bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of intra-day variability of gaseous measurements in sheep using portable accumulation chambers
Authors: O’ Connor Edel , McHugh Nóirín , Boland Tommy M , Dunne Eoin , McGovern Fiona M
Published: May 2021

Portable accumulation chambers (PAC) enable short-term spot measurements of gaseous emissions including methane (CH4), carbon dioxide (CO2), and oxygen (O2) consumption from small ruminants. To date the differences in morning and evening gaseous measurements in the PAC have not been investigated. The objectives of this study were to investigate: 1) the optimal measurement time in the PAC, 2) the appropriate method of accounting for the animal’s size when calculating the animal’s gaseous output, and 3) the intra-day variability of gaseous measurements. A total of 12 ewe lambs (c. 10 to 11 months of age) were randomly selected each day from a cohort of 48 animals over nine consecutive days. Methane emissions from the 12 lambs were measured in 12 PAC during two measurement runs daily, AM (8 to 10 h) and PM (14 to 16 h). Animals were removed from Perennial ryegrass silage for at least 1 h prior to measurements in the PAC and animals were assigned randomly to each of the 12 chambers. Methane (ppm) concentration, O2 and CO2 percentage were measured at 5 time points (T1 = 0.0 min, T2 = 12.5 min, T3 = 25.0 min, T4 = 37.5 min, and T5 = 50.0 min from entry of the first animal into the first chamber) using an Eagle 2 monitor. The correlation between time points T5-T1 (i.e., 50 min minus 0 min after entry of the animal to the chamber) and T4-T1 was 0.95, 0.92, and 0.77 for CH4, O2, and CO2, respectively (P < 0.01). The correlation between CH4 and CO2 output and O2 consumption, calculated with live-weight and with body volume was 0.99 (P < 0.001). The correlation between the PAC measurement recorded on the same animal in the AM and PM measurement runs was 0.73. Factors associated with CH4 production included: day and time of measurement, the live-weight of the animal and the hourly relative humidity. Results from this study suggest that the optimal time for measuring an animal’s gaseous output in the PAC is 50 min, that live-weight should be used in the calculation of gaseous output from an animal and that the measurement of an animal’s gaseous emissions in either the AM or PM does not impact on the ranking of animals when gaseous emissions are measured using the feeding and measurement protocol outlined in the present study.
Quantitation of Methamphetamine and Amphetamine in Postmortem Canine Tissues and Fluids
Authors: Buchweitz John P , Johnson Margaret , Wixson Margaret , Puschner Birgit
Published: May 2021

The production and use of the highly addictive stimulant methamphetamine are a serious public health problem in the USA and globally. Because of its increased popularity with recreational drug users, accidental or intentional poisoning incidents in companion animals have become an unavoidable scenario in veterinary medicine. We describe a case of methamphetamine poisoning in a 4-year-old female German Shepherd, with postmortem analytical quantitation of methamphetamine and its metabolite, amphetamine, in bodily tissues and fluids. Many tissues and bodily fluids can be tested to confirm methamphetamine exposure. More importantly, the higher concentrations found in stomach contents and liver, kidney and heart tissues suggest these are the most useful diagnostic specimens for postmortem confirmation of toxicosis in pets, especially in cases in which the source material is not available for testing or in cases with no postmortem evaluation.
Periprosthetic Osteolysis in Cervical Total Disc Arthroplasty: A Single Institutional Experience
Authors: Ebinu Julius O , Ramanathan Dinesh , Kurtz Steven M , Lawandy Shokry , Kim Kee D
Published: May 2021

BACKGROUND

Cervical disc arthroplasty (CDA) affords an excellent alternative to cervical fusion for the treatment of symptomatic patients with degenerative disc disease. As more surgeons perform CDAs, an understanding of the complications associated with this technique is crucial. Periprosthetic osteolysis (PO) is a rare potential complication associated with CDA.

OBJECTIVE

To highlight potential complications associated with CDA.

METHODS

A retrospective chart review of patients who underwent CDA at our institution was performed. Patient outcomes and relevant clinical and radiographical data were analyzed in addition to associated complications. Explanted devices were subjected to macroscopic and microscopic analyses.

RESULTS

A total of 88 patients were included: 68 patients underwent 1-level CDA and 20 patients had 2-level CDA. Implants used in this series included Mobi-C (Zimmer Biomet), Prestige LP (Medtronic), Secure C (Globus), Advent (Orthofix), and ProDisc C (DePuy). One patient demonstrated symptoms of myeloradiculopathy that correlated with radiographical periprosthetic osteolysis and required surgical intervention in the form of disc explantation, corpectomy, and cervical instrumented fusion. Device retrieval analysis demonstrated evidence of elevated oxidation levels and increased wear in the presence of high concentrations of metal ions and debris in the surrounding tissue. The tissue did not exhibit any immune response, infection, or acute inflammation.

