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Accidental awareness during general anaesthesia is a major complication. Despite the routine use of continuous electroencephalographic monitoring, accidental awareness during general anaesthesia remains relatively frequent and constitutes a significant additional cost. The prediction of patients' arousal during general anaesthesia could help preventing accidental awareness and some researchers have suggested that heart rate variability (HRV) analysis contains valuable information about the patient arousal during general anaesthesia. We conducted pilot study to investigate HRV ability to detect patient arousal. RR series and the Bispectral IndexTM (BISTM) were recorded during general anaesthesia. The pre-arousal period T0 was defined as the time at which the BISTM exceeded 60 at the end of surgery. HRV parameters were computed over several time periods before and after T0 and classified as "BISTM<60" or "BISTM≥60". A multivariate logistic regression model and a classification and regression tree algorithm were used to evaluate the HRV variables' ability to detect "BISTM≥60". All the models gave high specificity but poor sensitivity. Excluding T0 from the classification increased the sensitivity for all the models and gave AUCROC>0.7. In conclusion, we found that HRV analysis provided encouraging results to predict arousal at the end of general anaesthesia., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Julien De Jonckheere and Mathieu Jeanne are shareholders and scientific consultants for MDoloris Medical Systems. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright: © 2024 Wojtanowski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Previous research has demonstrated that basal forebrain (BF) regulates arousal during propofol anesthesia. However, as the BF comprises cholinergic neurons alongside two other types of neurons, the specific role of cholinergic neurons has not been definitively elucidated. In our study, calcium signal imaging was utilized to monitor the real-time activities of cholinergic neurons in the BF during propofol anesthesia. Additionally, we selectively stimulated these neurons to investigate EEG and behavioral responses during propofol anesthesia. Furthermore, we specifically lesioned cholinergic neurons in the BF to investigate the sensitivity to propofol and the induction time. The results revealed that propofol suppressed calcium signals of cholinergic neurons within the BF following intraperitoneal injection. Notably, upon recovery of the righting reflex, the calcium signals partially recovered. Spectral analysis of the EEG elucidated that optical stimulation of cholinergic neurons led to a decrease in δ power underlie propofol anesthesia. Conversely, depletion of cholinergic neurons in the BF enhanced sensitivity to propofol and shortened the induction time. These findings clarify the role of cholinergic neurons in the anesthesia-arousal process, as well as the depth and the sensitivity of propofol anesthesia., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Dopaminergic psychostimulants can restore arousal in anaesthetised animals, and dopaminergic signalling contributes to hippocampal-dependent memory formation. We tested the hypothesis that dopaminergic psychostimulants can antagonise the amnestic effects of isoflurane on visuospatial working memory., Methods: Sixteen adult Sprague-Dawley rats were trained on a trial-unique nonmatching-to-location (TUNL) task which assessed the ability to identify a novel touchscreen location after a fixed delay. Once trained, the effects of low-dose isoflurane (0.3 vol%) on task performance and activity, assessed by infrared beam breaks, were assessed. We attempted to rescue deficits in performance and activity with a dopamine D1 receptor agonist (chloro-APB), a noradrenergic reuptake inhibitor (atomoxetine), and a mixed dopamine/norepinephrine releasing agent (dextroamphetamine). Anaesthetic induction, emergence, and recovery from anaesthesia were also investigated., Results: Low-dose isoflurane impaired working memory in a sex-independent and intra-trial delay-independent manner as assessed by task performance, and caused an overall reduction in activity. Administration of chloro-APB, atomoxetine, or dextroamphetamine did not restore visuospatial working memory, but chloro-APB and dextroamphetamine recovered arousal to levels observed in the baseline awake state. Performance did not differ between induction and emergence. Animals recovered to baseline performance within 15 min of discontinuing isoflurane., Conclusions: Low-dose isoflurane impairs visuospatial working memory in a nondurable and delay-independent manner that potentially implicates non-hippocampal structures in isoflurane-induced memory deficits. Dopaminergic psychostimulants counteracted sedation but did not reverse memory impairments, suggesting that isoflurane-induced amnesia and isoflurane-induced sedation have distinct underlying mechanisms that can be antagonised independently., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Traumatic brain injury (TBI) is a complex pathophysiological process that results in a variety of neurotransmitter, behavioral, and cognitive deficits. The locus coeruleus-norepinephrine (LC-NE) system is a critical regulator of arousal levels and higher executive processes affected by TBI including attention, working memory, and decision making. LC-NE axon injury and impaired signaling within the prefrontal cortex (PFC) is a potential contributor to the neuropsychiatric symptoms after single, moderate to severe TBI. The majority of TBIs are mild, yet long-term cognitive deficits and increased susceptibility for further injury can accumulate after each repetitive mild TBI. As a potential treatment for restoring cognitive function and daytime sleepiness after injury psychostimulants, including methylphenidate (MPH) that increase levels of NE within the PFC, are being prescribed "off-label". The impact of mild and repetitive mild TBI on the LC-NE system remains limited. Therefore, we determined the extent of LC-NE and arousal dysfunction and response to therapeutic doses of MPH in rats following experimentally induced single and repetitive mild TBI. Microdialysis measures of basal NE efflux from the medial PFC and arousal measures were significantly lower after repetitive mild TBI. Females showed higher baseline PFC-NE efflux than males following single and repetitive mild TBI. In response to MPH challenge, males exhibited a blunted PFC-NE response and persistent arousal levels following repetitive mild TBI. These results provide critical insight into the role of catecholamine system dysfunction associated with cognitive deficits following repeated injury, outcome differences between sex/gender, and lack of success of MPH as an adjunctive therapy to improve cognitive function following injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The lateral hypothalamus (LHA) is an evolutionarily conserved structure that regulates basic functions of an organism, particularly wakefulness. To clarify the function of LHA GABA neurons and their projections on regulating general anesthesia is crucial for understanding the excitatory and inhibitory effects of anesthetics on the brain. The aim of the present study is to investigate whether LHA GABA neurons play either an inhibitory or a facilitatory role in sevoflurane-induced anesthetic arousal regulation., Methods: We used fiber photometry and immunofluorescence staining to monitor changes in neuronal activity during sevoflurane anesthesia. Opto-/chemogenetic modulations were employed to study the effect of neurocircuit modulations during the anesthesia. Anterograde tracing was used to identify a GABAergic projection from the LHA to a periaqueductal gray (PAG) subregion., Results: c-Fos staining showed that LHA GABA activity was inhibited by induction of sevoflurane anesthesia. Anterograde tracing revealed that LHA GABA neurons project to multiple arousal-associated brain areas, with the lateral periaqueductal gray (LPAG) being one of the dense projection areas. Optogenetic experiments showed that activation of LHA GABA neurons and their downstream target LPAG reduced the burst suppression ratio (BSR) during continuous sevoflurane anesthesia. Chemogenetic experiments showed that activation of LHA GABA and its projection to LPAG neurons prolonged the anesthetic induction time and promoted wakefulness., Conclusions: In summary, we show that an inhibitory projection from LHA GABA to LPAG GABA neurons promotes arousal from sevoflurane-induced loss of consciousness, suggesting a complex control of wakefulness through intimate interactions between long-range connections., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Participants completed two sessions of an auditory attention task and intermittently responded to thought probes asking about their level of mind-wandering. After the first session one group received 200 mg of caffeinated chewing gum (n = 61) and another group received regular (placebo) chewing gum (n = 66). The gum was chewed for 20-minutes and then disposed of before beginning the second session. Participants who received caffeine showed a performance benefit as well as reported being more on task and fewer instances of spontaneous mind-wandering compared to those in the placebo group. Participants who received caffeine also reported greater positive affect and arousal, as well as less feelings of boredom, sleepiness, and mental effort required to stay on task compared to those who received placebo. These results suggest that caffeine may benefit attentional engagement as well as performance during a sustained attention task., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Ammonia inhalants, also known as smelling salts, are preparations of ammonia designed to treat fainting but more commonly used by athletes to boost awareness and arousal during competition. Despite their widespread use, the physiological and performance-enhancing effects of ammonia inhalants remain poorly understood. The aim of the present study was to review the current literature surrounding the benefits, risks, and physiological effects of ammonia inhalants., Evidence Acquisition: An extensive literature review of articles pertaining to ammonia inhalants was performed through MEDLINE and Google Scholar. The search terms "smelling salts," "ammonia inhalants," "strength," "performance," "head injury," and "concussion" were used., Study Design: Clinical review., Level of Evidence: Level 4., Results: The physiological response to acute ammonia inhalation includes cerebral vasodilation and heart rate elevation without change in blood pressure. The existing evidence demonstrates an ergogenic benefit to ammonia inhalant use only during repeated bouts of high-intensity exercise; in these subjects, ammonia inhalation was associated with increased power as measured by the Wingate anaerobic test. In contrast, there is no performance benefit to ammonia inhalants in a short burst of maximal effort despite elevated arousal and an associated perception of performance enhancement. Importantly, ammonia inhalants have no role in medical management of head injuries, as they have the potential to exacerbate an underlying brain injury due to the involuntary withdrawal reflex associated with ammonia inhalation. Furthermore, the signs and symptoms of a concussion or more threatening head injury may be masked by ammonia inhalation and lead to continued participation in competition, causing additional harm., Conclusion: Ammonia inhalants have no role in medical management of head injuries and have limited benefit with regards to sports performance., Strength of Recommendation: B., Competing Interests: The following author declared potential conflicts of interest: C.P. has received education payments from Gotham Surgical Solutions and Arthrex.

