bluuebunny/crossref_metadata_2025_split huggingface dataset:
0026 Novel home-based circadian phase assessment tool to enhance accessible quality care of circadian rhythm disorders- Circadia Study
Authors: Love Jessica , Lane Jacqueline , Saxena Richa , Scheer Frank , Bormes Gregory 
Published: May 2023

Abstract

Introduction
Circadian rhythm sleep-wake disorders (CRSWDs), shifted timing of physiology with the external environments. CRSWDs, often undiagnosed, can increase risk of cardiometabolic and psychiatric disorders, and may have substantial financial and social impacts. Dim light melatonin onset assay (DLMO), the current gold-standard diagnostic test for CRSWDs is expensive/difficult. We aim to develop a more accessible melatonin assessment.

Methods
Our DLMO assay kit is low-cost, home-based and self-administered. It contains all necessary components for a home-based DLMO assay, including 18 time-stamped saliva samples, a Philips Actiwatch, and a lux meter. We tested the feasibility of the kit across two DLMO assessments, one-week apart, in CRSWDs patients (N=5) and controls (N=5). We concurrently assessed sleep with wrist actigraphy and sleep diary over four weeks through a self-guided study website.

Results
We enrolled participants with delayed (n=4) and advanced (n=1) sleep disorder and 5 control participants (mean 38.2 y.o., SD 11.66 y.o.; biological sex: 9 female, 1 male (control)). Participants were 100% compliant completing questionnaires and sleep logging with little intervention and no in-person guidance. 5/10 participants completed 100% of sleep diary days. Average duration of study involvement, from consent to study completion, was 42.4 days. Participants successfully set up their collection space and collected saliva samples, remaining compliant to objectively-measured study protocols: 86.67% of samples were taken under sufficiently low light, and 82% were taken within five minutes of scheduled collection. We obtained and averaged two DLMO times for 7/10 participants (delayed sleep phase disorder (DPSD): 12:05 AM, controls: 9:56 PM). DLMO times were on average 3:18 hours earlier than self-reported sleep times.

Conclusion
Our pilot study, with both CRSWDs patients (N=5) and controls (N=5), found the at-home kits feasible and reproducible (5/6 participants had their DLMO times within an hour of each other). Using the kit, we confirmed their previous DSPD diagnoses and correctly classified controls through melatonin samples. We used objective measures (Actigraph) to verify the testing procedure was followed. These procedures will be tested on a larger scale in the Circadia Study (circadiastudy.org), set to launch in February 2023.

Support (if any)
This work was supported by the National Institutes of Health [DHHS] (grant number 1R35GM146839-01).
0030 Insomnia is associated with lower serum antioxidants in the Hispanic Community Health Study/Study of Latinos
Authors: Cabrera Jose Santos , Zhang Ying , Huang Tianyi , Chung Joon , Yu Bing , Qi Qibin , Ramos Alberto , Daviglus Martha , Zee Phyllis , Kaplan Robert , González Hector , Isasi Carmen , Redline Susan , Sofer Tamar 
Published: May 2023

Abstract

Introduction
Insomnia is associated with neurodegenerative diseases. Concentration levels of some metabolites are associated with pathophysiologic changes, possibly in a sex-specific manner. Thus, serum metabolite levels are useful for understanding insomnia-related pathophysiological changes and how they potentially relate to neurodegenerative disease.

Methods
The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a longitudinal cohort study following self-reported Hispanic/Latino individuals in the U.S. At baseline, insomnia symptoms were captured using the Women Health Initiative Insomnia Rating Scale (WHIIRS), insomnia being defined as WHIIRS≥9. Metabolites were measured using blood serum from the baseline exam in independent discovery and replication datasets. In discovery, metabolite associations with WHIIRS and with insomnia were estimated in linear regression. Significant associations (FDR p-values&lt; 0.05) were tested in the replication dataset and considered replicated if their p-value&lt; 0.05 and the direction of association matched with the discovery analysis. Associations were further studied for gender interaction. All analyses were adjusted for age, self-reported gender, study center, and Hispanic/Latino background.