CONCLUSION

PO is a potential complication of CDA that occurs irrespective of the type of implant used. We describe its occurrence and management and highlight the importance of being aware of this understated phenomenon.
Integration of Microanatomy, Neuronavigation, Dynamic Neurophysiologic Monitoring, and Intraoperative Multimodality Imaging for the Safe Removal of an Insular Glioma: 2-Dimensional Operative Video
Authors: Wu Kyle , Bi Wenya Linda , Essayed Walid Ibn , Patel Viharkumar , Kadri Paulo , Al-Mefty Ossama
Published: May 2021

Insular gliomas are located amongst myriad critical neurovascular structures, including lenticulostriate vessels, long insular perforators, putamen, internal capsule, frontal and temporal opercula, and key fasciculi.
1-6
Each of these critical structures engenders key function of the brain, which must be preserved. Although anatomic knowledge remains the cornerstone of insular glioma surgery, novel tools have been developed to aid the surgeon in identifying and preserving these essential structures. Modern surgery of the insular glioma calls for seamless integration of these techniques to maximize the safety and totality of insular glioma resection, which has been shown to improve length of survival and seizure control, while reducing risk of tumor transformation.
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Neuronavigation can be used to help plan the craniotomy to achieve adequate exposure and assist during tumor resection. Brain “shift” can be corrected by re-registration following intraoperative magnetic resonance imaging (MRI). Interval ultrasound imaging reflects real-time progressive tumor resection. Dynamic neurophysiologic monitoring using thresholding techniques guides the surgeon as he resects tumor at its depth and posterior pole—close to the internal capsule. Intraoperative magnetic resonance imaging depicts residual infiltrative tumor that may require additional resection. The patient is a 33-yr-old woman with progressive growth of a right insular tumor and has consented to surgery, photography, and video recording.

 Figure at 1:57, © Ossama Al-Mefty, used with permission.
005 Samelisant (SUVN-G3031), a histamine H3 receptor inverse agonist in animal models of sleep disorders
Authors: Daripelli Saivishal , Molgara Parusharamulu , Muddana Nageswararao , Jayarajan Pradeep , Mekala Venkat Reddy , Reballi Veena , Achanta Pramod Kumar , Nirogi Ramakrishna
Published: May 2021

Introduction

Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness, sudden attacks of sleep and sometimes accompanied by cataplexy. Although the orexin deficiency is considered to be the primary cause of this disorder, lot of attention has been diverted on targeting histaminergic neurotransmission by blockade of histamine H3 receptor (H3R). Samelisant (SUVN-G3031) is one of the potent and selective H3R inverse agonist currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). In the current research work, Samelisant was evaluated for neurotransmitter changes in rats and sleep EEG in orexin knockout mice, a reliable proof-of-concept study for treatment of excessive daytime sleepiness and cataplexy in narcolepsy.

Methods

Binding affinity of Samelisant towards human and rat histamine H3R was evaluated in in-vitro radioligand binding assay and functionality in GTP□S assay. Effect of Samelisant was studied in (R)-α-methyl histamine induced dipsogenia. In rat brain microdialysis, Samelisant was evaluated for its effects on modulation of neurotransmitters like histamine, dopamine and norepinephrine. Male orexin knockout mice were implanted with telemetric device for simultaneous monitoring of electroencephalography (EEG) and electromyography. Effects of Samelisant (3 and 10 mg/kg, p.o.) were evaluated during active period of animals.

Results

Samelisant is an inverse agonist at histamine H3 receptors with hKi of 8.7 nM and showed minimal binding against over 70 target sites. Samelisant produced significant increase in histamine, dopamine and norepinephrine levels in cortex. Samelisant produced no change in the striatal and accumbal dopamine levels in rats, suggesting no propensity to induce abuse liability. Samelisant blocked R-α-methyl histamine induced water intake and produced dose dependent increase in tele-methylhistamine levels in various brain regions and in cerebrospinal fluid of male Wistar rats. Samelisant produced significant increase in wakefulness with concomitant decrease in non-rapid eye movement sleep in orexin knockout mice. Samelisant also significantly decreased number of cataplectic episodes in orexin knockout mice.

Conclusion

Samelisant is an inverse agonist at histamine H3 receptor and results from the preclinical studies presented here provide a strong evidence for the potential utility of Samelisant in the treatment of narcolepsy with and without cataplexy.

Support (if any):
008 ARC Genotype Modulates Slow Wave Sleep Following Total Sleep Deprivation
Authors: Satterfield Brieann , Lawrence-Sidebottom Darian , Schmidt Michelle , Wisor Jonathan , Van Dongen Hans
Published: May 2021

Introduction

The activity-regulated cytoskeleton associated protein (ARC) gene is an immediate early gene that is involved in synaptic plasticity. Recent evidence from a rodent model suggests that Arc may also be involved in sleep homeostasis. However, little is known about the molecular mechanisms regulating the sleep homeostat. In humans, sleep homeostasis is manifested by a marked increase in slow wave sleep (SWS) following acute total sleep deprivation (TSD). There are large, trait individual differences in the magnitude of this SWS rebound effect. We sought to determine whether a single nucleotide polymorphism (SNP) of the ARC gene is associated with individual differences in SWS rebound following TSD.

