bluuebunny/crossref_metadata_2025_split huggingface dataset:
059 Daridorexant: A dual, equipotent, and insurmountable antagonist of both orexin-1 and orexin-2 receptors
Authors: Grandjean Celia Mueller , Kiry Manon , Vaillant Catherine , Nayler Oliver , Gatfield John 
Published: May 2021

Abstract

Introduction
The orexin neuropeptide–receptor system is a central sleep and wake regulator in the brain. The two orexin receptor subtypes, OX1R and OX2R, are expressed either alone or together in all major wake-promoting brain areas. OX1R and OX2R activation by orexins causes elevation of intracellular calcium, which enhances synaptic transmission in secondary, monoaminergic wake- and arousal-promoting neurotransmitter circuits. Orexin receptor antagonists represent a novel and specific treatment of insomnia, which is different from classical therapy that more broadly inhibits brain activity via GABAA activation. Here we describe the molecular pharmacology of daridorexant, an orexin receptor antagonist which has proven highly effective in improving sleep and daytime functioning in insomnia patients.

Methods
Orexin-A(OxA)-induced calcium release assays in OX1R- and OX2R-expressing recombinant cell lines were applied to measure the antagonistic potency and kinetic properties of daridorexant in functional assays. Whole-cell competitive binding assays, using an orthosteric tracer were employed to determine the Ki of daridorexant. Comparisons were made with suvorexant and lemborexant.

Results
In OxA-induced calcium release assays with 2-h pre-incubation time, daridorexant displayed apparent Kb values of 0.5 nM (OX1R) and 0.8 nM (OX2R) with insurmountable antagonism on both receptors, demonstrating equipotent and highly effective functional inhibition of both receptor subtypes. On-target residence times of daridorexant (37oC) expressed as receptor occupancy half-lives (ROt1/2) were 4 min (OX1R) and 8 min (OX2R). In binding assays, daridorexant behaved as highly potent orthosteric antagonist. Also suvorexant behaved as dual insurmountable antagonist at OX1R/OX2R (appKb=0.7nM/1.0nM; ROt1/2=9 min/6 min) and as potent orthosteric antagonist in binding assays. Interestingly, lemborexant displayed a different interaction profile at OX1R/OX2R (appKb=13nM/0.4nM, ROt1/2&lt;2min/&lt;2min), i.e. it behaved as preferential OX2R antagonist with a very short on-target residence time and little insurmountability.

Conclusion
Daridorexant displays the desired target interaction profile of a dual, equipotent, and insurmountable antagonist of both OX1R and OX2R, which ensures equally efficient inhibition of both arousal-/wake-promoting receptor subtypes. Daridorexant′s on-target residence times are long enough to cause insurmountable inhibition, but short enough to avoid pharmacodynamic effects after drug elimination.

Support (if any)
Funded by Idorsia Pharmaceuticals Ltd.
066 Noradrenaline and acetylcholine inhibit sleep-promoting neurons of ventrolateral preoptic area through a local GABAergic circuit
Authors: De Luca Roberto , Nardone Stefano , Zhu Lin , Arrigoni Elda 
Published: May 2021

Abstract

Introduction
The ventrolateral preoptic (VLPO) nucleus is a key area involved in the initiation and maintenance of sleep. During wakefulness, sleep-promoting galanin neurons in the VLPO are directly inhibited by arousal signals including noradrenaline and acetylcholine. We have found that while these neurotransmitters directly inhibit VLPO galanin neurons, they also activate GABAergic neurons in the VLPO that do not express galanin. We propose that when activated by monoaminergic and cholinergic inputs, these local VLPO GABAergic neurons provide an additional inhibition of the VLPO galanin sleep-promoting neurons. We tested this model in brain slices in mice.

Methods
We studied VLPO galanin neurons in mouse brain slices using patch-clamp recordings. We recorded from fluorescently labeled VLPO galanin neurons following the injection of a cre-dependent AAV encoding for mCherry, into the VLPO of Gal-cre mice. For the optogenetic studies we expressed channelrhodopsin-2 (ChR-2) in VLPO VGAT neurons and mCherry in galanin neurons by injecting a flp-dependent and a cre-dependent AAV encoding respectively for ChR2 and mCherry into the VLPO of VGAT-flp::Gal-cre mice. We photo-stimulated local GABAergic neurons and recorded from labeled VLPO galanin neurons. Noradrenaline, carbachol and receptor antagonists were bath-applied.