General anesthesia in calves is easier to perform under field conditions, total intravenous anesthesia (TIVA) than using inhalation anesthesia. In the present study, cardiopulmonary function, anesthetic effects, quality of arousal, hematology, and blood biochemistry were assessed during continuous infusion of a combination solution of 0.01% xylazine, 0.001% butorphanol, and 0.2% propofol (XBP) at doses of 6 (G6; 10 μg/kg/min xylazine, 1 μg/kg/min butorphanol, 200 μg/kg/min propofol) and 9 mL/kg/h (G9; 15 μg/kg/min xylazine, 1.5 μg/kg/min butorphanol 300 μg/kg/min propofol). For both groups, five castrated Holstein calves received intravenous injections of xylazine (0.2 mg/kg) and propofol (2 mg/kg), followed by a continuous infusion of XBP for 60 min to maintain anesthesia. Respiratory management consisted of tracheal intubation followed by spontaneous inhalation of pure oxygen. Cardiopulmonary, anesthesia, hematology, and blood biochemistry variables were assessed at rest (baseline) and every 5 or 15 min after the start of the XBP infusion. Quality of arousal was assessed based on the swallowing reflex recovery time from the stop of XBP infusion, and the sternal position time and standing time after atipamezole administration. XBP produced adequate sedation, analgesia, and muscle relaxation in all calves and maintained stable anesthesia for 60 min. As XBP infusion time passed, rectal temperature and heart rate became lower, and mean arterial blood pressure increased. In both groups, hematologic and blood biochemical effects were mild. The quality of arousal was not different, and all calves were standing. The results of the present study suggested that XBP is useful for TIVA in calves., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The ventral subiculum (vSUB), the major output structure of the hippocampal formation, regulates motivation, stress integration, and anxiety-like behaviors that rely on heightened arousal. However, the roles and underlying neural circuits of the vSUB in wakefulness are poorly known. Using in vivo fiber photometry and multichannel electrophysiological recordings in mice, we found that the vSUB glutamatergic neurons exhibited high activities during wakefulness. Moreover, activation of vSUB glutamatergic neurons caused an increase in wakefulness and anxiety-like behaviors and induced a rapid transition from sleep to wakefulness. In addition, optogenetic stimulation of vSUB glutamatergic terminals and retrograde-targeted chemogenetic activation of vSUB glutamatergic neurons revealed that vSUB promoted arousal by innervating the lateral hypothalamus (LH), nucleus accumbens (NAc) shell, and prefrontal cortex (PFC). Nevertheless, local microinjection of dopamine D1 or D2/D3 receptor antagonist blocked the wake-promoting effect induced by chemogenetic activation of vSUB pathways. Finally, chemogenetic inhibition of vSUB glutamatergic neurons decreased arousal. Altogether, our findings reveal a prominent contribution of vSUB glutamatergic neurons to the control of wakefulness through several pathways., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Dexmedetomidine (DEX) has been described as a safe sedative in clinical practice, but its effects on the pathophysiological traits of obstructive sleep apnea (OSA) are unclear. We estimated the effects of DEX sedation on the four key pathophysiological traits of OSA (pharyngeal collapsibility, dilator muscle function, arousal threshold, and loop gain) in adult patients with OSA by conducting a secondary analysis of a prospective diagnostic trial. Pathophysiological traits estimated from polysomnography and the respiratory parameters under natural sleep and DEX-induced sleep were compared. Bivariate and multivariate linear regression analyses were used to estimate the relationship between pathophysiological traits and OSA severity for both sleep states. Adult patients with OSA had a significantly higher pharyngeal collapsibility (V passive : 44.9 [15.7 to 53.8] vs. 53.3 [34.2 to 66.3] % eupnea , p < 0.001), arousal threshold (178.5 [132.5 to 234.6] vs. 140.5 [123.2 to 192.3] % eupnea , p < 0.001), and loop gain (LG1: 0.74 ± 0.25 vs. 0.60 ± 0.17, p < 0.001; LGn: 0.52 ± 0.12 vs. 0.44 ± 0.08, p < 0.001) during DEX-induced sleep compared with natural sleep. There was no significant difference in dilator muscle function or PSG respiratory parameters between natural versus DEX-induced sleep states. Bivariate regression analysis showed varying degrees of correlation between OSA traits and severity. Multiple regression analysis indicated that collapsibility was the strongest predictor of the apnea-hypopnea index for both sleep states. Dexmedetomidine sedation in patients with OSA increased the pharyngeal collapsibility without impairing dilator muscle function, while elevating arousal threshold and increasing loop gain., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Background: Ventral tegmental area (VTA) glutamatergic neurons promote wakefulness in the sleep-wake cycle; however, their roles and neural circuit mechanisms during isoflurane (ISO) anesthesia remain unclear., Methods: Fiber photometry and in vivo electrophysiology were used to observe the changes in neuronal or terminal activity during ISO anesthesia and arousal processes. Optogenetic and anesthesia behaviors were used to investigate the effects of VTA glutamatergic neurons and their projections to the lateral septum (LS) during ISO anesthesia and arousal. Anterograde and retrograde tracings were performed to identify the connections between VTA glutamatergic neurons and the LS., Results: Population activity and firing rates of VTA glutamatergic neurons decreased during ISO anesthesia (ISO: 95% confidence interval [CI], 0.83-2.06 Spikes.s -1 vs wake: 95% CI, 3.53-7.83 Spikes.s -1 ; P =.0001; n = 34 from 4 mice). Optogenetic activation of VTA glutamatergic neurons reduced the burst-suppression ratio in electroencephalography (laser: 95% CI, 13.09%-28.76% vs pre: 95% CI, 52.85%-71.59%; P =.0009; n = 6) and facilitated emergence (ChR2: 95% CI, 343.3-388.0 seconds vs mCherry: 95% CI, 447.6-509.8 seconds; P < .0001; n = 11/12) from ISO anesthesia. VTA glutamatergic neurons monosynaptically innervated LS γ-aminobutyric acid (GABA)-ergic neurons. The activity of VTA glutamatergic terminals in the LS decreased during ISO anesthesia, and optogenetic activation of the VTA glutamatergic terminals in the LS facilitated emergence from ISO anesthesia. Furthermore, optogenetic activation of VTA glutamatergic terminals increased the firing rates of LS γ-aminobutyric acid-ergic (GABAergic) neurons (laser: 95% CI, 0.85-4.03 Spikes.s -1 vs pre: 95% CI, 0.24-0.78 Spikes.s -1 ; P =.008; n = 23 from 4 mice) during ISO anesthesia., Conclusions: VTA glutamatergic neurons facilitated emergence from ISO anesthesia involving excitation of LS GABAergic neurons., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