Methods

64 healthy normal sleepers (ages 27.2 ± 4.8y; 32 females) participated in one of two in-laboratory TSD studies. In each study, subjects had a baseline day with 10h sleep opportunity (TIB 22:00–08:00) which was followed by 38h TSD. The studies concluded with 10h recovery sleep opportunity (TIB 22:00–08:00). Baseline and recovery sleep were recorded polysomnographically and scored visually by a trained technician. Genomic DNA was extracted from whole blood. The ARC c.*742 + 58C>T non-coding SNP, rs35900184, was assayed using real-time PCR. Heterozygotes and T/T homozygotes were combined for analysis. The genotype effect on time in SWS was assessed using mixed-effects ANOVA with fixed effects for ARC genotype (C/C vs. T carriers), night (baseline vs. recovery), and their interaction, controlling for study.

Results

The genotype distribution in this sample – C/C: 41; C/T: 17; T/T: 6 – did not vary significantly from Hardy-Weinberg equilibrium. There was a significant interaction between ARC genotype and night (F1,62=7.27, p=0.009). Following TSD, T allele carriers exhibited 47.6min more SWS compared to baseline, whereas C/C homozygotes exhibited 62.3min more SWS compared to baseline. There was no significant difference in SWS between genotypes at baseline (F1,61=0.69, p=0.41).

Conclusion

ARC T allele carriers exhibited an attenuated SWS rebound following TSD compared to those homozygous for the C allele. This suggests that the ARC SNP is associated with trait individual differences related to sleep homeostasis, and may thus influence molecular mechanisms involved in long-term memory.

Support (if any)

ONR N00014-13-1-0302, NIH R21CA167691, and USAMRDC W81XWH-18-1-0100.
015 Modulating melatonin dynamics at transcription level using virtual knockout approaches: an advanced perspective in sleep medicine
Authors: Chowdhury Debajyoti , Fung Yip Hiu , Wang Chao , TAI Xue Cheng , LU* Aiping
Published: May 2021

Introduction

Sleep disorders, the most neglected public-health issues, are threatening overall health. It is tightly associated with the individual’s exposures to the light/dark (LD)-cycles linked to their circadian rhythms. Lifestyle, shift-work, frequent travels, and post-pandemic-stress lead unintentional compromise of sleep, thus circadian homeostasis. Melatonin (MT), a pivotal natural hormone for circadian and sleep health, attains acrophase in the dark. MT mediates LD-triggered circadian rhythms through its dynamic expressions. Circadian phases are greatly reflected by MT-dynamics. Dim-light-MT-onsets (DLMO) act as a marker, reporting internal circadian-timing in mammals. Estimating this is essential in therapeutic-designing against misaligned circadian conditions. Despite many experimental approaches, there is still a slit hacking the MT-dynamics from molecules to systems. Inclusive perspectives on endogenous factors affecting MT’s synthesis, secretions and bioavailability over time-course are not extensively exposed. MT-dynamics has multiplexed stochastic interactions across numerous genes, TFs, and regulators, and they are coupled non-linearly. Small changes used to compound through the genetic networks and reflected in systems-wide events marking distinct signalling response dynamics. Understanding such responses is challenging yet imperative. A robust quantitative model is inevitable to investigate such stochastic intricacy.

Methods

We proposed a quantitative framework to model MT signalling networks using diverse kinetic parameters linked in its genetic circuits and perturbing them must alter the MT-dynamics. We used a robust computational approach, LogicTRN to decode the systematic controls of the MT-dynamics. It combines multi-layered transcriptome-wide data as input. Computing this returned the regulatory TF-logics in the transcriptional regulatory networks for MT. We developed transcriptional simulations with virtual-knockout mutants and performed genetic network perturbation study.

Results

The results showed the reconstruction of robust quantitative regulatory networks decrypting transcriptional controls for MT-dynamics to estimate the influence of the multiple kinetically distinct inputs affecting those dynamics. This offered competitive advantages in terms of scalability, robustness, and iterations to characterize the effective molecular-targets to modulate the genetic circuit of MT-dynamics effectually.

Conclusion

Quantitative reconstruction and characterization of the regulatory interactome of MT may facilitate us to strategize the adjustments of regulatory controls to effectively modulate MT-dynamics. This foundation may enhance the advancement of circadian and sleep medicine in future.

Support (if any):
017 The Circadian Variation of the Cortisol Awakening Response
Authors: Blanco Ignacio Roura , Kosmadopoulos Anastasi , Boivin Diane
Published: May 2021

Introduction

The Cortisol Awakening Response (CAR) is a rapid increase in cortisol levels at awakening that lasts for about 1 hour. This secretory phenomenon has been proposed to be independent of circadian cortisol regulation. However, the contribution of the circadian system to the CAR remains unclear. The aim of this study is to assess the circadian variation of the CAR.