Results
Noradrenaline and carbachol inhibited VLPO galanin neurons by alpha-2 and muscarinic receptors and these effects were maintained in the presence of tetrodotoxin (TTX) indicating, as previously proposed, a direct inhibitory effect of noradrenaline and carbachol on VLPO galanin neurons. In addition, both noradrenaline and carbachol increased the frequency of spontaneous inhibitory post-synaptic currents (sIPSCs) of VLPO galanin neurons, suggesting an additional inhibitory action on VLPO galanin neurons. Finally, optogenetic stimulation of local VLPO GABAergic neurons produced short latency, TTX-resistant, opto-evoked IPSCs in VLPO galanin neurons. Both noradrenaline and carbachol increased the amplitude of these opto-evoked IPSCs by the activation of alpha-1 and muscarinic receptors.

Conclusion
Our results demonstrate that noradrenaline and acetylcholine inhibit VLPO galanin neurons directly and indirectly. Both noradrenaline and acetylcholine increase GABAergic afferent inputs to VLPO galanin neurons by activating local GABAergic neurons. We propose that during wakefulness this feedforward inhibition provides additional inhibition of VLPO galanin sleep-promoting neurons.

Support (if any)
NS091126 and HL149630
084 Does Alignment between the Timing of Sleep and Circadian Rhythm Predict Behavioral Decision Making?
Authors: Hisler Garrett , Dickinson David , Hasler Brant 
Published: May 2021

Abstract

Introduction
Cognitive performance and decision making have been shown to suffer under conditions of misalignment between circadian preference and time-of-assessment; however, little is known about how misalignment between the timing of sleep and circadian rhythm impacts decision making. To this end, this study captured naturally occurring degrees of alignment between the timing of sleep and the circadian rhythm (i.e., alignment of sleep-wake timing with circadian phase) to examine if greater misalignment predicts worse behavioral decision making.

Methods
Over the course of two weeks, 32 participants (18–22 years of age; 61% female; 69% White) continuously wore actigraphs and completed two overnight in-lab visits (Thursday and Sunday) in which both dim light melatonin onset (DLMO) and behavioral decision-making (risk taking, framing, and strategic reasoning tasks) were assessed. Sleep-wake timing was assessed by actigraphic midsleep from the two nights prior to each in-lab visit. Alignment was operationalized as the interval between DLMO and average midsleep. Multilevel modeling was used to predict performance on decision making tasks from circadian alignment during each in-lab visit; nonlinear associations were also examined.

Results
Misalignment characterized by shorter time between DLMO and midsleep predicted decision-making in a curvilinear fashion (i.e., squared misalignment term predicted performance). Specifically, shorter time between DLMO and midsleep predicted greater risk-taking under conditions of potential loss (B = .10, p = .04), but less risk-taking under conditions of potential reward (B = -.14, p = .04) in a curvilinear fashion. Misalignment did not predict decision-making in the framing and strategic reasoning tasks.

Conclusion
Findings suggest that naturally occurring degrees of misalignment between the timing of sleep and the circadian rhythm may impact risky decision-making, further extending accumulating evidence that sleep/circadian factors are tied to risk-taking preferences. Future studies will need to replicate findings and experimentally probe whether manipulating alignment influences risky decision making.

Support (if any)
R21AA023209; R01DA044143
095 Steering Wheel Angle Excursions as a Measure of Fatigue-Related Driver Performance Impairment
Authors: Muck Rachael , Van Dongen Hans 
Published: May 2021

Abstract

Introduction
Fatigue from sleep loss and circadian misalignment causes automobile driving performance impairment. Metrics based on steering wheel angle, which is straightforward to measure, could be used to quantify this impairment. As the tail of the distribution of steering wheel angles (absolute magnitude of deviation from center) increases with fatigue, we investigated whether driving performance impairment could be quantified based on the prevalence of steering wheel excursions beyond a given angle threshold. We used data from two published laboratory studies of simulated shift work, in which fatigue remained low during day shifts but increased across time awake during night shifts.