The repeated use of small doses of psychedelics (also referred to as "microdosing") to facilitate benefits in mental health, cognition, and mood is a trending practice. Placebo-controlled studies however have largely failed to demonstrate strong benefits, possibly because of large inter-individual response variability. The current study tested the hypothesis that effects of low doses of LSD on arousal, attention and memory depend on an individual's cognitive state at baseline. Healthy participants (N = 53) were randomly assigned to receive repeated doses of LSD (15 mcg) or placebo on 4 occasions divided over 2 weeks. Each treatment condition also consisted of a baseline and a 1-week follow-up visit. Neurophysiological measures of arousal (resting state EEG), pre-attentive processing (auditory oddball task), and perceptual learning and memory (visual long-term potentiation (LTP) paradigm) were assessed at baseline, dosing session 1 and 4, and follow-up. LSD produced stimulatory effects as reflected by a reduction in resting state EEG delta, theta, and alpha power, and enhanced pre-attentive processing during the acute dosing sessions. LSD also blunted the induction of LTP on dosing session 4. Stimulatory effects of LSD were strongest in individuals with low arousal and attention at baseline, while inhibitory effects were strongest in high memory performers at baseline. Decrements in delta EEG power and enhanced pre-attentive processing in the LSD treatment condition were still present during the 1-week follow-up. The current study demonstrates across three cognitive domains, that acute responses to low doses of LSD depend on the baseline state and provides some support for LSD induced neuroadaptations that sustain beyond treatment., (© 2024. The Author(s).)

Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion - substantia nigra pars compacta (SNc), reinforcement/motivation - ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) - VTA; arousal - ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation., Competing Interests: Declaration of conflicting interestsThe author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

To assess the effects of warm-up music and low dose (3 mg·kg -1 ) of caffeine (CAF) on female taekwondo athlete's activity profile and psychophysiological responses during simulated combat. In a double-blinded, randomized, crossover study, 16 female athletes participated in simulated combats under one control and 5 experimental conditions [i.e., CAF alone (CAF), placebo alone (PL), CAF with music (CAF + M), PL with music (PL + M), and no supplement with music (M)]. After warming-up, athletes rated their felt arousal (FAS). Mean (HR mean ) and peak (HR peak ) heart rate values were determined for each combat. After fighting, athletes rated their perceived exertion (RPE), feeling scale (FS), FAS, and physical enjoyment (PACES). Time-motion and technical-tactical variables were analyzed. CAF + M induced shorter skip and pause time, while attack time increased compared to other conditions (p < 0.05). Moreover, CAF + M increased single attacks, combined attacks, counter-attacks (p < 0.001), and defensive actions (p < 0.05) than other conditions. HR mean and HR peak were lower under CAF + M than other conditions (p < 0.05). Additionally, higher FAS post-combat, FS, and PACES were observed under CAF + M, while RPE was lower (except CAF condition) compared to the other conditions (p < 0.05.Using CAF with warm-up music may increase combat cadence and improve the psychological state in female athletes more effectively than either strategy alone., (© 2024. The Author(s).)

The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine's effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine's temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine's antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In the 19 th century, the discovery of general anesthesia revolutionized medical care. In the 21 st century, anesthetics have become indispensable tools to study consciousness. Here, I review key aspects of the relationship between anesthesia and the neurobiology of consciousness, including interfaces of sleep and anesthetic mechanisms, anesthesia and primary sensory processing, the effects of anesthetics on large-scale functional brain networks, and mechanisms of arousal from anesthesia. I discuss the implications of the data derived from the anesthetized state for the science of consciousness and then conclude with outstanding questions, reflections, and future directions., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To compare emotional responses elicited by four cosmetic products on different sensory modalities (smell, visual, and touch), and analyze the link between objective instrumental analysis results and subjective evaluation of participants occurring within dimensional valence-arousal model of emotions., Methods: In this study, four cream products exhibiting variations in olfactory perception, visual appearance and perception usability were selected. Electroencephalography (EEG) and a subjective emotion scale were used to assess participants' emotional responses during the sensory experience of utilizing the creams., Results: The study revealed that the objective emotional valence and arousal of different cream products exhibited certain variations at distinct stages of usage. The trend of valence differences induced by different products measured by EEG at the same stage was almost as same as measured by subjective evaluation. The correspondence between the valence measured by EEG closely approximated that obtained through subjective evaluation across various products at distinct stages of usage. These findings demonstrate a significant correlation between EEG-based valence and subjective valence, however, no such relationship was observed for arousal., Conclusion: This study demonstrates the feasibility of using EEG as a method to assess emotions elicited by various stages of cosmetics application, including smelling, looking, rubbing, and afterfeel. This technique serves as a valuable supplement to traditional methods for examining emotional responses by providing more objective evidence., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Degeneration of the cholinergic basal forebrain is implicated in the development of cognitive deficits and sleep/wake architecture disturbances in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Indirect-acting muscarinic cholinergic receptor agonists, such as acetylcholinesterase inhibitors (AChEIs), remain the only FDA-approved treatments for the cognitive impairments observed in AD that target the cholinergic system. Novel direct-acting muscarinic cholinergic receptor agonists also improve cognitive performance in young and aged preclinical species and are currently under clinical development for AD. However, little is known about the effects of direct-acting muscarinic cholinergic receptor agonists on disruptions of sleep/wake architecture and arousal observed in nonpathologically aged rodents, nonhuman primates, and clinical populations. The purpose of the present study was to provide the first assessment of the effects of the direct-acting M 1 /M 4 -preferring muscarinic cholinergic receptor agonist xanomeline on sleep/wake architecture and arousal in young and nonpathologically aged mice, in comparison with the AChEI donepezil, when dosed in either the active or inactive phase of the circadian cycle. Xanomeline produced a robust reversal of both wake fragmentation and disruptions in arousal when dosed in the active phase of nonpathologically aged mice. In contrast, donepezil had no effect on either age-related wake fragmentation or arousal deficits when dosed during the active phase. When dosed in the inactive phase, both xanomeline and donepezil produced increases in wake and arousal and decreases in nonrapid eye movement sleep quality and quantity in nonpathologically aged mice. Collectively, these novel findings suggest that direct-acting muscarinic cholinergic agonists such as xanomeline may provide enhanced wakefulness and arousal in nonpathological aging, MCI, and AD patient populations.

Eighteen non-anxious volunteers underwent sleep recordings and daytime tests of sleepiness, performance, and mood while receiving, either alprazolam 0.5 mg b.i.d. or diazepam 5 mg b.i.d. for 7 consecutive days. Recordings and tests were done before treatment and on the 1st and 7th days of treatment. Nocturnal sleep changes were similar for both groups; there were no statistically significant changes in mood. However, levels of daytime sleepiness differed. Alprazolam subjects showed more daytime sedation than diazepam subjects on treatment day 1, but showed a significant decreased in Day 1-7 daytime sedation. Although diazepam subjects were less sedated at the onset, they showed no tolerance to this effect; thus by treatment day 7, the two groups did not differ in levels of daytime sleepiness. Results suggested that tolerance to alprazolam's sedative effects (which develops during the 1st week of treatment) may be separable from tolerance to its antianxiety effects (which develops after at least 4 weeks). As daytime sedation is common and potentially dangerous with most anxiolytics, selective tolerance to this side effect is highly desirable. [ABSTRACT FROM AUTHOR]

There is lack of research on effects of red wine on consciousness when drank in wine bars designed to enhance the pleasurableness of the wine drinking experience. Effects of a moderate dose of red wine (≈ 40.98 g of ethanol) on consciousness were examined in a naturalistic study taking place in a wine bar located in one of the most touristic areas of Lisbon, Portugal. One hundred two participants drank in one of three conditions: alone, in dyad, or in groups up to six people. Red wine increased pleasure and arousal, decreased the awareness of time, slowed the subjective passage of time, increased the attentional focus on the present moment, decreased body awareness, slowed thought speed, turned imagination more vivid, and made the environment become more fascinating. Red wine increased insightfulness and originality of thoughts, increased sensations of oneness with the environment, spiritual feelings, all-encompassing love, and profound peace. All changes in consciousness occurred regardless of volunteers drinking alone, in dyad or in group. Men and women did not report different changes in consciousness. Older age correlated with greater increases in pleasure. Younger age correlated with greater increases in fascination with the environment of the wine bar. Drinking wine in a contemporaneous Western environment designed to enhance the pleasurableness of the wine drinking experience may trigger changes in consciousness commonly associated with mystical-type states., Competing Interests: The authors have declared that no competing interests exist.