Methods

A total of eleven healthy participants (1 woman; 22.6 ± 3.4 years old) were enrolled. Following an 8-h baseline sleep period aligned to their habitual sleep times, participants underwent a 72-h ultradian sleep-wake cycle procedure (USW) consisting of 60-min wake periods in dim light (<10 lux) alternating with 60-min nap opportunities in total darkness. Participants remained in a semi-recumbent posture during the procedure. Salivary cortisol samples were collected at 0, 15, 30, and 50 minutes after waking up from each nap. Linear mixed-effects regression analyses were performed on log-transformed cortisol data from wake periods corresponding to the habitual bedtime (biological night) and habitual wake-time (biological morning). These served as proxies of circadian phases characterised by lowest and maximal cortisol secretory activity, respectively. Total cortisol secretion and CAR magnitude during these periods were computed, respectively, as the Area Under the Curve with respect to ground (AUCg) and to increase (AUCi) and compared with paired-samples t-tests.

Results

Significant main effects of wake period (p<.001) and sample time (p=.023) were found, with no interaction (p=.167). Cortisol levels were higher in the biological morning compared to the biological night and increased with elapsed time awake. The total amount of cortisol secreted (AUCg) after waking in the biological morning was significantly greater than during the biological night (p<.001). No significant differences between circadian phases were found in the AUCi (p=.223).

Conclusion

Our study suggests that some features of the CAR may at least partially be under circadian control. These findings are relevant for the understanding of the physiological mechanisms underlying circadian misalignment in shift workers and patients with severe sleep disorders.

Support (if any)

Project funded by the Canadian Institutes of Health Research. I.R.B received a Barrie Foundation Fellowship. A.K. received a Fonds de Recherche en Santé du Québec postdoctoral fellowship.
022 Cytokines as correlates of reported symptoms in disorders of hypersomnolence
Authors: Maness Caroline , Trotti Lynn Marie
Published: May 2021

Introduction

Cytokines are known for their role in inflammation, and more recently in sleepiness and fatigue. There is a paucity of data regarding cytokines in Idiopathic Hypersomnia (IH) and Narcolepsy Type 2 (NT2) as defined by the International Classifications of Sleep Disorders-Third Edition. Additionally the heterogenous cohort of patients with excessive daytime sleepiness (EDS), but do not meet criteria for a sleep disorder, has not been studied separately from IH patients.

Methods

The study cohort was a convenience sample evaluated at a single tertiary-care sleep center between 2016 and 2019. Diagnoses were IH, NT2, EDS, and controls (based on sleep laboratory testing). The following cytokines were measured using the Mesoscale U-PLEX biomarker assay: G-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, MCP-1, and TNF-α. Demographic data and survey data pertaining to sleepiness, depression, and sleep inertia were available for all.

Results

The study cohort consisted of 22 controls, 26 patients with EDS, 51 patients with IH, and 12 patients with NT2. There were no significant differences between diagnosis and any cytokine. Pearson correlations showed significant negative correlations between G-CSF concentrations with depression (p=0.05) and sleep inertia (p<0.01) in patients but not controls. In controls, hours slept per week positively correlated with G-CSF (p=0.05), but this was not true in patients with EDS, IH, or NT2. IL-8 level was negatively correlated with reported sleep inertia in sleepy patients (p=0.05), but not controls.

Conclusion

Though differences in cytokines levels between diagnostic groups did not reach significance, several cytokines correlated with severity of reported symptoms in disorders of hypersomnolence. G-CSF and IL-8 may serve as a biomarker for symptoms of depression and sleep inertia in sleepiness disorders, and thus could be a targeted for therapies.

Support (if any)

Hypersomnia Foundation Grant
025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex
Authors: Jones Carolyn , Olson Randall , Chau Alex , Wickham Peyton , Leriche Ryan , Reynolds Christina , Moore Cynthia , Puranik Niyati , Chu Sung Sik , Marsh Paul , Meshul Charles , Cao Hung , Lim Miranda
Published: May 2021

Introduction

Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors.

Methods

Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood.

Results

Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines.

Conclusion

In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior.

Support (if any)

NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643
029 Median preoptic dual control over sleep regulation
Authors: Machado Natalia , Todd William , Saper Clifford
Published: May 2021

Introduction

Previous studies suggest that the median preoptic nucleus (MnPO) plays an important role in regulating the wake-sleep cycle and in particular homeostatic sleep drive. However, the precise cellular phenotypes, targets and central mechanisms by which the MnPO neurons regulate the wake-sleep cycle remain unknown. Both glutamatergic (Vglut2+) and GABAergic (Vgat+) MnPO neurons innervate brain regions implicated in sleep promotion and maintenance, suggesting that both cell types may participate on sleep control.

Methods

In this study, we used two genetically-targeted approaches associated with electroencephalographic (EEG) and electromyographic (EMG) recordings in Vgat-IRES-cre and Vglut2-IRES-cre mice to investigate the role of the MnPOVgat and MnPOVglut2 neurons in modulating wake-sleep behavior.

