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Chronic sleep disruption is a risk factor for Alzheimer's disease (AD), yet mechanisms by which sleep disturbances might promote or exacerbate AD are not understood. Short-term sleep loss acutely increases hippocampal amyloid β(Aβ) in wild type (WT) mice and long-term sleep loss increases amyloid plaque in AD transgenic mouse models. Both effects can be influenced by the wake-promoting neuropeptide, hypocretin (HCRT), but whether HCRT influences amyloid accumulation independent of sleep and wake timing modulation remains unclear. Here, we induced chronic fragmentation of sleep (CFS) in WT and HCRT-deficient mice to elicit similar arousal indices, sleep bout lengths and sleep bout numbers in both genotypes. We then examined the roles of HCRT in CFS-induced hippocampal Aβ accumulation and injury. CFS in WT mice resulted in increased Aβ42 in the hippocampus along with loss of cholinergic projections and loss of locus coeruleus neurons. Mice with HCRT deficiency conferred resistance to CFS Ab42 accumulation and loss of cholinergic projections in the hippocampus yet evidenced similar CFS-induced loss of locus coeruleus neurons. Collectively, the findings demonstrate specific roles for orexin in sleep disruption hippocampal injury. [ABSTRACT FROM AUTHOR]

Genome-wide profiling of rhythmic gene expression has offered new avenues for studying the contribution of circadian clock to diverse biological processes. Sleep has been considered one of the most important physiological processes that are regulated by the circadian clock, however, the effects of chronic sleep loss on rhythmic gene expression remain poorly understood. In the present study, we exploited Drosophila sleep mutants insomniac1 (inc1) and wide awakeD2 (wakeD2) as models for chronic sleep loss. We profiled the transcriptomes of head tissues collected from 4-week-old wild type flies, inc1 and wakeD2 at timepoints around the clock. Analysis of gene oscillation revealed a substantial loss of rhythmicity in inc1 and wakeD2 compared to wild type flies, with most of the affected genes common to both mutants. The disruption of gene oscillation was not due to changes in average gene expression levels. We also identified a subset of genes whose loss of rhythmicity was shared among animals with chronic sleep loss and old flies, suggesting a contribution of aging to chronic, sleep-loss-induced disruption of gene oscillation.

Chronic sleep disruption is a risk factor for Alzheimer’s disease (AD), yet mechanisms by which sleep disturbances might promote or exacerbate AD are not understood. Short-term sleep loss acutely increases hippocampal amyloid β (Aβ) in wild type (WT) mice and long-term sleep loss increases amyloid plaque in AD transgenic mouse models. Both effects can be influenced by the wake-promoting neuropeptide, hypocretin (HCRT), but whether HCRT influences amyloid accumulation independent of sleep and wake timing modulation remains unclear. Here, we induced chronic fragmentation of sleep (CFS) in WT and HCRT-deficient mice to elicit similar arousal indices, sleep bout lengths and sleep bout numbers in both genotypes. We then examined the roles of HCRT in CFS-induced hippocampal Aβ accumulation and injury. CFS in WT mice resulted in increased Aβ42 in the hippocampus along with loss of cholinergic projections and loss of locus coeruleus neurons. Mice with HCRT deficiency conferred resistance to CFS Aβ42 accumulation and loss of cholinergic projections in the hippocampus yet evidenced similar CFS-induced loss of locus coeruleus neurons. Collectively, the findings demonstrate specific roles for orexin in sleep disruption hippocampal injury.Significance statementChronic fragmentation of sleep (CFS) occurs in common conditions, including sleep apnea syndromes and chronic pain disorders, yet CFS can induce neural injury. Our results demonstrate that under conditions of sleep fragmentation, hypocretin/orexin is essential for the accumulation of amyloid-β and loss of cholinergic projections in the hippocampus observed in response to CFS yet does not influence locus coeruleus neuron response to CFS.