Caffeine, a natural stimulant, is known to be effective for weight loss. On this basis, we screened the arousal-inducing effect of five dietary supplements with a weight loss effect ( Garcinia cambogia , Coleus forskohlii , Camellia sinensis L., Irvingia gabonensis , and Malus pumila M.), of which the G. cambogia peel extract (GC) showed a significant arousal-inducing effect in the pentobarbital-induced sleep test in mice. This characteristic of GC was further evaluated by analysis of electroencephalogram and electromyogram in C57L/6N mice, and it was compared to that of the positive control, caffeine. Administration of GC (1500 mg/kg) significantly increased wakefulness and decreased non-rapid eye movement sleep, similar to that of caffeine (25 mg/kg), with GC and caffeine showing a significant increase in wakefulness at 2 and 6 h, respectively. Compared to that of caffeine, the shorter duration of efficacy of GC could be advantageous because of the lower possibility of sleep disturbance. Furthermore, the arousal-inducing effects of GC (1500 mg/kg) and caffeine (25 mg/kg) persisted throughout the chronic (3 weeks) administration study. This study, for the first time, revealed the arousal-inducing effect of GC. Our findings suggest that GC might be a promising natural stimulant with no side effects. In addition, it is preferential to take GC as a dietary supplement for weight loss during the daytime to avoid sleep disturbances owing to its arousal-inducing effect.

Background: Although evidence of both beneficial and adverse biological effects of lighting has accumulated, biologically favorable lighting often does not match subjectively comfortable lighting. By controlling the correlated color temperature (CCT) of ambient lights, we investigated the feasibility of combined lighting that meets both biological requirements and subjective comfort., Methods: Two types of combined lightings were compared; one consisted of a high-CCT (12000 K) light-emitting diode (LED) panel as the ambient light and a low-CCT (5000 K) LED stand light as the task light (high-low combined lighting), and the other consisted of a low-CCT (4500 K) LED panel as the ambient light and the same low-CCT (5000 K) stand light as the task light (low-low combined lighting) as control. Ten healthy subjects (5 young and 5 elderly) were exposed to the two types of lighting on separate days. Autonomic function by heart rate variability, psychomotor performances, and subjective comfort were compared., Results: Both at sitting rest and during psychomotor workload, heart rate was higher and the parasympathetic index of heart rate variability was lower under the high-low combined lighting than the low-low combined lighting in both young and elderly subject groups. Increased psychomotor alertness in the elderly and improved sustainability of concentration work performance in both age groups were also observed under the high-low combined lighting. However, no significant difference was observed in the visual-analog-scale assessment of subjective comfort between the two types of lightings., Conclusions: High-CCT ambient lighting, even when used in combination with low-CCT task lighting, could increase autonomic and psychomotor arousal levels without compromising subjective comfort. This finding suggests the feasibility of independent control of ambient and task lighting as a way to achieve both biological function regulation and subjective comfort., (© 2021. The Author(s).)

Aims: General anesthesia has been widely applied in surgical or nonsurgical medical procedures, but the mechanism behind remains elusive. Because of shared neural circuits of sleep and anesthesia, whether serotonergic system, which is highly implicated in modulation of sleep and wakefulness, regulates general anesthesia as well is worth investigating., Methods: Immunostaining and fiber photometry were used to assess the neuronal activities. Electroencephalography spectra and burst-suppression ratio (BSR) were used to measure anesthetic depth and loss or recovery of righting reflex to indicate the induction or emergence time of general anesthesia. Regulation of serotonergic system was achieved through optogenetic, chemogenetic, or pharmacological methods., Results: We found that both Fos expression and calcium activity were significantly decreased during general anesthesia. Activation of 5-HT neurons in the dorsal raphe nucleus (DRN) decreased the depth of anesthesia and facilitated the emergence from anesthesia, and inhibition deepened the anesthesia and prolonged the emergence time. Furthermore, agonism or antagonism of 5-HT 1A or 2C receptors mimicked the effect of manipulating DRN serotonergic neurons., Conclusion: Our results demonstrate that 5-HT neurons in the DRN play a regulative role of general anesthesia, and activation of serotonergic neurons could facilitate emergence from general anesthesia partly through 5-HT 1A and 2C receptors., (© 2021 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Propofol is widely used for the induction and maintenance of anesthesia, which causes a rapid loss of consciousness. However, the mechanisms underlying the hypnosis effect of propofol are still not fully understood. The thalamic reticular nucleus (TRN) is crucial for regulating wakefulness, sleep rhythm generation, and sleep stability, while the role of TRN in the process of propofol-induced anesthesia is still unknown. Here, we investigated the function of the anterior TRN in propofol general anesthesia. Our results demonstrated that the neural activity of anterior TRN is suppressed during propofol anesthesia, whereas it is robustly activated from anesthesia by recording the calcium signals using fiber photometry technology. The results showed that the activation of anterior TRN neurons by chemogenetic and optogenetic methods shortens the emergency time without changing the induction time. Conversely, chemogenetic or optogenetic inhibition of the TRN neurons leads to a delay in the recovery time. Our study showed that anterior TRN is crucial for behavioral arousal without affecting the induction time of propofol anesthesia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis., Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days., Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well., Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone., Lay Summary: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug., Clinical Trial Registration Number: EudraCT 2016-003651-30., Competing Interests: Conflict of interest Torbjörn Bäckström, Mette Lauridsen, Maria Månsson, Joe Mauney, Masoud Mokhatarani, Sara Montagnese, Dag Nilsson, Lars-Erik Lins, Per Samuelson, Martin Schalling, Bruce F. Scharschmidt, Fredrik Thunarf, Hendrik Vilstrup and Lisa Zarantonello are current or recent consultants to Umecrine Cognition, AB. Torbjörn Bäckström and Bruce F. Scharschmidt are also Board members and shareholders of Umecrine Cognition AB. Magnus Doverskog and Maja Johansson, and Eva Arlander are current or recent employees of Umecrine Cognition AB. Géza Lakner, Sergey Fitilev, Igor Zupanets, Irina Kozlova, Elena Bunkova, Krzysztof Tomasiewicz, Jan Erik Berglund, Fredrik Rorsman, Hannes Hagström, Stergios Kechagias and Carin Edmark Ocklind have received investigator grants from Umecrine Cognition AB to support the cost of performing the clinical study. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Activation of dopamine (DA) neurons is essential for the transition from sleep to wakefulness and maintenance of awakening, and sufficient to accelerate the emergence from general anesthesia in animals. Dopamine receptors (DR) are involve in arousal mediation. In the present study, we showed that the olfactory tubercle (OT) was active during emergence from isoflurane anesthesia, local injection of dopamine D1 receptor (D1R) agonist chloro-APB (1 mg/mL) and D2 receptor (D2R) agonist quinpirole (1 mg/mL) into OT enhanced behavioural and cortical arousal from isoflurane anesthesia, while D1R antagonist SCH-23390 (1 mg/mL) and D2R antagonist raclopride (2.5 mg/mL) prolonged recovery time. Optogenetic activation of DAergic terminals in OT also promoted behavioural and cortical arousal from isoflurane anesthesia. However, neither D1R/D2R agonists nor D1R/D2R antagonists microinjection had influences on the induction of isoflurane anesthesia. Optogenetic stimulation on DAergic terminals in OT also had no impact on the anesthesia induction. Our results indicated that DA signals in OT accelerated emergence from isoflurane anesthesia. Furthermore, the induction of general anesthesia, different from the emergence process, was not mediated by the OT DAergic pathways.