Results

First, using a chemogenetic approach, we found that activation of MnPOVgat neurons reduced the latency for the first NREM sleep episode, produced an increase in NREM sleep and reduced wakefulness. Then, to test the role of MnPOVgat and MnPOVglut2 neurons in regulating sleep homeostasis, we recorded EEG and EMG responses in mice that had the Vgat+ or Vglut2+ neurons deleted from the MnPO. After deletion of MnPOVgat neurons, mice showed a reduction of NREM sleep and an increase in wakefulness during the light phase. Deletion of MnPOVgat neurons also reduced sleep recovery after 4 hours of sleep deprivation (SD). On the other hand, deletion of the MnPOVglut2 neurons did not change the wake-sleep cycle during the 24h baseline condition, but prevented the sleep recovery immediately after SD. To understand the underlying mechanism in preventing sleep recovery in both MnPOVglut2- and MnPOVgat-deleted mice groups, we exposed these animals to a psychological stress protocol. In response to a psychological stressor, mice with deletion of glutamatergic, but not GABAergic MnPO neurons, had an exacerbation of the stress-induced insomnia.

Conclusion

Our results suggest that both neuron populations differentially participate in wake-sleep control, with MnPOVgat neurons being critically involved in sleep homeostasis, and MnPOVglut2 neurons promoting sleep during allostatic (stressful) challenges.

Support (if any)

NIH Grants NS085477, NS072337, HL095491 and Sleep Research Society Foundation (Award 026-JP-20).
035 Activating the concept of “relaxation” during sleep using relaxation-related words
Authors: Beck Jonas , Loretz Erna , Rasch Björn
Published: May 2021

Introduction

Cognitive processes (e.g., rumination, perception of an unfamiliar sleeping environment, relaxation techniques) alter our sleep, but the underlying mechanisms are still unknown. Theories of embodied or grounded cognition assume that semantic meaning is stored in multimodal neuronal networks. We therefore assume that cognitive concepts are closely linked to related bodily functions. We propose that mental processes are active to a greater or lesser extent during sleep and that this degree of activation affects our sleep depth.

Methods

We examined this notion by activating the concept of “relaxation” during sleep using relaxation-related words in 50 healthy participants. After an adaption night, subjects slept in the sleep laboratory for two experimental nights according to a within-subject cross-over design. During one experimental night, relaxing words (e.g., “sea”, “relax”) were presented to promote sleep depth. During the other experimental night, control words were presented (e.g., “produce”, “materials”). As the amount of SWS peaks within the first sleep cycle, words were presented during NREM sleep starting with the second sleep cycle (at the latest 120 min after sleep onset). In addition, a mood and a subjective sleep quality questionnaire was conducted.

Results

In support of our hypothesis, playing relaxing words during non-rapid eye movement sleep extended the time spent in slow-wave sleep during the period, when words were presented. Furthermore, power in the slow-wave activity band was increased several seconds after the cue for relaxing compared with control words. The increased sleep depth by means of relaxing words was accompanied by a reduced interhemispheric asymmetry of SWA and slow-wave density in the during-cueing period. The changes observed in objective sleep translated to the subjective level with an increase in subjective sleep quality and alertness ratings.

Conclusion

The present study showed that the semantic meaning of words presented during NREM sleep is capable of affecting sleep physiology, SWS maintenance and the subjective evaluation of sleep quality. Our results support the notion that the activation of mental concepts during sleep can influence sleep depth and provide a basis for interventions using targeted activations to promote sleep depth and sleep quality to foster well-being and health.

Support (if any):
038 Sleep and Hippocampal Function during an Associative Memory Task are Influenced by Surgical Menopause at Midlife
Authors: Brown Alana , Gervais Nicole , Gravelsins Laura , Nicoll Gina , Rieck Jenny , Almey Anne , Sun Dorothy Leqi , Ge Jennifer Xiangning , Laird Kaz , Reuben Rebekah , Karkaby Laurice , Perovic Mateja , Grady Cheryl , Einstein Gillian
Published: May 2021

Introduction

17β-estradiol loss is related to Alzheimer’s disease (AD) risk factors, including disordered sleep and associative memory decrements. Women have higher risk for AD than men, and those with mid-life 17β-estradiol loss due to surgical menopause, including bilateral salpingo-oophorectomy (BSO) before age 48, have even higher risk. We wondered whether sleep and associative memory in women with BSO (mean age 44–46) would be comparable to those with spontaneous/natural menopause (SM; mean age 57), and whether 17β-estradiol-based hormone therapy (ET) might mitigate these effects.

Methods

We assessed sleep using the average of three nights of portable polysomnography (Temec) in women with BSO either taking ET (BSO+ET; n=16), or not (BSO; n=18), and in older spontaneously menopausal women (SM; n=14). Using EEG (Fp1-Fp2), we obtained sleep staging automatically (Neurobit Technologies). Participants also completed a face-name associative memory task during functional magnetic resonance imaging. Recognition accuracy and brain activation during encoding were measured.

Results

BSO exhibited reduced sleep efficiency compared to BSO+ET. For BSO, there was no relationship between percent of total sleep time in N3 and hippocampal activation during associative encoding, even though percent of total sleep time in N3 was negatively associated with hippocampal activation during associative encoding in BSO+ET. For all groups, including BSO, lower latency to consolidated N3 correlated with better associative memory accuracy. There were no group differences in associative memory accuracy. In contrast to BSO, SM showed significantly longer latency to consolidated N3 than BSO+ET.