Results
3,895 individuals participated in the discovery analysis, and 2,121 in replication analysis. Female individuals were aged 46.5 on average (SD 15.1) and 35% had insomnia, while male individuals were aged 44.8 (14.8) and 24% had insomnia. After quality control, 767 metabolites were tested for association. Six metabolites were associated with WHIIRS (FDR&lt; 0.05) in the gender-combined analysis. Three were xenobiotics which were on the benzoate or salicylic acid metabolism pathway. Of the 6 metabolite associations, two replicated (p-value&lt; 0.05): hydrocinnamate and indolepropionate. These two metabolites had spearman correlation of 0.44. Higher levels of both metabolites were associated with lower WHIIRS, showing stronger associations in females (interaction p-value =0.04 for hydrocinnamate and p-value=0.13 for indolepropionate). Associations remained essentially unchanged in a model further adjusting for hypertension and diabetes. When removing 534 individuals who self-reported using sleeping pills at least once a week, the associations attenuated slightly: from an effect estimates of -0.0075 to -0.0069 (hydrocinnamate) and from -0.0082 to -0.0068 (indolepropionate).

Conclusion
Among the HCHS/SOL target population, insomnia symptom severity is associated with a lower concentrations of some plasma metabolite levels which are important antioxidant needed in preventing oxidative stress and neurodegeneration.

Support (if any)
R01HL161012.
0033 Genome-wide association analysis of composite sleep scores in 413,904 individuals
Authors: Goodman Matthew , Nagarajan Pavithra , Lane Jacqueline , Dashti Hassan , Chung Joon , Sofer Tamar , Purcell Shaun , Zhu Xiaofeng , Rutter Martin , Redline Susan , Saxena Richa , Wang Heming 
Published: May 2023

Abstract

Introduction
Recent genome-wide association studies (GWAS) of individual sleep traits have identified hundreds of genetic loci, often implicating genes and biological pathways that are shared across sleep phenotypes. Modeling multiple dimensions of sleep may allow identification of common underlying genetic mechanisms and complement analyses of individual traits. Moreover, construction of novel sleep health scores, accounting for correlations between traits, has the potential to enhance specificity and power for genetic analyses.

Methods
We performed GWAS of composite sleep scores derived from five sleep questions characterizing 413,904 individuals of European ancestry from the UK Biobank. We constructed an additive sleep score (SS-add) as a sum of up to five favorable self-reported sleep behaviors (sleep duration of 7-8 hours, early chronotype, few insomnia symptoms, no snoring, and no excessive daytime sleepiness) as well as five principal component scores (SS-PC1 – SS-PC5) using the underlying sleep traits. SNP-level association studies of the sleep scores were complemented with multiple follow-up analyses, including investigation of pathway, tissue, and cell-type enrichments, as well as comprehensive genetic correlation (381 representative phenotypes) and bi-directional Mendelian randomization (MR) analyses (40 selected phenotypes).

Results
Sleep scores SS-PC1 (interpretable as longer duration sleep without insomnia symptoms) and SS-PC2 (healthy sleep without snoring or sleepiness) showed higher heritability (respectively 11.7% and 9.3%) compared with their primary underlying traits. SS-PC3 (loading strongly on chronotype) showed highest overall heritability (15.3%). Accounting for the six GWAS, we identified 28 significant novel loci (p&lt; 8.3e-9), 31 additional novel loci (p&lt; 5e-8), and 341 loci previously reported (p&lt; 5e-8) by GWAS of individual sleep traits. Associated loci mapped to genes enriched in expression in brain tissues, and in metabolic and neuronal pathways. Numerous neurological, cardiometabolic and other traits were genetically correlated with sleep health (104 with|rho_g|&gt;0.3, p&lt; 2e-5). MR associations (p&lt; 2e-4) pointed to causes (BMI [SS-PC2/PC4], smoking [SS-add/PC1], lower socio-economic status [SS-add/PC5]) and consequences (coronary heart disease [SS-add/PC1], pain [SS-PC1/5]) of poor sleep.

Conclusion
Composite sleep health scores revealed novel genetic mechanisms of related sleep behaviors, helped clarify relationships with neurological and cardiometabolic traits, and deserve further investigation.

Support (if any)
R01HL153814 (to H.W.), NHLBI R35HL135818 (to S.R.), 1R01HL146751 (to R.S.), UKB Application 6818.
0041 Neuronal circuits convergently disrupted in the genetic basis of sleep phenotypes and rare neurodevelopmental syndromes
Authors: Moyses-Oliveira Mariana , Paschalidis Mayara , Souza-Cunha Lais , Guerreiro Pedro , Adami Luana , Kloster Anna , Mosini Amanda , Moreira Gustavo , Doria Sandra , Tempaku Priscila , Pires Gabriel , Andersen Monica , Tufik Sergio 
Published: May 2023

Abstract

Introduction
Sleep-related phenotypes have been frequently reported in early on-set epileptic encephalopathies (EE) and in developmental delay (DD) syndromes, in particular in syndromes related to autism spectrum disorder (ASD). Yet the convergent pathogenetic mechanisms between these comorbidities are largely unknown.