Background: While romantic jealousy may help to maintain relationships, following partner infidelity and an irretrievable loss of trust it can also promote break-ups. The neuropeptide oxytocin can enhance the maintenance of social bonds and reduce couple conflict, although its influence on jealousy evoked by imagined or real infidelity is unclear., Aims: This study aimed to investigate the effects of intranasal oxytocin (24 IU) on romantic jealousy in both males and females in imagined and real contexts., Methods: Seventy heterosexual couples participated in this double-blind, placebo-controlled, between-subject design study. Jealousy was firstly quantified in the context of subjects imagining partner infidelity and secondly in a Cyberball game where their partner interacted preferentially with an opposite-sexed rival stranger to simulate partner exclusion, or rejected a neutral stranger but not the partner., Results: Oxytocin primarily decreased jealousy and arousal ratings towards imagined emotional and sexual infidelity by a partner in both sexes. During the Cyberball game, while male and female subjects in both groups subsequently threw the ball least often to the rival stranger, under oxytocin they showed reduced romantic jealousy and arousal ratings for stranger players, particularly the rival one, and reported reduced negative and increased positive feelings while playing the game., Conclusions: Together, our results suggest that oxytocin can reduce the negative emotional impact of jealousy in established romantic partners evoked by imagined or real infidelity or exclusive social interactions with others. This provides further support for oxytocin promoting maintenance of relationships.

Rationale: Alcohol priming can modulate the value of rewards, as observed through the effects of acute alcohol administration on cue reactivity. However, little is known about the psychophysiological mechanisms driving these effects. Here, we examine how alcohol-induced changes in bodily states shape the development of implicit attentional biases and explicit cue reactivity., Objectives: To characterize the interoceptive correlates of alcohol priming effects on alcohol attentional biases and cue reactivity., Methods: In a two-session double-blind alcohol administration procedure, participants (n=31) were given a 0.4-g/kg dose of alcohol or a placebo drink. Cardiovascular responses were measured before and after alcohol administration to observe the effects of alcohol on viscero-afferent reactivity, as indexed through changes in heart rate variability (HRV) at or near 0.1 Hz (0.1-Hz HRV). Next, participants completed a modified flanker task to examine implicit alcohol attentional biases and provided subjective valence and arousal ratings of alcohol cues to examine explicit cue reactivity., Results: We found that changes in 0.1-Hz HRV after alcohol administration positively correlated with attentional biases, and negatively correlated with alcohol valence ratings; blood alcohol content was a null predictor., Conclusions: This is novel evidence that suggests alcohol-induced changes in bodily states may mediate the occurrence of alcohol priming effects and highlights the potentially generative role of interoceptive mechanisms in alcohol-related behaviors. The differential patterns revealed by implicit biases and explicit response tendencies are considered within the context of the dissociation between wanting and liking.

Background: It is commonly believed that drugs, including stimulants, are used recreationally because of their ability to induce pleasurable subjective effects. However, recreational drug use sometimes occurs in the absence of positive subjective effects, suggesting that other factors contribute. Here, we examine the extent to which the direct subjective effects of amphetamine, a commonly misused stimulant, predict subsequent choice of the drug vs placebo., Methods: Healthy adults (N = 112) participated in a five-session amphetamine choice study. On the first four sessions, participants sampled either 20 mg d-amphetamine or placebo in color-coded capsules two times each. On the fifth session, they chose which color (d-amphetamine or placebo) they preferred. We examined the choice of drug vs placebo in relation to demographic characteristics, baseline mood states, personality and subjective and cardiovascular responses to acute administration of the drug., Results: Eighty-one participants chose amphetamine (Choosers) while 31 chose placebo (Non-choosers). Overall, amphetamine produced typical stimulant-like effects on subjective questionnaires, and it elevated heart rate and blood pressure vs placebo. Choosers reported greater positive mood, elation and stimulant-like effects following amphetamine compared to Non-choosers. The Choosers also exhibited a greater increase in systolic blood pressure, but not heart rate. The groups did not differ on demographic characteristics, mood states before drug administration or personality., Conclusions: These findings support the idea that pleasurable subjective responses to amphetamine, including positive mood, elation, and stimulant-like effects influence behavioral choice of the drug., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Marchigian Sardinian alcohol-preferring (msP) rats serve as a unique model of heightened alcohol preference and anxiety disorders. Their innate enhanced stress and poor stress-coping strategies are driven by a genetic polymorphism of the corticotropin-releasing factor receptor 1 ( CRF1 ) in brain areas involved in glucocorticoid signaling. The activation of glucocorticoid receptors (GRs) regulates the stress response, making GRs a candidate target to treat stress and anxiety. Here, we examined whether mifepristone, a GR antagonist known to reduce alcohol drinking in dependent rats, decreases innate symptoms of anxiety in msPs. Male and female msPs were compared to non-selected Wistar counterparts across three separate behavioral tests. We assessed anxiety-like behavior via the novelty-induced hypophagia (NIH) assay. Since sleep disturbances and hyperarousal are common features of stress-related disorders, we measured sleeping patterns using the comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Rats received an acute administration of vehicle or mifepristone (60 mg/kg) 90 min prior to testing on NIH, acoustic startle response, and CLAMS. Our results revealed that both male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Male msPs also displayed reduced sleeping bout duration versus Wistars, and female msPs displayed greater acoustic startle responses versus male msPs. Importantly, the enhanced anxiety-like behavior and startle responses were not reduced by mifepristone. Together, these findings suggest that increased expression of stress-related behaviors in msPs are not solely mediated by acute activation of GRs.

Prior research demonstrates contextual influences on drug responses in both animals and humans, although studies in humans typically focus on only one aspect of context (e.g., social) and examine a limited range of subjective experiences. The current study sought to address these limitations by examining the impact of both social and physical context on the full range of subjective alcohol effects. The sample included 448 young adult social drinkers (57% male, 66.5% White) randomly assigned to consume alcohol (target blood alcohol concentration of .08 g%) or placebo in 1 of 4 contexts (solitary lab, group lab, solitary bar, group bar). Results indicated that high arousal positive (HAP) effects of alcohol (e.g., talkative, lively) were stronger in nonbar relative to bar contexts and that low arousal positive (LAP) effects (e.g., relaxed, calm) were only present in the group lab context. There were also main effects of social context such that high arousal effects (both positive and negative) were stronger in group contexts, regardless of beverage condition. These findings highlight the importance of considering context when examining alcohol effects. Studies designed to isolate pharmacological HAP effects may benefit from a nonbar setting, and studies of LAP effects might be most effective in a simulated living room or home environment, although future studies are needed to directly address this possibility. Further, studies with an explicit focus on expectancies or that need strong control for expectancies might benefit from a group context, particularly when studying high arousal effects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Trauma patients treated with ketamine during emergency care present aggravated early post- traumatic stress reaction which is highly predictive of post-traumatic stress disorder (PTSD) development and severity. The use of ketamine in the acute trauma phase may directly or indirectly interfere with neural processes of memory consolidation of the traumatic event, thus leading to the formation of maladaptive memories, a hallmark symptom of PTSD. We have recently shown that ketamine anesthesia, immediately after a traumatic event, enhances memory consolidation and leads to long-lasting alterations of social behavior in rats. Based on the evidence that ketamine induces a robust central and peripheral adrenergic/noradrenergic potentiation and that activation of this system is essential for the formation of memory for stressful events, we explored the possibility that the strong sympathomimetic action of ketamine might underlie its memory enhancing effects. We found that rats given immediate, but not delayed, post-training ketamine anesthesia (125 mg/kg) presented enhanced 48-h memory retention in an inhibitory avoidance task and that these effects were blocked by adrenal medullectomy, lesions of the locus coeruleus, systemic or intra-basolateral amygdala ß-adrenergic receptor antagonism. Thus, the memory enhancing effects of ketamine anesthesia are time-dependent and mediated by a combined peripheral-central sympathomimetic action. We elucidated a mechanism by which ketamine exacerbates acute post-traumatic reaction, possibly leading to development of PTSD symptomatology later in life. These findings will help guide for a better management of sedation/anesthesia in emergency care to promote the prophylaxis and reduce the risk of developing trauma-related disorders in trauma victims., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Caffeine has been demonstrated to enhance olfactory function in rodents, but to date, the sparse research in humans has not shown any equivalent effects. However, due to the methodological nature of those human studies, a number of questions remain unanswered, which the present study aimed to investigate. Using a double-blind experimental design, participants (n = 40) completed baseline mood measures, standardised threshold and identification tests and were then randomly allocated to receive a capsule containing either 100 mg of caffeine or placebo, followed by the same olfactory tests and mood measures. Results revealed that despite a trend toward elevated arousal following caffeine for habitual caffeine consumers, there were no changes in odour function. In contrast, for non-caffeine consumers, caffeine acted to enhance odour (threshold) sensitivity but reduce odour identification. Overall, these findings demonstrate a complex profile of effects of caffeine on odour function and, given the evidence from the wider caffeine literature, it is proposed that the effects of caffeine might be limited to older populations.