Conclusion

Younger women with BSO have comparable sleep to older women in SM. In younger women with BSO, ET improves sleep efficiency. Further, while associative memory may be disrupted by increased latency to consolidated N3 in all women, BSO and BSO+ET showed similar associative memory accuracy and latency to consolidated N3. Only BSO+ET exhibited a significant correlation between hippocampal activity during associative encoding and time spent in N3, indicating that ET may support the negative relationship between N3 and hippocampal function. Overall, ET in younger women with BSO potentially ameliorates poor sleep and associative memory decrements.

Support (if any)

Alzheimer’s Association/Brain Canada Foundation: AARF-17-504715; Wilfred and Joyce Posluns Chair in Women’s Brain Health and Aging
039 Sleep Preferentially Supports Problem-Solving Skills via Greater Functional Connectivity Between the Caudate and Cerebral Cortex
Authors: van den Berg Nicholas , Smith Dylan , Fang Lydia , Fogel Stuart
Published: May 2021

Introduction

Sleep consolidates memory, including newly acquired procedural skills. One putative systems-level mechanism for this function of sleep is via sleep-dependent strengthening of functional connectivity between the putamen and the cortico-hippocampal-striatal-cerebellar network, which supports procedural motor skills. For procedural motor skills that also require problem solving and rule-learning, sleep preferentially benefits the cognitively complex aspects over the motor skills required to execute the solution itself. The caudate is implicated in higher-order cognitive components of skill learning, which include error monitoring and automizing new information. In the current study, we investigated how sleep alters functional connectivity in higher-order learning networks that support problem solving and rule learning-related procedural skills.

Methods

Participants (n = 38) were trained on a procedural skills task; the Tower of Hanoi (ToH), that requires the acquisition of a novel cognitive strategy (e.g., recursive logic), while undergoing functional magnetic resonance imaging (fMRI). After either a full night of sleep (n=19) or a full day of wakefulness (n=19), participants were retested on the same task in the fMRI. Resting state activity was acquired before (R1) and after the training session (R2), and before the retest session (R3).

Results

Behavioral performance on the ToH improved following sleep compared to wake (reduced number of errors: t(38)=2.92, p=0.006, d=1.24). Regions associated with higher-order learning and cognitive complexity (i.e., the caudate) and regions typically implicated in sequence learning (i.e., the putamen, hippocampus, cerebellum) were selected as regions of interest (ROI). Increased functional connectivity across the retention interval (R3-R2) was observed in the sleep vs. wake condition between the caudate and the motor cortex (t(36)=3.32, p=0.042, FWE). By contrast, changes in functional connectivity were not observed between the putamen and other ROIs.

Conclusion

These results suggest that sleep supports improved consolidation of motor skills that involve the acquisition of a novel cognitive strategy. Sleep enhanced functional connectivity in brain areas associated with higher-order cognitive skills (i.e., the caudate), but not regions typically associated with motor skills (i.e., the putamen) that are required to execute the solution to the cognitive procedural skill.

Support (if any)

Natural Science and Engineering Research Council of Canada
042 A look at sex differences on sleep’s impact on working memory improvement
Authors: Zhang Jing , Whitehurst Lauren , Mednick Sara
Published: May 2021

Introduction

Studies have shown that sleep affects working memory (WM) improvement, but specific electrophysiological features are unclear (Sattari et al., 2019; MacDonald et al., 2018). In addition, sex differences have been found in both sleep and working memory (Mong, 2016; Harness, 2008). The goal of this study is to identify sex differences in EEG correlates of working memory over a night of sleep.

Methods

Sixty-three healthy (33 females), college-aged adults without sleep disorder were enrolled. A 32-channel electroencephalogram (EEG) cap was used to record brain activity during sleep. Operation span (OS) task was used to evaluate WM performance. Participants reported to the laboratory in the evening, performed OS before sleep (test1) and after sleep (test2). Trials were divided into easy and hard trials based on the number of letters subjects had to recall. A repeated-measure analysis of variance was conducted to examine the effects of time and trial difficulty. Paired-sample t-tests between test 1 and test 2 were conducted for males and females. Pearson’s correlations were examined between WM performance at test 1 and the difference score between test 1 and test 2 and EEG frequency bands. The Benjamini–Hochberg method was used to control for multiple comparisons.

Results

There was an increase in performance across the night in WM hard trials across all subjects (F(1,62)=4.86, p=0.03), no effect for easy trials (p>0.05). Females, but not males, showed a significant decrease in easy trials (t62= 2.40, p=0.02), while both males and females showed improvement in hard trials across the night. Females showed a positive correlation between test 1 hard trials and slow sigma, delta, slow oscillation in stage 3, this correlation is not seen in males. No correlations between overnight improvement and EEG bands were found.

Conclusion

Consistent with previous studies, participants showed better memory performance over a night of sleep, and the WM performance was associated with slow wave activity in females. Slow sigma also plays a role in the WM performance for females, indicating a possible role of sleep spindles. These associations were not shown in males, suggesting sex hormones mediate sleep’s impact on WM performance.

