the basal forebrain, many of which are vulnerable to the accumulation of abnormal protein deposits associated with neurodegenerative conditions. In AD, while sleep disturbances are commonly attributed to the accumulation of amyloid beta, patients often first experience sleep issues prior to the appearance of amyloid beta plaques, on a timeline that more closely corresponds to the first appearance of abnormal tau neurofibrillary tangles in sleep/wake regulating areas of the brainstem. Sleep disturbances also occur in pure tauopathies, providing further support that tau is a major contributor. Here, we provide an overview of the neuroanatomy of sleep/wake centers discovered in animal models, and review the evidence that tau-driven neuropathology is a primary driver of sleep disturbance in AD.

The association between various characteristics of hypnotics and cardiac autonomic control in community-dwelling older adults: the Yilan Study, Taiwan.

BACKGROUND: Alteration of cardiac autonomic function may underlie the link between hypnotics use and the risk for cardiovascular morbidity and mortality. This study aimed to examine the relationship between the various characteristics of benzodiazepine receptor agonists (BzRAs) and heart rate variability (HRV). METHODS: A community-based survey using the cohort from the Yilan Study, Taiwan was conducted. Older adults aged 65 and older were randomly selected to participate from August 2013 to November 2016. Cardiac autonomic function was evaluated using HRV, and the lowest quartiles of HRV parameters were defined as unhealthy. Those who used BzRAs as a sleep aid were defined as BzRA hypnotic users. The characteristics of BzRA use were further detailed and included the half-life, drug compound, frequency of use, and cumulative daily equivalent dosage. RESULTS: Of all participants, 379 (14.5%) were BzRA hypnotic users. After controlling for covariates, BzRA hypnotic users had a higher risk for unhealthier HRV than non-users. Among all BzRA hypnotic users, those who only used benzodiazepines (BZDs), used short half-life BzRAs, and used the middle tertile of daily cumulative BZD equivalent had a higher risk for poor total power (odds ratio [OR]: 2.11, 95% confidence interval [CI]: 1.07-4.16), high frequency (OR: 3.43, 95% CI: 1.07-10.97), and high frequency (OR: 2.94, 95% CI: 1.35-6.42), respectively, than their counterparts. CONCLUSIONS: BzRA hypnotics are linked with poor cardiac autonomic function. Various characteristics of BzRA hypnotics showed an independent pattern of association with cardiac autonomic function.

Profound degeneration of wake-promoting neurons in Alzheimer's disease.

INTRODUCTION: Sleep-wake disturbances are a common and early feature in Alzheimer's disease (AD). The impact of early tau pathology in wake-promoting neurons (WPNs) remains unclear. METHODS: We performed stereology in postmortem brains from AD individuals and healthy controls to identify quantitative differences in morphological metrics in WPNs. Progressive supranuclear palsy (PSP) and corticobasal degeneration were included as disease-specific controls. RESULTS: The three nuclei studied accumulate considerable amounts of tau inclusions and showed a decrease in neurotransmitter-synthetizing neurons in AD, PSP, and corticobasal degeneration. However, substantial neuronal loss was exclusively found in AD. DISCUSSION: WPNs are extremely vulnerable to AD but not to 4 repeat tauopathies. Considering that WPNs are involved early in AD, such degeneration should be included in the models explaining sleep-wake disturbances in AD and considered when designing a clinical intervention. Sparing of WPNs in PSP, a condition featuring hyperinsomnia, suggest that interventions to suppress the arousal system may benefit patients with PSP.

Sleep- and Wake-Promoting Drugs: Where Are They Being Sourced, and What Is Their Impact?

Background: Recent decades have seen both an increased number of shift workers in order to deliver services 24/7, and increased potential for social interactions at all hours of the day. People have sought to engage in strategies, which either promote vigilance or facilitate sleep, with the use of sleep- and wake-promoting drugs representing one strategy. Methods: We investigated use of sleep- and wake-promoting drugs in participants (n = 377) who completed a survey investigating the type and source of sleep- and wake-promoting drugs, and their impact on sleep and performance outcomes. Results: The most commonly reported wake-promoting drugs were amphetamine and dextroamphetamin salts, modafinil, and illicit substances including methamphetamine and cocaine, while the most commonly reported sleep-promoting drugs were benzodiazepines and antihistamines. Use of a sleep-promoting drug in the past month was associated with higher odds of having poorer sleep quality (OR = 3.15) and moderate-high insomnia (OR = 3.30), while use of a wake-promoting drug was associated with poor sleep quality (OR = 3.76), or making a fatigue-related error (OR = 2.65). Conclusions: These findings represent novel data on the use and source of sleep- and wake-promoting- drugs, and suggest that despite their use, poor sleep and performance outcomes persist, likely representing individuals struggling to keep up with the 24/7 world.