Background: Anxiolytic premedication requires careful consideration owing to potential side effects including delayed recovery after ambulatory anesthesia. We aimed to compare the effect of midazolam on recovery profiles postoperatively, depending on whether propofol or sevoflurane was the primary anesthetic., Methods: We enrolled 226 patients (age, 18-50 years) undergoing ambulatory gynecologic laparoscopic surgery. Patients were categorized into propofol without midazolam (P), propofol with midazolam (MP), sevoflurane without midazolam (S), and sevoflurane with midazolam (MS) groups. As premedication, placebo or 0.02 mg/kg intravenous midazolam was used. The primary outcome was the difference in the time from anesthetic discontinuation to eye opening in response to verbal command. Secondary outcomes included postoperative nausea and pain occurrence and time to reach the discharge score., Results: The time from anesthetic discontinuation to eye opening was longer in the MP group (n = 49) than in the P group (n = 50; P < .001) but was not significantly different between the MS (n = 50) and S groups (n = 49; P = .1). Midazolam premedication did not significantly affect postoperative nausea in the MP group compared with that in the P group (P = .3) but had a nausea prevention effect in the MS group compared with that in the S group (P < .001). The time to reach the discharge score was similar in all patients regardless of midazolam administration., Conclusion: In the recovery from short-duration ambulatory gynecologic surgery in young patients, intravenous midazolam premedication showed positive effects on postoperative nausea without affecting the time from anesthetic discontinuation to eye opening with sevoflurane-based anesthesia but prolonged the time from anesthetic discontinuation to eye opening with propofol-based anesthesia. Because this difference between the propofol groups is not clinically significant, the results support midazolam premedication in young women. Further studies assessing larger populations are needed.

Background: Subjective response (SR) to acute alcohol reflects individual variance to the sensitivity of alcohol's pharmacological effects. It has been argued that measures of stimulation and sedation may not fully capture the full-range SR, with 2 novel domains proposed: high arousal negative and low arousal positive. While substantial progress has been made in the field of SR and alcohol use risk, it remains unknown how these novel domains correspond to traditional SR measures. Therefore, the current study examined the latent structure of traditional and novel SR measures at rising breath alcohol concentrations (BrACs) during alcohol administration., Methods: Heavy drinkers (n = 67; 36M/31F) participated in an intravenous alcohol administration. Questionnaires assessing stimulation, sedation, mood, valence and arousal, and craving were assessed at baseline and at BrACs of 20, 40, and 60 mg%. A series of exploratory factor analyses were conducted to examine the latent factor structure of SR at each time point. Correlations examined the association between the generated factors and measures of problematic alcohol use., Results: The analysis generated a 3-factor solution, consistent across all time points. The factors measured the following effects of SR: (i) stimulation and positive mood, (ii) sedation and aversive effects, and (iii) tension reduction. The tension reduction factor was most commonly associated with problematic alcohol use in this sample., Conclusion: This study extends upon the literature evaluating the biobehavioral effects of alcohol by examining a novel combination of SR to alcohol measures. This study demonstrates that the proposed low arousal positive domain, which loaded onto the tension reduction factor, provides novel information not captured by previous SR measures. Going forward, studies of alcohol's subjective effects should use this dimensional approach to reduce multiple comparisons across a wide range of scales and to build a literature grounded on the underlying structure of SR as a translational phenotype for AUD., (© 2020 by the Research Society on Alcoholism.)

Background: The medial prefrontal cortex (mPFC) is a brain region involved in the evaluation and selection of motivationally relevant outcomes. Neural activity in mPFC is altered following acute ethanol (EtOH) use and, in rodent models, doses as low as 0.75 g/kg yield cognitive deficits. Deficits in decision making following acute EtOH are thought to be mediated, at least in part, by decreases in mPFC firing rates (FRs). However, the data leading to this conclusion have been generated exclusively in anesthetized rodents. The present study characterizes the effects of acute EtOH injections on mPFC neural activity in awake-behaving rodents., Methods: Awake-behaving and anesthetized in vivo electrophysiological recordings were performed. We utilized 3 groups: the first received 2 saline injections, the second received a saline injection followed by 1.0 g/kg EtOH, and the last received saline followed by 2 g/kg EtOH. One week later, an anesthetized recording occurred where a saline injection was followed by an injection of 1.0 g/kg EtOH., Results: The anesthetized condition showed robust decreases in neural activity and differences in up-down states (UDS) dynamics. In the awake-behaving condition, FRs were grouped according to behavioral state: moving, not-moving, and sleep. The differences in median FRs were found for each treatment and behavioral state combination. A FR decrease was only found in the 2.0 g/kg EtOH treatment during not-moving states. However, robust decreases in FR variability were found across behavioral state in both the 1.0 and 2.0 g/kg EtOH treatment. Sleep was separately analyzed. EtOH modulated the UDS during sleep producing decreases in FRs., Conclusions: In conclusion, the changes in neural activity following EtOH administration in anesthetized animals are not conserved in awake-behaving animals. The most prominent difference following EtOH was a decrease in FR variability suggesting that acute EtOH may be affecting decision making via this mechanism., (© 2020 by the Research Society on Alcoholism.)

The neuropeptide oxytocin (OT) is suggested to exert a pivotal role in a variety of complex human behaviors, including trust, attachment, social perception and fear regulation. Previous studies have demonstrated that intranasal administration of OT reduces subjective and neuroendocrine stress responses and dampens amygdala reactivity. OT has also been proposed to modulate activity of the autonomic nervous system. Here, a randomized double-blind, placebo-controlled study (with parallel design) was conducted with 56 healthy adult men to investigate whether a single-dose of OT (24 IU) modulates sympathetic autonomic arousal upon live dyadic gaze interactions. To do so, electrodermal recordings of skin conductance were performed during the engagement of eye contact with a live model in a two-person social context. In accordance to prior research, direct eye gaze elicited a significant enhancement in skin conductance responses, but OT did not specifically enhance or dampen the overall magnitude (amplitude) of the skin conductance response. Administration of OT did facilitate the recovery of skin conductance responses back to baseline (reduced recovery time), indicating a role of OT in restoring homeostatic balance. Notably, the treatment-effect on autonomic recovery was most prominent in participants with low self-reported social responsiveness, indicating that person-dependent factors play an important role in determining OT treatment-responses. Exploratory, it was shown that OT also significantly reduced self-reported feelings of tension and (at trend-level) worrying about how one presents oneself. Together, these observations add further evidence to a role of OT in modulating activity of the autonomic nervous system, primarily by facilitating a restoration of homeostatic balance after stimulus-induced increases in sympathetically-driven autonomic arousal., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Cognitive dysfunction is common in Parkinson's disease (PD) and predicts poor clinical outcomes. It is associated primarily with pathologic involvement of basal forebrain cholinergic and prefrontal dopaminergic systems. Impairments in executive functions, attention, and visuospatial abilities are its hallmark features with eventual involvement of memory and other domains. Subtle symptoms in the premotor and early phases of PD progress to mild cognitive impairment (MCI) which may be present at the time of diagnosis. Eventually, a large majority of PD patients develop dementia with advancing age and longer disease duration, which is usually accompanied by immobility, hallucinations/psychosis, and dysautonomia. Dopaminergic medications and deep brain stimulation help motor dysfunction, but may have potential cognitive side effects. Central acetylcholinesterase inhibitors, and possibly memantine, provide modest and temporary symptomatic relief for dementia, although there is no evidence-based treatment for MCI. There is no proven disease-modifying treatment for cognitive impairment in PD. The symptomatic and disease-modifying role of physical exercise, cognitive training, and neuromodulation on cognitive impairment in PD is under investigation. Multidisciplinary approaches to cognitive impairment with effective treatment of comorbidities, proper rehabilitation, and maintenance of good support systems in addition to pharmaceutical treatment may improve the quality of life of the patients and caregivers.