Methods
We first performed a gene enrichment study that identified shared risk genes among rare EE/neurodevelopmental disorders (NDD), rare DD genetic syndromes and sleep disturbances. We then determined cellular and molecular pathways enriched among genes shared between sleep phenotypes and those two early onset mental illnesses, aiming to identify genetic disparities and commonalities among these phenotypic groups.

Results
The sleep gene set was observed as significantly overlapped with the two gene lists associated to rare genetic syndromes (i.e. EE/NDD and DD gene sets), suggesting shared genetic contribution. Similarities across significantly enriched pathways between the two intersect lists comprehended mostly synapse-related pathways, such as retrograde endocannabinoid signaling, serotonergic and GABAergic synapse. Network analysis indicates EE/NDD vs sleep specific clusters and DD vs sleep specific clusters related to synaptic and transcriptional regulation, respectively. Longstanding functional patterns previously described in EE and NDD genetic architecture were recaptured after dissecting the overlap between the genes associated to those developmental phenotypes and sleep disturbances, suggesting that during neurodevelopment different molecular and functional mechanisms are related to alterations on circadian rhythm.

Conclusion
The overlapping gene set and biological pathways highlighted by this study may serve as a primer for new functional investigations of shared molecular mechanisms between sleep disturbances and rare developmental syndromes, with or without epilepsy.

Support (if any)
Our studies are supported by Associação Fundo de Incentivo à Pesquisa (AFIP). S.T. and M.L.A. received CNPq fellowships.
0042 EEP-PROMOTING GABAERGIC NEURONS IN THE PARAFACIAL ZONE PLAY A ROLE IN ANESTHETIC-INDUCED UNCONSCIOUSNESS IN MICE
Authors: Imamura Toshihiro , Wasilczuk Andrzej , Kelz Max , Pack Allan 
Published: May 2023

Abstract

Introduction
Although the precise mechanisms by which anesthetics induce unconsciousness are unknown, there is evidence that shared brain circuits are engaged during sleep and general anesthesia. The parafacial zone (PZ) of the brainstem has recently been identified as a sleep-promoting region. Specifically, GABAergic neurons in the PZ (PZ-GABA) are active during non-REM sleep. The role of sleep-promoting PZ-GABA during anesthetic-induced hypnosis is unknown. We hypothesized that PZ-GABA are active during general anesthesia and contribute to anesthetic-induced hypnosis.

Methods
Adult C57BL6 mice (n = 3) were subjected to two-hour exposures of a hypnotic dose of an inhaled general anesthetic (isoflurane 1.2%) in oxygen, a non-immobilizer, F6, that lacks hypnotic properties (1,2-dicholorohexafluorocyclobutane 3%) in oxygen, or oxygen alone. The brains were harvested immediately following these exposures. The sections of brain were immunostained for c-Fos and GAD. To study the role of PZ-GABA in isoflurane-induced hypnosis, ablation of PZ-GABA was performed in adult bitransgenic Vgat-ires-Cre;Ai6 mice in which GABAergic neurons express a fluorescent reporter (n = 5 per group). Anesthesia sensitivity was evaluated weekly for four weeks after the virus injections by assessing the presence of a righting reflex during the exposures.

Results
In the PZ, a hypnotic dose of Isoflurane selectively activated GAD-positive GABAergic neurons compared to mice treated with F6 and oxygen. (P &lt; 0.01 for both F6 and oxygen vs. Isoflurane, one-way ANOVA) Furthermore, mice lacking PZ-GABA demonstrated resistance to anesthetic induction, decreased sensitivity during the maintenance phase, and consistently increased the propensity to emerge from anesthesia. (For both induction and emergence, the upper 95% CI of EC50 at baseline was lower than the lower 95% CI at all time points after the injections. For maintenance phase, P &lt; 0.05 for baseline vs. 1-week, one-way ANOVA)

Conclusion
PZ-GABA was active during isoflurane exposure. Moreover, the absence of PZ-GABA resulted in resistance to isoflurane-induced hypnosis. These findings suggest that PZ-GABA, a sleep-promoting region in the brainstem, plays an important role in general anesthesia.