Pharmacological Modulation of Sleep Homeostasis in Rat: Novel Effects of an mGluR2/3 Antagonist.

Increasing vigilance without incurring the negative consequences of extended wakefulness such as daytime sleepiness and cognitive impairment is a major challenge in treating many sleep disorders. The present work compares two closely related mGluR2/3 antagonists LY3020371 and LY341495 with two well-known wake-promoting compounds caffeine and d-amphetamine. Sleep homeostasis properties were explored in male Wistar rats by manipulating levels of wakefulness via (1) physiological sleep restriction (SR), (2) pharmacological action, or (3) a combination of these. A two-phase nonlinear mixed-effects model combining a quadratic and exponential function at an empirically estimated join point allowed the quantification of wake-promoting properties and any subsequent sleep rebound. A simple response latency task (SRLT) following SR assessed functional capacity of sleep-restricted animals treated with our test compounds. Caffeine and d-amphetamine increased wakefulness with a subsequent full recovery of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep and were unable to fully reverse SR-induced impairments in SRLT. In contrast, LY3020371 increased wakefulness with no subsequent elevation of NREM sleep, delta power, delta energy, or sleep bout length and count, yet REM sleep recovered above baseline levels. Prior sleep pressure obtained using an SR protocol had no impact on the wake-promoting effect of LY3020371 and NREM sleep rebound remained blocked. Furthermore, LY341495 increased functional capacity across SRLT measures following SR. These results establish the critical role of glutamate in sleep homeostasis and support the existence of independent mechanisms for NREM and REM sleep homeostasis.

The Taurine Transporter Eaat2 Functions in Ensheathing Glia to Modulate Sleep and Metabolic Rate.

Sleep is critical for many aspects of brain function and is accompanied by brain-wide changes in the physiology of neurons and synapses [1, 2]. Growing evidence suggests that glial cells contribute to diverse aspects of sleep regulation, including neuronal and metabolic homeostasis [3-5], although the molecular basis for this remains poorly understood. The fruit fly, Drosophila melanogaster, displays all the behavioral and physiological characteristics of sleep [1, 2], and genetic screening in flies has identified both conserved and novel regulators of sleep and wakefulness [2, 6, 7]. With this approach, we identified Excitatory amino acid transporter 2 (Eaat2) and found that its loss from glia, but not neurons, increases sleep. We show that Eaat2 is expressed in ensheathing glia, where Eaat2 functions during adulthood to regulate sleep. Increased sleep in Eaat2-deficient flies is accompanied by reduction of metabolic rate during sleep bouts, an indicator of deeper sleep intensity. Eaat2 is a member of the conserved EAAT family of membrane transport proteins [8], raising the possibility that it affects sleep by controlling the movement of ions and neuroactive chemical messengers to and from ensheathing glia. In vitro, Eaat2 is a transporter of taurine [9], which promotes sleep when fed to flies [10]. We find that the acute effect of taurine on sleep is abolished in Eaat2 mutant flies. Together, these findings reveal a wake-promoting role for Eaat2 in ensheathing glia through a taurine-dependent mechanism.

Skin temperature, sleep, and vigilance.

A large number of studies have shown a close association between the 24-hour rhythms in core body temperature and sleep propensity. More recently, studies have have begun to elucidate an intriguing association of sleep with skin temperature as well. The present chapter addresses the association of sleep and alertness with skin temperature. It discusses whether the association could reflect common underlying drivers of both sleep propensity and skin vasodilation; whether it could reflect efferents of sleep-regulating brain circuits to thermoregulatory circuits; and whether skin temperature could provide afferent input to sleep-regulating brain circuits. Sleep regulation and concomitant changes in skin temperature are systematically discussed and three parallel factors suggested: a circadian clock mechanism, a homeostatic hourglass mechanism, and a third set of sleep-permissive and wake-promoting factors that gate the effectiveness of signals from the clock and hourglass in the actual induction of sleep or maintenance of alert wakefulness. The chapter moreover discusses how the association between skin temperature and arousal can change with sleep deprivation and insomnia. Finally it addresses whether the promising laboratory findings on the effects of skin temperature manipulations on vigilance can be applied to improve sleep in everyday life.

Behavioural state-specific neurons in the mouse medulla involved in sleep-wake switching.