Support (if any):
045 Associations of Actigraphic Sleep and Circadian Rest/Activity Rhythms with Cognition in the Early Phase of Alzheimer’s Disease
Authors: Alfini Alfonso , Albert Marilyn , Faria Andreia , Soldan Anja , Pettigrew Corinne , Wanigatunga Sarah , Zipunnikov Vadim , Spira Adam
Published: May 2021

Introduction

Alterations in sleep and circadian rhythms are common in persons with Alzheimer’s disease (AD) dementia, but the nature of such changes in the early phases of AD remains unclear. This study compared sleep and circadian rest/activity rhythms (RARs), measured by standard and novel actigraphic indices, between participants with normal cognition or mild cognitive impairment (MCI), and examined cross-sectional associations between these measures and cognition.

Methods

Actigraphy data were collected in 179 individuals (mean age=72.6 years, gender=64.8% female) with normal cognition (n=153) or MCI (n=26) from the Biomarkers for Older Controls at Risk of Dementia (BIOCARD) study. Standard sleep parameters (i.e., total sleep time [TST], sleep efficiency [SE], wake after sleep onset [WASO], average wake bout length [WBL]), and standard non-parametric RAR metrics (i.e., relative amplitude [RA], intradaily variability [IV], interdaily stability [IS]) were generated. Functional principal component (fPC) methods were used to generate three novel RAR indices (fPC1, fPC2, fPC3) representing 69% of the total variance. Cognitive test scores were used to generate composite measures reflecting the domains of episodic memory and executive function using factor analysis. Regression models were used to compare sleep and circadian RAR parameters between the diagnostic groups and to evaluate their associations with cognitive performance.

Results

After adjustment for age, sex, education, and APOE-4 genotype, compared to normal controls, MCI subjects had significantly lower SE, lower RA, and lower scores on the novel RAR measure fPC3, which reflects a later rhythm phase, lower amplitude, and lower activity both at night and early in the day. In analyses combining data from participants with MCI and controls, several standard RAR parameters (e.g., higher RA and IS) and higher fPC3 scores were associated with both better episodic memory and executive function. Additionally, several standard measures (e.g., lower WASO and IV) and lower fPC1 scores (reflecting higher rhythm amplitude and greater activity throughout daytime hours) were linked with better executive function.

Conclusion

MCI participants have sleep and circadian alterations, which are significantly associated with cognitive performance. A novel RAR measure, fPC3, showed differences in rhythm patterns that extended from the night into the daytime.

Support (if any)

Funding-support NIA (U19-AG033655, T32-AG027668, R01-AG050507) and AASMF (#223-BS-19).
047 Fear-Potentiated Startle and Sleep in Trauma-Exposed Men and Women with and without PTSD
Authors: Richards Anne , Inslicht Sabra , Huie J Russell , Yack Leslie , Straus Laura , Felmingham Kim , Woodward Steve , Neylan Thomas
Published: May 2021

Introduction

Animal and human studies indicate that fear conditioning disrupts subsequent sleep, including REM sleep (REMS). REMS is thought to be central to fear information processing. We utilized an afternoon nap protocol to examine the effects of fear-potentiated startle (FPS), a variant of fear conditioning, on subsequent sleep integrity and REMS in trauma-exposed participants with varying levels of PTSD. We also examined the effects of changes in sleep integrity and REMS on subsequent retention and extinction of pre-sleep learning.

Methods

Participants (N=47) participated in 3 nap visits. The first was an adaptation nap. The second and third nap visits were counterbalanced: a stress-condition nap, during which participants underwent FPS procedures prior to a nap and assessment of retention of fear and safety signal learning and fear extinction after the nap, and a control visit during which participants had a nap opportunity without stressful procedures. Canonical correlation analysis assessed the relationship between FPS responses and change in subsequent sleep relative to a control nap, as well as the relationship between change in sleep from control to stress condition and both subsequent fear and safety learning retention, and subsequent extinction.

Results

Results demonstrated a relationship between fear learning and change in sleep and supported a relationship between safety signal learning and subsequent REMS, as well as differential conditioning and wake after sleep onset. Sleep did not predict measures of fear retention or extinction. PTSD symptoms did not predict fear learning or sleep measures.

Conclusion

These findings replicate prior work showing a relationship between safety learning and REMS, suggesting that this is a core mechanism through which stress impacts fear processing. Further research is critical to further understand this effect, and to examine how different aspects of fear learning impact different components of sleep. This study also demonstrates that nap studies can be a valuable approach for studying the stress-sleep relationship.

Support (if any)

VA Career Development Award to Dr. Richards (5IK2CX000871-05)
052 APOE-ε4 is associated with impaired sleep-dependent memory consolidation in healthy carriers
Authors: Djonlagic Ina , Guo Mengshuang , Igue Moroke , Kishore Divya , Marshall Lisa , Malhotra Atul , Stickgold Robert
Published: May 2021

Introduction

The Apolipoprotein E (APOE)-ε4 genotype is a marker of susceptibility for late-onset Alzheimer’s disease (AD). Sleep disturbances may accelerate the aging process and increase the risk for future development of cognitive impairment and dementia. Given that the pathophysiological process of AD can predate its clinical manifestations by years or even decades, the aim of this study was to assess the role of the APOε4 allele on sleep-dependent memory consolidation in cognitively healthy adults.