Support (if any)
NIH (T32HL7713-27, T32 NS091006), ATS-ASPIRE
0043 Modulation of ultra-slow calcium oscillation in the dentate gyrus during Non-REM sleep
Authors: Turi Gergely , Chen Xinyue , Teng Sasa , Peng Yueqing 
Published: May 2023

Abstract

Introduction
The function of sleep in memory consolidation has been well established. Hippocampal CA1 and CA3 subregions are thought to be particularly important in this process. The current working hypothesis postulates that episodic memory traces captured during waking hours are replayed in the hippocampal CA1-CA3 areas and transferred to the cortex for long-term storage during sleep. Even though the sensory and spatial information from higher-order cortical areas such as the entorhinal cortex primarily enters the hippocampus via the dentate gyrus (DG), this structure has always been considered as the “silent partner” in memory consolidation. Whether and how the captured memory traces are transferred from the DG toward the downstream hippocampal areas is less known.

Methods
Here, we used fiber photometry, two-photon calcium imaging, and EEG recording to examine the activity of DG during sleep.

Results
Strikingly, we found that DG cells are even more active during sleep than wakefulness and the calcium activity in the DG slowly oscillates during non-REM (NREM) sleep epochs. Furthermore, we also found that the cycles of this activity coinciding with microarousals are tightly locked to brief serotonin (5-HT) release during NREM sleep. Pharmacological blockade of 5-HT1a receptors abolished the calcium oscillations in the DG. Furthermore, genetic knockdown of 5-HT1a receptors in the DG leads to memory impairment in spatial and contextual memory tasks.

Conclusion
Together, our results indicate that ultra-slow calcium oscillations in the DG during NREM sleep are driven by serotonin fluctuations and they are required for memory consolidation.

Support (if any)
0046 Chemogenetic activation of A2AR neurons in Nucleus Accumbens increases sleep, affecting cognition and behavior in mice
Authors: Grabau Natasha , LeKites Vander , Brousseau Emma , Kroeger Daniel 
Published: May 2023

Abstract

Introduction
Sleep influences various cognitive and physiologic processes; however, the mechanisms through which sleep affects these different functions are not fully understood. The Nucleus Accumbens (NAc) was recently identified as a sleep regulating center. We hypothesized that manipulation of sleep via chemogenetic activation of sleep active Adenosine-2A receptor (A2aR) neurons in the NAc core could induce restorative sleep and affect memory, anxiety and depression-like states in mice.

Methods
We transfected A2A neurons in NAc core of A2AR-Cre transgenic mice with an adeno-associated virus (AAV) carrying the gene sequence for hM3Dq. Using Clozapine-N-Oxide (CNO) at varying concentrations (0.1, 0.3, 0.9, 2.7 mg/kg), we activated these neurons and analyzed EEG/EMG traces for rapid eye movement (REM) sleep, non-REM (NREM) sleep and wakefulness. Mice were then divided into three separate conditions: normal sleep, sleep deprivation or increased sleep for 4 hr. Following this sleep intervention mice underwent the following behavioral tests 1) Novel object recognition (NOR) test for memory, 2) the open field test (OFT) for anxiety and 3) the forced swim test (FST) for depression-like states.

Results
During the first 4 hours of chemogenetic activation of NAc A2AR neurons, we observed a 105% increase of NREM sleep at the highest dose of CNO when compared to saline ­treatment. REM sleep was increased similarly. Analysis of the behavioral tests revealed that mice in the increased sleep condition tended to perform better at the NOR test, suggesting increased memory performance. In the OFT, sleep deprived mice showed a significant increase in %time spent in the center zone and total distance travelled within the arena. They also spent significantly less time immobile. Sleep deprived mice also exhibited a trend towards spending more time swimming in the FST, indicating lower levels of depression-like states.

Conclusion
Our results suggest that chemogenetic activation of A2AR neurons in the NAc core strongly increases NREM and REM sleep, confirming the importance of these neurons in sleep/wake regulation. Moreover, we observed that increased sleep improves memory performance but does not significantly affect levels of anxiety or depression-like states. Instead, reduced sleep significantly decreases anxiety and tends to reduce depressive-like states.

Support (if any)
0055 Effect of acute sleep restriction on sleep physiology and emotional imagery memory in schizophrenia
Authors: Kam Korey , Ospina Luz , Fagan Samantha , Beck-Felts Katie , Messer Sylvie , Valencia Daphne , Balbuena Mayrelis , Aybar Vladimir , Mullins Anna , Parekh Ankit , Rapoport David , Ayappa Indu , Varga Andrew , Kimhy David 
Published: May 2023

Abstract

Introduction
Cognitive dysfunction in individuals with schizophrenia (SZ) represents a major determinant of poor functioning and may arise in part due to deficits in sleep quality that have been reported in in this population. In the current project, we investigate the effect of acute sleep restriction on a sleep-dependent emotional memory task.