Objectives: Acute and chronic sleep loss and circadian timing interact such that, depending on their combination, small or very large performance decrements are observed in tasks of attention. Here, we tested whether such nonlinear interactions extend to a physiological measure of spontaneous visual attentional failures, indicating a fundamental principle of sleep-wake regulation., Methods: Nine healthy volunteers completed an in-laboratory 3-week forced desynchrony protocol consisting of 12 consecutive 42.85-hour cycles with a sleep-wake ratio of 1:3.3. The protocol induced increasing chronic sleep loss, while extended wake (32.85 hours) and sleep episodes (10 hours) occurred at multiple circadian phases. Attentional failure rate was quantified from continuous electrooculograms (number of 30-second epochs with slow eye movements/h of wakefulness) as a function of time since scheduled wake (acute sleep loss), week of study (chronic sleep loss), and circadian (melatonin) phase., Results: During the first ∼8 hours awake, attentional failure rate was low, irrespective of the week. During the following wake hours, attentional failure rate increased steadily but at a faster rate in weeks 2 and 3 compared to week 1. The effects of acute and chronic sleep loss on attentional failure rate were magnified during the biological night compared to the biological day., Conclusions: A single extended sleep episode can only temporarily reverse attentional impairment associated with chronic sleep loss. Multiplicative effects of acute and chronic sleep loss-further amplified during the biological night-substantiate the interaction of 2 homeostatic response mechanisms and caution against underestimating their disproportionate combined impact on performance, health, and safety., Competing Interests: Declaration of conflicts of interest DA, DAC, BJL, and SLC declare no conflicts of interest. EBK: Consulting: American Academy of Sleep Medicine Foundation, Circadian Therapeutics, National Sleep Foundation, Sleep Research Society Foundation, and Yale University Press; Travel: European Biological Rhythms Society; Scientific Advisory Board: Chronsulting (unpaid); and Other: partner is the founder, owner, and chief scientific officer of Chronsulting., (Copyright © 2024 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Mathematical models of human neurobehavioral performance that include the effects of acute and chronic sleep restriction can be key tools in assessment and comparison of work schedules, allowing quantitative predictions of performance when empirical assessment is impractical., Methods: Using such a model, we tested the hypothesis that resident physicians working an extended duration work roster, including 24-28 hours of continuous duty and up to 88 hours per week averaged over 4weeks, would have worse predicted performance than resident physicians working a rapidly cycling work roster intervention designed to reduce the duration of extended shifts. The performance metric used was attentional failures (ie, Psychomotor Vigilance Task lapses). Model input was 169 actual work and sleep schedules. Outcomes were predicted hours per week during work hours spent at moderate (equivalent to 16-20 hours of continuous wakefulness) or high (equivalent to ≥20 hours of continuous wakefulness) performance impairment., Results: The model predicted that resident physicians working an extended duration work roster would spend significantly more time at moderate impairment (p = .02, effect size=0.2) than those working a rapidly cycling work roster; this difference was most pronounced during the circadian night (p < .001). On both schedules, performance was predicted to decline from weeks 1 + 2 to weeks 3 + 4 (p < .001), but the rate of decline was significantly greater on extended duration work roster (p < .01). Predicted performance impairment was inversely related to prior sleep duration (p < .001)., Conclusions: These findings demonstrate the utility of a mathematical model to evaluate the predicted performance profile of schedules for resident physicians and others who experience chronic sleep restriction and circadian misalignment., Competing Interests: Declaration of conflict of interest Dr. Phillips has received research funding from Versalux and Delos, and he is co-founder and co-director of Circadian Health Innovations PTY LTD. He also holds a patent (US20150080756A1) for estimating arousal states from ambulatory recordings by using sleep and wake models. Dr. St Hilaire has received grant/research support from NIH, NASA, and Merrimack College. Dr. Barger reports honorariums from AAA Foundation, University of Arizona and University of British Columbia. Mr. O’Brien has no COI to report from the past 3 years. Dr. Rahman holds patents for (1) Method and device for preventing alterations in circadian rhythm (U.S. patent application Ser. No. 10/525,958), and (2) Methods and devices for improving sleep performance in subject exposed to light at night (U.S. Application No. 61/810,985); owns equity in Melcort Inc; has provided paid consulting services to Sultan & Knight Limited, Bambu Vault LLC, Lucidity Lighting Inc; and has received honoraria as an invited speaker and travel funds from Starry Skies Lake Superior, University of Minnesota Medical School, PennWell Corp, and Seoul Semiconductor Co Ltd, FALK FOUNDATION E.V.; and has received grant/research support from Seoul Semiconductor Co Ltd, Biological Innovation and Optimization Systems, LLC, Merck & Co, Inc, Pfizer Inc, Vanda Pharmaceuticals Inc, Lighting