Methods
N=37 healthy adults (ages 26.8±5.2y; 25 men) were assigned to a simulated night shift schedule (awake 20:00-10:00) or day shift schedule (awake 08:00-22:00; study 1 only). After an adaptation period, participants underwent two 5-day shift cycles with an intervening rest period. Driving performance was measured on a high-fidelity simulator during adaptation (data not used) and four times at 3h intervals during each shift day. Every drive involved 30min driving at 55mph, including ten 0.5mi uneventful straightaways being considered here. Steering wheel angle was measured at 72Hz (study 1) or 60Hz (study 2). A total of 1,471 drives (31,394,498 angle measurements) were available for analysis.

Results
We investigated angle thresholds across 0.01-0.25rad in 0.01rad intervals and counted the corresponding number of threshold excursions in each drive for each participant. For study 1, we applied mixed-effects ANOVA with fixed effects for condition and time awake, and their interaction, and determined the local effect size for interaction. A 0.03rad (1.7°) threshold yielded the greatest effect size, f²=0.031 (small). For this threshold, we repeated the analysis using the data from both studies, controlling for study. The interaction was significant (F[3,1428]=13.23, p&lt;0.001), showing low driving impairment across time awake during day shifts but increasing impairment across time awake during night shifts.

Conclusion
The prevalence of steering wheel excursions beyond a 1.7° angle threshold yielded sensitivity to fatigue-related driving performance impairment during simulated night shifts. Further research will extend our results to driving through curves and with greater fatigue levels.

Support (if any)
FMCSA DTMC75-07-D-00006
123 Detrimental effects of acute sleep deprivation on perceptual metacognition
Authors: Bigica Marco , Jiang Chunxiang , D’Onofrio Ilenia , Liu Zhishan , Song Chen 
Published: May 2021

Abstract

Introduction
Sleep deprivation (SD) impairs cognitive performance but its impact on metacognition – i.e. the ability to introspect about cognitive performance – is less clear. A few studies have assessed metacognitive accuracy after acute sleep deprivation in tasks of executive functions and found no impairments. However, whether SD has no influence on metacognition of other cognitive domains such as perception has not been investigated. In this study, we examined how metacognitive accuracy in perceptual decision tasks is affected by 32 hours of sustained wakefulness.

Methods
14 participants (3 males, aged 20-32) repeated four visual psychophysical tasks (orientation discrimination, two-flicker fusion, vernier acuity and a novel face/house discrimination in noise) at regular intervals during 32 hours of sustained wakefulness and once after 8 hours recovery sleep. In each task, we concurrently measured quantitative indices of perceptual threshold, confidence rating and metacognitive accuracy (i.e. how well confidence ratings discriminate correct vs incorrect perceptual judgements).

Results
We observed a gradual increase of perceptual threshold in all tasks with increased time awake. Furthermore, metacognitive accuracy gradually decreased during sustained wakefulness in all tasks. Specifically, the decrease in metacognitive accuracy was driven by over-estimated confidence in trials when participants made incorrect perceptual judgements. After recovery sleep, perceptual thresholds were reset to baseline for all tasks, while metacognitive accuracy was reset to baseline for the orientation discrimination and two-flicker fusion tasks only.

Conclusion
We showed that sustained wakefulness up to 32 hours increasingly impairs metacognitive accuracy in perceptual decision tasks. These results are consistent across different perceptual tasks, but are in contrast to previous studies showing preserved metacognition of executive functions after SD. Overall, this suggests that the fundamental mechanisms of perceptual metacognition may be similarly affected by sleep deprivation, but that SD selectively impacts different domains of metacognition, such as perceptual metacognition and metacognition of executive functions.

Support (if any)
MB - Cardiff University PhD Funding CS - Wellcome Trust 209192/Z/17/Z
167 Food Insecurity and Cardiometabolic Risks in Urban American Indian/Alaska Native (AI/AN) Youth: The Role of Sleep Health
Authors: Dong Lu , D’Amico Elizabeth , Dickerson Daniel , Brown Ryan , Palimaru Alina , Johnson Carrie , Troxel Wendy 
Published: May 2021

Abstract

Introduction
American Indian/Alaska Native (AI/AN) individuals experience significant health disparities, including poor sleep health and cardiometabolic disease, and these risks emerge early in life. Food insecurity (lack of consistent access to healthy foods) is an important social determinant of health, and AI/AN people are one of the highest risk groups for experiencing food insecurity. Yet, little is known about how food insecurity contributes to health outcomes in urban AI/AN youth. This is the first study to examine the association between food insecurity and sleep (both self-reported sleep disturbance and a composite index of sleep health) and cardiometabolic outcomes in urban AI/AN youth, and whether sleep may be an indirect path between food insecurity and cardiometabolic outcomes.