Methods
Six individuals with medication-controlled SZ encoded consensus-rated emotionally valent and neutral pictures from the International Affective Picture System in the evening before 2 counterbalanced, polysomnographically-recorded nights containing either ad libitum sleep (~11pm to 7am) or sleep restriction (SR) to 4 hours between 3 and 7 am. Image recall occurred within 1 hour of wake time. We compared memory performance for negative emotional/neutral memory and PSG measures across the two sleep conditions with paired signed-rank tests.

Results
Mean age was 38 years and 50% were women. Acute sleep restriction resulted in reduced total sleep time (Adlib: median 372 min. (interquartile-range 53) vs SR: 209 (16) min., p=0.03), including reduction in duration of N1 (Ad lib: 44 min. (44) vs. SR: 29 min. (33), p=0.03), N2 (Ad lib: 158 min. (86) vs. SR: 60 min. (33), p=0.03) and REM sleep (Ad lib: 18 min. (5) vs. SR: 13 min. (13), p=0.03). We did not observe differences in N3 duration, sleep efficiency, and arousal index. Measures of breathing such as AHI4%, AHI3A, and SpO2 nadir were not significantly different between conditions. Compared to SR, the false alarm rate for emotional images was increased in ad lib sleep (n=6, p=0.03) with no difference in false alarm rate for neutral images (p=0.19). Correct rejection rate for emotional images was increased in SR compared to ad lib sleep (p=0.03) with no difference in neutral images (p=0.19). No other change was observed in accuracy of recall for emotional or neutral, miss rate for emotional or neutral and d-prime for emotional or neutral images.

Conclusion
In subjects with SZ, unrestricted sleep was associated with a greater false alarm rate for emotional, but not neutral scenes, suggesting a deficit in veridical memory or generalization of emotionally encoded information.

Support (if any)
R21MH126357, R01AG066870, R01AG056682, K24HL109156, AASMF Focus award/AARG-D
0062 Slow Oscillatory Transcranial Direct Current Stimulation During Restricted Nighttime Sleep Enhances Memory Consolidation
Authors: Riedy Samantha , Doty Tracy Jill , Balkin Thomas , Stekl Emily , Alger Sara , Hughes John 
Published: May 2023

Abstract

Introduction
Slow oscillatory transcranial direct current stimulation (SO-tDCS) during the first 30 min of nighttime sleep has been shown to improve memory consolidation of word pairs encoded immediately prior to sleep onset. We examined whether SO-tDCS administered during the second half of a restricted nighttime sleep opportunity likewise improves memory consolidation for previously encoded word pairs and mitigates subsequent performance deficits.

Methods
After three nights of baseline sleep in the laboratory, healthy subjects (ages 18-33, n=27, 17 females) were administered SO-tDCS (N=12) or SHAM (N=15) during the second hour of a 2h sleep period (between the hours of 23:00 and 03:00). Prior to this 2h sleep period, subjects were presented a series of 55 word-pairs. They were asked to recall 46 of the pairs immediately after learning (T0), and again at 20 min (T20) and 120 min (T120) post-awakening. Number of pairs recalled at T20 and T120 relative to T0 were analyzed with a mixed-effects ANOVA. Negative values indicate that subjects forgot pairs post-awakening relative to the initial learning recall.

Results
Subjects correctly recalled 35.0 ± 9.2 words (mean ± SD) at T0. Relative to T0, subjects in the SHAM condition correctly recalled significantly fewer words post-awakening than those in the SO-tDCS condition (SHAM: -0.8 ± 1.6 words; SO-tDCS: 0.3 ± 1.3 words; F=6.20, p=0.02), and fewer words at T20 than T120 (T20: -0.6 ± 1.5 words; T120: -0.1 ± 1.6 words; F=4.67, p=0.04). On average, subjects in the SHAM condition forgot words upon awakening relative to T0 (T20: -1.0 ± 1.4; T120: -0.6 ± 1.7 words), while those in the SO-tDCS condition forgot few to no words at T20 (0.0 ± 1.5 words) and actually recalled more words at T120 than T0 (0.6 ± 1.1 words).

Conclusion
Participants in the SHAM condition recalled fewer words after the restricted sleep period, whereas those in the SO-tDCS group increased recall following 2h of sleep. The present findings have important implications for the development of fatigue mitigation strategies during military operations, when sustaining performance in the face of insufficient sleep is critical.

Support (if any)
Department of Defense Military Operational Medicine Research Program (MOMRP)