Background: G protein signaling pathways are key neuromodulatory mechanisms for behaviors and neurological functions that affect the impact of ethanol (EtOH) on locomotion, arousal, and synaptic plasticity. Here, we report a novel role for the Drosophila G protein-coupled receptor kinase 2 (GPRK2) as a member of the GRK4/5/6 subfamily in modulating EtOH-induced behaviors., Methods: We studied the requirement of Drosophila Gprk2 for naïve sensitivity to EtOH sedation and ability of the fly to develop rapid tolerance after a single exposure to EtOH, using the loss of righting reflex (LORR) and fly group activity monitor (FlyGrAM) assays., Results: Loss-of-function Gprk2 mutants demonstrate an increase in alcohol-induced hyperactivity, reduced sensitivity to the sedative effects of EtOH, and diminished rapid tolerance after a single intoxicating exposure. The requirement for Gprk2 in EtOH sedation and rapid tolerance maps to ellipsoid body neurons within the Drosophila brain, suggesting that wild-type Gprk2 is required for modulation of locomotion and alertness. However, even though Gprk2 loss of function leads to decreased and fragmented sleep, this change in the sleep state does not depend on Gprk2 expression in the ellipsoid body., Conclusion: Our work on GPRK2 has established a role for this GRK4/5/6 subfamily member in EtOH sensitivity and rapid tolerance., (© 2020 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcoholism.)

Background: Studies indicate that standard doses of hypnotics reduce or do not change the apnea-hypopnea index (AHI) or pharyngeal muscle activity. A 1-month trial of nightly zopiclone (7.5 mg) modestly reduced the AHI vs baseline without changing other sleep parameters or next-day sleepiness., Research Question: This study aimed to determine the effects of high-dose zopiclone (15 mg) on AHI, arousal threshold, genioglossus muscle responsiveness, and next-day alertness in selected people with OSA (low to moderate arousal thresholds without major overnight hypoxemia). We hypothesized that high-dose zopiclone would yield greater increases in arousal threshold and therefore larger reductions in AHI but may come at the expense of increased hypoxemia and next-day impairment., Study Design and Methods: Twenty-eight participants (AHI = 29 ± 20 events/h) suspected to have low to moderate arousal thresholds were studied during two in-laboratory polysomnographies, separated by 1 week, with an epiglottic pressure catheter and genioglossus intramuscular electrodes. Participants received 15 mg of zopiclone or placebo at each visit according to a double-blind, randomized, crossover design. Each morning, subjective sleepiness and alertness via a driving simulator task were assessed., Results: The AHI did not change from placebo to zopiclone (-1.5 events/h; 95% CI, -6.6 to 3.5 events/h; P = .54). Arousal threshold, genioglossus muscle responsiveness, and most other sleep parameters and measures of next-day sleepiness and alertness also did not change with zopiclone., Interpretation: A single night of treatment with high-dose zopiclone does not systematically reduce the AHI or increase the arousal threshold in selected people with OSA. The mechanisms for these unexpected findings require further investigation., Trial Registry: Australian New Zealand Clinical Trials Registry; No.: ACTRN12617000988358; URL: https://www.anzctr.org.au., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Forming effective responses to threatening stimuli requires the adequate and coordinated emergence of stress-related internal states. Such ability depends on early-life experiences and, in connection, the adequate formation of neuromodulatory systems, particularly serotonergic signaling. Here, we assess the serotonergic background of experience-dependent behavioral responsiveness using male and female zebrafish ( Danio rerio ). For the first time, we have characterized a period during behavioral metamorphosis in which zebrafish are highly reactive to their environment. Absence of social stimuli during this phase established by isolated rearing fundamentally altered the behavioral phenotype of postmetamorphic zebrafish in a challenge-specific manner, partially due to reduced responsiveness and an inability to develop stress-associated arousal state. In line with this, isolation differentially affected whole-brain serotonergic signaling in resting and stress-induced conditions, an effect that was localized in the dorsal pallium and was negatively associated with responsiveness. Administration of the serotonin receptor 1A partial agonist buspirone prevented the isolation-induced serotonin response to novelty in the level of the whole brain and the forebrain as well, without affecting catecholamine levels, and rescued stress-induced arousal along with challenge-induced behaviors, which together indicates functional connection between these changes. In summary, there is a consistent negative association between behavioral responsiveness and serotonergic signaling in zebrafish, which is well recognizable through the modifying effects of developmental perturbation and pharmacological manipulations as well. Our results imply a conserved serotonergic mechanism that context-dependently modulates environmental reactivity and is highly sensitive to experiences acquired during a specific early-life time window, a phenomenon that was previously only suggested in mammals. SIGNIFICANCE STATEMENT The ability to respond to challenges is a fundamental factor in survival. We show that zebrafish that lack appropriate social stimuli in a sensitive developmental period show exacerbated alertness in nonstressful conditions while failing to react adequately to stressors. This shift is reflected inversely by central serotonergic signaling, a system that is implicated in numerous mental disorders in humans. Serotonergic changes in brain regions modulating responsivity and behavioral impairment were both prevented by the pharmacological blockade of serotonergic function. These results imply a serotonergic mechanism in zebrafish that transmits early-life experiences to the later phenotype by shaping stress-dependent behavioral reactivity, a phenomenon that was previously only suggested in mammals. Zebrafish provide new insights into early-life-dependent neuromodulation of behavioral stress-responses., (Copyright © 2020 the authors.)

Studies have reported associations between environmental manganese (Mn) exposure and impaired cognition, attention, impulse control, and fine motor function in children. Our recent rodent studies established that elevated Mn exposure causes these impairments. Here, rats were exposed orally to 0, 25, or 50 mg Mn kg -1  day -1 during early postnatal life (PND 1-21) or lifelong to determine whether early life Mn exposure causes heightened behavioral reactivity in the open field, lasting changes in the catecholaminergic systems in the medial prefrontal cortex (mPFC), altered dendritic spine density, and whether lifelong exposure exacerbates these effects. We also assessed astrocyte reactivity (glial fibrillary acidic protein, GFAP), and astrocyte complement C3 and S100A10 protein levels as markers of A1 proinflammatory or A2 anti-inflammatory reactive astrocytes. Postnatal Mn exposure caused heightened behavioral reactivity during the first 5-10 min intervals of daily open field test sessions, consistent with impairments in arousal regulation. Mn exposure reduced the evoked release of norepinephrine (NE) and caused decreased protein levels of tyrosine hydroxylase (TH), dopamine (DA) and NE transporters, and DA D1 receptors, along with increased DA D2 receptors. Mn also caused a lasting increase in reactive astrocytes (GFAP) exhibiting increased A1 and A2 phenotypes, with a greater induction of the A1 proinflammatory phenotype. These results demonstrate that early life Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the impaired arousal regulation, attention, impulse control, and fine motor function reported in these animals, suggesting that mPFC catecholaminergic dysfunction may underlie similar impairments reported in Mn-exposed children., (© 2019 International Society for Neurochemistry.)