Methods

16 healthy APOE-ε4 carriers (mean age=49.9±13.7) and 32 healthy non-carriers (age=45.7±12.9) were included in the main analysis. Baseline screening included the Epworth Sleepiness Scale, Morningness-Eveningness scale, Wechsler Adult Intelligence Scale (WAIS) and Beck Depression Inventory (BDI), as well as a baseline polysomnogram (PSG), which also served as an adaptation night. Participants subsequently underwent an overnight testing session, which included computer sessions of the Psychomotor Vigilance Task (PVT) and the declarative Verbal Paired-Associates Task (VPA) in the evening followed by a full night PSG and repeat PVT and VPA sessions in the morning. For further reference, we added an age matched group of 16 non-carriers with newly diagnosed obstructive sleep apnea (OSA, age=48.1±15.1), who underwent the same study procedures.

Results

APOE-ε4 carriers had higher BDI (p=0.04) and ESS (p=0.01) scores than non-carriers. There were no significant group differences for sleep macrostructure. Evening VPA performance was similar for both groups (p=0.77). The following morning, APOE-ε4 carriers improved by 7.5±6.4 % from the evening before, compared to 13.5±7.0% for the healthy non-carriers (p=0.005). OSA subjects improved by 5.0± 8.1%, which was similar to APOE-ε4 carriers (p=0.34).

Conclusion

To our knowledge, this is the first study to reveal that healthy APOE-ε4 carriers while showing similar initial learning (encoding) on a declarative memory task compared to healthy controls, exhibit a deficit in sleep-dependent memory consolidation, similar to patients with obstructive sleep apnea. Consequently, this study provides evidence that impaired sleep-related memory processes could be an important harbinger in otherwise healthy individuals, who are at high risk for AD.

Support (if any)

NIH grant # K23HL103850 (Ina Djonlagic) and American Sleep Medicine Foundation grant #54-JF-10 (Ina Djonlagic)
053 REM Sleep Apnea Severity Contributes to Poor Verbal Memory in Cognitively Asymptomatic Older Adults
Authors: Lui Kitty , Sprecher Kate , Dave Abhishek , Heston Margo , Chappel-Farley Miranda , Chen Ivy , Riedner Brady , Bendlin Barbara , Mander Bryce , Benca Ruth
Published: May 2021

Introduction

The prevalence of obstructive sleep apnea (OSA) rises with age, leading to increased dementia risk and memory decline. However, it remains unclear which OSA features drive this relationship. Here, we examine associations between verbal memory and multiple OSA features in healthy older adults.

Methods

58 cognitively asymptomatic adults (61.4±6.3 years; 38 females) underwent polysomnography (PSG) and the Rey Auditory Verbal Learning Test (RAVLT; 0.2±0.5 years between assessments). OSA measures included apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and desaturation index in both NREM and REM sleep. RAVLT measures included total learning (sum of trials 1–5), short-delayed recall, and long-delayed recall. Pearson correlations with FDR correction were calculated between OSA-related measures and RAVLT. Multiple regression was then used to adjust for OSA features in other sleep stages (i.e., REM versus NREM), age, sex, time between PSG and neuropsychological assessments, years of education, and APOE4 status. We also explored whether age moderated these relationships.

Results

REM RDI is negatively associated with RAVLT total learning (r=-0.31, p<0.01 with age moderating the effect at 1SD above mean: B=-0.22, t(49)=-2.88, p=0.01) and RAVLT long-delayed recall (r=-0.36, p<0.001; with age moderating the effect at mean: B=-0.05, t(49)=-2.38, p=0.02; and moderating at 1SD above mean: B=-0.09, t(49)=-3.91, p<0.01). REM desaturation index was also associated with RAVLT total learning (r=-0.21, p<0.01) and RAVLT long-delayed recall (r=-0.34, p<0.01). REM AHI was negatively correlated to RAVLT long-delayed recall (r=-0.34, p<0.01; with age significantly moderating the effect at the mean: B=-0.06, t(49)=-2.87, p=0.01; and moderating at 1SD above the mean: B=-0.11, t(49)=-4.23, p<0.01). Of note, NREM OSA features were not significantly correlated to RAVLT measures when REM OSA features were included in the model.

Conclusion

These findings demonstrate that REM OSA features in particular contribute to poor verbal memory encoding and retrieval, especially at older ages. Verbal memory decline has been predictive of conversion to Alzheimer’s disease (AD). Future studies including brain imaging, AD biomarkers, REM sleep oscillations, and comprehensive neuropsychological testing may elucidate the underlying mechanisms linking REM OSA features to memory decline and dementia risk.

Support (if any)

This research was supported by R56 AG052698 and P50AG033514.