Methods
Participants were 142 urban AI/AN youth (mean age = 14, 58% female, 53% living in single-parent households). The Child Food Security Survey Module assessed food insecurity. Sleep disturbance was measured using the School Sleep Health Survey. A multi-dimensional sleep health composite was derived using questionnaire measures (i.e., satisfaction, alertness) and actigraphy-derived indices (i.e., duration, efficiency, regularity, timing). Cardiometabolic measures included body mass index (BMI), blood pressure, glycosylated hemoglobin (HbA1c), waist circumference, cholesterol, and triglycerides. Covariates were sex and age, and single-parent household.

Results
Greater food insecurity was significantly associated with greater BMI (b = 0.12, p = 0.015), higher systolic blood pressure (b = 0.93, p = 0.03), and greater sleep disturbance (b = 1.49, p &lt; .001), and marginally associated with poorer sleep health via the sleep health composite (b = -0.09, p = 0.08). Food insecurity was not associated with any other cardiometabolic outcomes. There was a significant indirect path from greater food insecurity to greater waist circumference through lower sleep health composite score (0.11, 95% bootstrapping CI: [0.01, 0.30]).

Conclusion
Food insecurity is an important social determinant of sleep and cardiometabolic health. This is the first study of these associations in urban AI/AN youth. Sleep health may be an important, modifiable intervention target to mitigate the negative impact of food insecurity and reduce cardiometabolic risks in this vulnerable population.

Support (if any)
NIMHD R01MD012190
184 Racial awareness and insufficient sleep
Authors: Grigsby-Toussaint Diana , Shin Jong Cheol 
Published: May 2021

Abstract

Introduction
Population-based studies are needed to fully disentangle persistent racial and ethnic disparities in sleep health in the US. In this study, we examine whether the frequency of self-reflection on racial identify influences insufficient sleep among US adults.

Methods
The 2010 Behavioral Risk Factor Analysis Surveillance System (BRFSS) was used as the primary data source to explore the relationship between self-reflection of racial identity and insufficient sleep. Data was limited to states administering the “Reactions to Race Module,” which included Georgia, Kentucky, and Rhode Island (N=7,085). Frequency of self-reflection of race was assessed using the question “How often do you think about your race? Would you say never, once a year, once a month, once a week, once a day, once an hour, or constantly?” Insufficient sleep was determined using the item, “During the past 30 days, for about how many days have you felt you did not get enough rest or sleep?” Multivariate regression analyses were performed while controlling for age, sex, education, income, marital status, and poor mental and physical health.

Results: Results
Across the sample, participants reported an average of 8.95+/- 10.06 days of insufficient sleep per month. Participants from Georgia reported the highest number of days of insufficient sleep (9.83+/- 10.51) followed by Kentucky (8.64+/- 9.94) and Rhode Island (8.38+/- 9.67) (p&lt;0.05). After controling for age, sex, education, income, employment, and marital status, individuals reporting any self-reflection on their race were more likely to report insufficient sleep within a 30-day period (Beta=0.026, 95% CI [0.062, 1.02], p=0.027).

Conclusion: Conclusion
In a sample of US adults, self-reflection of race adversely impacted sleep quality. More studies are needed to fully explore the mechanisms underpinning this association.
Support (if any):
242 Sufficient sleep attenuates the impact of COVID-19 pandemic on executive function decline in late adolescents and young adults
Authors: Ji Xiaopeng , Saylor Jennifer 
Published: May 2021

Abstract

Introduction
Executive function (EF), which shows continued development into early adulthood, is essential to build resilience to cope with COVID-19-related social and environmental changes. However, how sleep interacts with the pandemic on affecting EF remains unclear, particularly among late adolescents and young adults. This study examined (1) the impact of COVID-19 pandemic on sleep and EF and (2) whether sleep moderated pandemic-related changes in EF among young people aged 18-21 years old.