During physical efforts and sport practice, vigilance is responsible for maintaining an optimal state of activation, guaranteeing the ability to quickly respond and detect unexpected, but critical, stimuli over time. Caffeine and physical exercise are able to modulate the activation state, affecting vigilance performance. The aim of the present work was to assess the specific effects and modulations of caffeine intake and two physical intensities on vigilance components. Participants performed an attentional task (ANTI-Vea) to measure the executive and arousal components of vigilance, in six double-blinded counterbalanced sessions combining caffeine, placebo, or no-ingestion, with light vs. moderate cyclergometer exercise. Exercise at moderate intensity improved executive vigilance with faster overall reaction time (RT), without impairing error rates. Instead, caffeine intake generally improved arousal vigilance. In conclusion, caffeine and acute exercise seems to moderate executive and arousal vigilance in different ways.

Purpose of Review: Recently in October 2019 a Global Consensus Position on the use of Testosterone Therapy for Women was published. The use of testosterone and other agents for female sexual dysfunction (FSD) is an important topic for the urologist focusing on sexual health. This review describes the known causes for FSD, and discusses the role of androgens in this disorder, the evidence for using testosterone treatment, and other current and emerging therapies., Recent Findings: A recent meta-analysis, published in The Lancet Diabetes & Endocrinology evaluated a total of 36 randomized control trials spanning 1990-2018 and includes a total of 8480 patients. The primary findings were that testosterone therapy (TTh) increased sexual function including satisfactory sexual event frequency, sexual desire, pleasure, arousal, orgasm, responsiveness, and self-image when compared with either a placebo or drug-control (e.g., estrogen ± progestogen). In addition, TTh reduced sexual concerns and distress in postmenopausal women. Side effects included an increase in weight, acne, and hair growth, but there was no increase in serious adverse events. Importantly, TTh duration was greater than 12 weeks in all randomized control trials included in this meta-analysis., Summary: TTh is effective to treat FSD in postmenopausal women. More data is required to evaluate the long-term safety data on the effects of TTh on cardiovascular health, breast health, cognitive function, and the musculoskeletal system in women.

The extent to which behavior is shaped by experience varies between individuals. Genetic differences contribute to this variation, but the neural mechanisms are not understood. Here, we dissect natural variation in the behavioral flexibility of two Caenorhabditis elegans wild strains. In one strain, a memory of exposure to 21% O 2 suppresses CO 2 -evoked locomotory arousal; in the other, CO 2 evokes arousal regardless of previous O 2 experience. We map that variation to a polymorphic dendritic scaffold protein, ARCP-1, expressed in sensory neurons. ARCP-1 binds the Ca 2+ -dependent phosphodiesterase PDE-1 and co-localizes PDE-1 with molecular sensors for CO 2 at dendritic ends. Reducing ARCP-1 or PDE-1 activity promotes CO 2 escape by altering neuropeptide expression in the BAG CO 2 sensors. Variation in ARCP-1 alters behavioral plasticity in multiple paradigms. Our findings are reminiscent of genetic accommodation, an evolutionary process by which phenotypic flexibility in response to environmental variation is reset by genetic change., (Copyright © 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.)

In resting-state functional connectivity experiments, a steady state (of consciousness) is commonly supposed. However, recent research has shown that the resting state is a rather dynamic than a steady state. In particular, changes of vigilance appear to play a prominent role. Accordingly, it is critical to assess the state of vigilance when conducting pharmacodynamic studies with resting-state functional magnetic resonance imaging (fMRI) using drugs that are known to affect vigilance such as (subanesthetic) ketamine. In this study, we sought to clarify whether the previously described ketamine-induced prefrontal decrease of functional connectivity is related to diminished vigilance as assessed by electroencephalography (EEG). We conducted a randomized, double-blind, placebo-controlled crossover study with subanesthetic S-Ketamine in N = 24 healthy, young subjects by simultaneous acquisition of resting-state fMRI and EEG data. We conducted seed-based default mode network functional connectivity and EEG power spectrum analyses. After ketamine administration, decreased functional connectivity was found in medial prefrontal cortex whereas increased connectivities were observed in intraparietal cortices. In EEG, a shift of energy to slow (delta, theta) and fast (gamma) wave frequencies was seen in the ketamine condition. Frontal connectivity is negatively related to EEG gamma and theta activity while a positive relationship is found for parietal connectivity and EEG delta power. Our results suggest a direct relationship between ketamine-induced functional connectivity changes and the concomitant decrease of vigilance in EEG. The observed functional changes after ketamine administration may serve as surrogate end points and provide a neurophysiological framework, for example, for the antidepressant action of ketamine (trial name: 29JN1556, EudraCT Number: 2009-012399-28)., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Approaches that facilitate the recovery from coma would have enormous impacts on patient outcomes and medical economics. Orexin-producing neurons release orexins (also known as hypocretins) energy-dependently to maintain arousal. Hyperbaric oxygen (HBO) could increase ATP levels by preserving mitochondrial function. We investigated, for the first time, the arousal effects of HBO and orexins mechanisms in a rat model of unconsciousness induced by ketamine or ethanol. A total of 120 Sprague-Dawley male rats were used in this study. Unconsciousness was induced either by intraperitoneal injection of ketamine or ethanol. The HBO treatment (100% O2 at 3 ATA) was administered immediately after unconsciousness induction for 1 hr. SB334867, orexin-1 receptor (OX1R) inhibitor, or JNJ10397049, orexin-2 receptor (OX2R) inhibitor was administered 30 min intraperitoneally before unconsciousness induction. Loss of righting reflex test (LORR) and Garcia test were used to evaluate the unconsciousness duration and neurological deficits after recovering from unconsciousness, respectively. Enzyme-linked immunosorbent assay was used to measure brain tissue ATP and orexin A levels. Ketamine or ethanol injection resulted in LORR immediately and neurological deficits 6 hr after unconsciousness induction. HBO treatment significantly reduced the LORR duration, improved Garcia scores and unregulated ATP and orexin A levels in the brain tissue. Administration of OX1R inhibitor or OX2 R inhibitor abolished arousal and neurological benefits of HBO. In conclusion, HBO exerted arousal-promoting effects on unconscious rats induced by ketamine or ethanol. The underlying mechanism was via, at least in part, ATP/orexin A upregulation. HBO may be a practical clinical approach to accelerate unconsciousness recovery in patients., (© 2019 Wiley Periodicals, Inc.)

Background: Residency training in anesthesiology involves care of hospitalized patients and necessitates overnight work, resulting in altered sleep patterns and sleep deprivation. Caffeine consumption is commonly used to improve alertness when fatigued after overnight work, in preparation for the commute home., Methods: We studied the impact of drinking a caffeinated energy drink (160 mg of caffeine) on driving performance in a high-fidelity, virtual reality driving simulator (Virginia Driving Safety Laboratory using the Driver Guidance System) in anesthesiology resident physicians immediately after 6 consecutive night-float shifts. Twenty-six residents participated and were randomized to either consume a caffeinated or noncaffeinated energy drink 60 minutes before the driving simulation session. After a subsequent week of night-float work, residents performed the same driving session (in a crossover fashion) with the opposite intervention. Psychomotor vigilance task (PVT) testing was used to evaluate reaction time and lapses in attention., Results: After 6 consecutive night-float shifts, anesthesiology residents who consumed a caffeinated energy drink had increased variability in driving for throttle, steering, and speed during the first 10 minutes of open-road driving but proceeded to demonstrate improved driving performance with fewer obstacle collisions (epoch 2: 0.65 vs 0.87; epoch 3: 0.47 vs 0.95; P = .03) in the final 30 minutes of driving as compared to driving performance after consumption of a noncaffeinated energy drink. Improved driving performance was most apparent during the last 30 minutes of the simulated drive in the caffeinated condition. Mean reaction time between the caffeine and noncaffeine states differed significantly (278.9 ± 29.1 vs 294.0 ± 36.3 milliseconds; P = .021), while the number of major lapses (0.09 ± 0.43 vs 0.27 ± 0.55; P = .257) and minor lapses (1.05 ± 1.39 vs 2.05 ± 3.06; P = .197) was not significantly different., Conclusions: After consuming a caffeinated energy drink on conclusion of 6 shifts of night-float work, anesthesiology residents had improved control of driving performance variables in a high-fidelity driving simulator, including a significant reduction in collisions as well as slightly faster reaction times.