The medullary reticular formation (RF) is involved in the maintenance of several vital physiological functions and level of vigilance. In this study, in nonanesthetised, head-fixed mice, I examined the role of medullary RF neurons in the control of sleep-wake states, that is, wakefulness (W), slow-wave sleep (SWS) and paradoxical (or rapid eye movement) sleep (PS). I showed, for the first time, that the mouse medullary RF contains presumed SWS-promoting, SWS-on neurons that remain silent during W, display a sharp increase in discharge rate at sleep onset, and discharge tonically and selectively during SWS. In addition, I showed the presence in the medullary RF of both PS-on and PS-off neurons, which, respectively, commence discharging or cease firing selectively just prior to, and during, PS. PS-off neurons were located in the raphe nuclei and ventral medulla, while PS-on neurons were found in both the lateral part of the ventral gigantocellular reticular nucleus and the raphe nuclei, as were SWS-on neurons. PS-off and SWS-on neurons appear to play an important role in both the W-SWS and SWS-PS switches, while PS-on and PS-off neurons play an important role in the PS-W switch. The present findings on the trends in spike activity at the transitions from SWS to PS and from PS to W are in line with the reciprocal interaction hypothesis according to which PS occurs as a result of the cessation of discharge of PS-off neurons, while PS ends as a result of the start of discharge of PS-off neurons.

Wake-promoting effects of vagus nerve stimulation after traumatic brain injury: upregulation of orexin-A and orexin receptor type 1 expression in the prefrontal cortex.

Orexins, produced in the lateral hypothalamus, are important neuropeptides that participate in the sleep/wake cycle, and their expression coincides with the projection area of the vagus nerve in the brain. Vagus nerve stimulation has been shown to decrease the amounts of daytime sleep and rapid eye movement in epilepsy patients with traumatic brain injury. In the present study, we investigated whether vagus nerve stimulation promotes wakefulness and affects orexin expression. A rat model of traumatic brain injury was established using the free fall drop method. In the stimulated group, rats with traumatic brain injury received vagus nerve stimulation (frequency, 30 Hz; current, 1.0 mA; pulse width, 0.5 ms; total stimulation time, 15 minutes). In the antagonist group, rats with traumatic brain injury were intracerebroventricularly injected with the orexin receptor type 1 (OX1R) antagonist SB334867 and received vagus nerve stimulation. Changes in consciousness were observed after stimulation in each group. Enzyme-linked immunosorbent assay, western blot assay and immunohistochemistry were used to assess the levels of orexin-A and OX1R expression in the prefrontal cortex. In the stimulated group, consciousness was substantially improved, orexin-A protein expression gradually increased within 24 hours after injury and OX1R expression reached a peak at 12 hours, compared with rats subjected to traumatic brain injury only. In the antagonist group, the wake-promoting effect of vagus nerve stimulation was diminished, and orexin-A and OX1R expression were decreased, compared with that of the stimulated group. Taken together, our findings suggest that vagus nerve stimulation promotes the recovery of consciousness in comatose rats after traumatic brain injury. The upregulation of orexin-A and OX1R expression in the prefrontal cortex might be involved in the wake-promoting effects of vagus nerve stimulation.

Effects of transcranial direct current stimulation on consciousness and expression of brain-derived neurotrophic factor in coma rats following traumatic brain injury / 中国康复医学杂志

Objective:To investigate wake-promoting effects of transcranial direct current stimulation (tDCS) on brain injury-induced coma and the possible mechanism.Method:Fifty-four adult SD rats were randomly divided into three groups with 18 rats in each group.They were blank group,traumatic brain injury-induced coma (TBI) group and tDCS group.Using classical free fall method to create brain injury-induced coma and then treated rats with tDCS,consciousness level of rats were assessed at 6h,12h,24h time points.After consciousness level evaluation,rats were put to death and then the prefrontal cortex (PFC) and hippocampus of rats were extracted.Western Blot method was used to determine the expression of brain-derived neurotrophic factor (BDNF) in three groups.Result:Eighteen rats in control group,6 rats in TBI group and 11 rats in tDCS group awakened.BDNF expression in TBI group was higher than that in blank group in PFC and hippocampus.More over,at 12h in PFC and at 6h in hippocampus,BDNF expression in tDCS group was higher than that in TBI group with statistically significant difference(P ＜ 0.05).Conclusion:tDCS can improve the consciousness level of coma rats following TBI and the mechanism may be related to upregulation of BDNF expression in the PFC and hippocampus of rats.