Methods
Between April and May 2020, university students with baseline data on sleep and EF (Spring and Fall semesters in 2019) available were invited to this follow-up study. Sleep duration, mid-sleep times, social jetlag (the difference between mid-sleep times on weekdays and weekends) and sleep latency were assessed using 7-day sleep diaries. Participants also completed the Pittsburgh Sleep Quality Index (PSQI), the Morningness/Eveningness Questionnaire, and the Behavior Rating Inventory of Executive function which yielded Global Executive Composite (GEC) scores. Paired t-test and multilevel random-effects models (STATA 16.0) estimated the associations. Covariates in multilevel models included age, sex, race, family income, parental education, COVID status, and health behaviors.

Results
Forty participants (19.25±1.12 years old) had paired data before and during COVID-19 pandemic. Participants slept 24 min longer (t= -2.07, p=0.03) but had increased sleep latency (t=-1.83, p=0.07) during the pandemic compared to pre-COVID baseline. Mid-sleep times shifted 40 min later (t= -3.22, p=0.003) during the pandemic. In multilevel models, GEC scores increased during pandemic (b=3.15, p=0.03) versus baseline, suggesting decreased executive function. Sleep duration (β=-4.72, p=0.03) significantly interacted with assessment time (before/during COVID-19), with increasing sleep duration attenuating the decline in EF during pandemic versus baseline. Although there was no interaction with COVID-19 pandemic, poor sleep quality (PSQI&gt;5) was independently associated with decreased EF (B=4.69, p=0.02). Other sleep variables were not associated with EF nor moderators.

Conclusion
Compared with pre-COVID-19 baseline, young people report longer sleep duration, later sleep phase, increased sleep latency, and worse executive function during the pandemic. Sufficient sleep represents a resilience factor against executive function decline during this unprecedented crisis.

Support (if any)
No
244 Physical fitness attenuates the deleterious association of sleep apnea with gray matter volume in the Wisconsin Sleep Cohort Study
Authors: Edmunds Kyle , Hagen Erika , Gaitán Julian , Barnet Jodi , Driscoll Ira , Lose Sarah , Motovylyak Alice , Okonkwo Ozioma , Peppard Paul 
Published: May 2021

Abstract

Introduction
Recent evidence has illustrated that gray matter (GM) atrophy, a diagnostic hallmark of Alzheimer’s disease (AD), may be influenced by psychosocial risk modifiers such as physical exercise and sleep. Cardiorespiratory fitness, a measure of oxygen delivery and utilization during exercise, is positively associated with both sleep quality and gray matter volume in brain areas associated with age-related cognitive decline, such as the hippocampus. In contrast, sleep apnea has been linked to global and regional gray matter atrophy, which is thought to be driven in-part by the incomplete modulation of cardiovascular and respiratory control during sleep. This study examines whether cardiorespiratory fitness modifies the deleterious relationship between sleep apnea and GM volume in a sample of non-demented older participants from the Wisconsin Sleep Cohort (WSC).

Methods
Using data from a subset of WSC participants (n=129, 51% female, mean [range] age at baseline=68 [49-85] years), cardiorespiratory fitness was estimated using a Non-Exercise CardioRespiratory Fitness Measure (NECRFM; based on age, sex, BMI, self-reported physical activity, and resting heart rate). Sleep apnea severity was measured by overnight polysomnography and characterized by the base 10 logarithm of the apnea-hypopnea index, log10(AHI+1). We assembled cross-sectional linear models of MRI-measured total GM volume using NECRFM and log10(AHI+1) as predictors while controlling for age, sex, BMI, education, and hypertension. Regional volumetric changes in the hippocampus and amygdala were assessed using analogous linear models, adjusting both outcome volumetrics for total intracranial volume.

Results
While the interaction between fitness and apnea severity was not significant (p=0.50), results stratified at the median NECRFM illustrated that among the less fit individuals, higher log10(AHI+1) was associated with a significant reduction in total GM volume (B(SE)=-0.06 (0.02); p=0.007); this relationship was not significant among those who were more fit (B(SE)=-0.03 (0.02); p=0.11). There were no significant effects in the hippocampus or amygdala.

Conclusion
These results indicate that cardiovascular fitness may attenuate the effect of severe sleep apnea on GM volume in older adults, supporting the protective role of cardiovascular fitness in aging brain health.

Support (if any)
This work was supported by United States National Institutes of Health grants R01AG058680, R01HL62252, 1R01AG036838, 1UL1RR025011, and R01AG062167.