Science Group, NIH, and NASA. These interests were reviewed and managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Dr. Landrigan holds equity in and has consulted with the I-PASS Patient Safety Institute, which seeks to train institutions in best handoff practices and aid in their implementation. In addition, Dr. Landrigan has received monetary awards, honoraria, and travel reimbursement from multiple academic and professional organizations for teaching and consulting on sleep deprivation, physician performance, handoffs, and safety, and has served as an expert witness in cases regarding patient safety and sleep deprivation. Dr. Lockley reports consulting fees from the Hintsa Performance AG, Stantec and View Inc, and has consulting contracts with Absolute Rest, Akili Interactive, Apex 2100 Ltd, Ashurst Risk Advisory, Consumer Sleep Solutions, KBR Wyle Services, Light Cognitive; Lighting Science Group Corporation/HealthE; and Mental Workout/Timeshifter. He has received honoraria and travel or accommodation expenses from Bloxhub, Clifton College, Danish Centre for Lighting, and University of Toronto; and travel or accommodation expenses (no honoraria) from Wiley; and royalties from Monash University and Oxford University Press. He holds equity in iSleep pty. He has received an unrestricted equipment gift and investigator-initiated grant from F. Lux Software LLC, and a Clinical Research Support Agreement and Clinical Trial Agreement with Vanda Pharmaceuticals Inc. He is an unpaid Board Member of the Midwest Lighting Institute (non-profit). He was a Program Leader for the CRC for Alertness, Safety and Productivity, Australia, through an adjunct professor position at Monash University (2015-2019). He is part-time adjunct professor at the University of Surrey, UK. He holds several pending patents (US2019366032A1; USD943612S1; US2021162164A1, US20220151552A1). He has served as a paid expert in legal proceedings related to light, sleep, and health. His interests are reviewed and managed by Mass General Brigham in accordance with their conflict-of-interest policies. Dr. Czeisler reports that he serves as the incumbent of an endowed professorship provided to Harvard Medical School by Cephalon, Inc and reports institutional support for a Quality Improvement Initiative from Delta Airlines and Puget Sound Pilots; education support to Harvard Medical School Division of Sleep Medicine and support to Brigham and Women’s Hospital from: Jazz Pharmaceuticals PLC, Inc, Philips Respironics, Inc, Optum, and ResMed, Inc; research support to Brigham and Women’s Hospital from Axsome Therapeutics, Inc, Dayzz Ltd, Peter Brown and Margaret Hamburg, Regeneron Pharmaceuticals, Sanofi SA, Casey Feldman Foundation, Summus, Inc, Takeda Pharmaceutical Co, LTD, Abbaszadeh Foundation, CDC Foundation; educational funding to the Sleep and Health Education Program of the Harvard Medical School Division of Sleep Medicine from ResMed, Inc, Teva Pharmaceuticals Industries, Ltd, and Vanda Pharmaceuticals; personal royalty payments on sales of the Actiwatch-2 and Actiwatch-Spectrum devices from Philips Respironics, Inc; personal consulting fees from Axsome Therapeutics, Bryte Foundation, With Deep, Inc and Vanda Pharmaceuticals; honoraria from the Associated Professional Sleep Societies, LLC for the Thomas Roth Lecture of Excellence at SLEEP 2022, from the Massachusetts Medical Society for a New England Journal of Medicine Perspective article, from the National Council for Mental Wellbeing, from the National Sleep Foundation for serving as chair of the Sleep Timing and Variability Consensus Panel, for lecture fees from Teva Pharma Australia PTY Ltd and Emory University, and for serving as an advisory board member for the Institute of Digital Media and Child Development, the Klarman Family Foundation, and the UK Biotechnology and Biological Sciences Research Council. CAC has received personal fees for serving as an expert witness on a number of civil matters, criminal matters, and arbitration cases, including those involving the following commercial and government entities: Amtrak; Bombardier, Inc; C&J Energy Services; Dallas Police Association; Delta Airlines/Comair; Enterprise Rent-A-Car; FedEx; Greyhound Lines, Inc/Motor Coach Industries/FirstGroup America; PAR Electrical Contractors, Inc; Puget Sound Pilots; the San Francisco Sheriff’s Department; Schlumberger Technology Corp; Union Pacific Railroad; United Parcel Service; and Vanda Pharmaceuticals. CAC has received travel support from Merck, Sharpe and Dohme for travel to Japan and Australia; equity interest in Vanda Pharmaceuticals, With Deep, Inc, WHOOP, Inc, and Signos, Inc; and institutional educational gifts to Brigham and Women’s Hospital from Johnson & Johnson, Mary Ann and Stanley Snider via Combined Jewish Philanthropies, Alexandra Drane, DR Capital, Harmony Biosciences, LLC, San Francisco Bar Pilots, Whoop, Inc, Harmony Biosciences LLC, Eisai Co, LTD, Idorsia Pharmaceuticals LTD, Sleep Number Corp, Apnimed, Inc, Avadel Pharmaceuticals, Bryte Foundation, f.lux Software, LLC, Stuart F. and Diana L. Quan Charitable Fund. Dr. Czeisler's interests were reviewed and are managed by the Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Dr. Klerman reports consulting for the American Academy of Sleep Medicine Foundation, Circadian Therapeutics, National Sleep Foundation, Puerto Rico Science, Technology, and Research Trust, Pfizer Pharmaceuticals, Sanofi-Genzyme, Sleep Research Society Foundation, and Yale University Press; travel support from the DGSM (Germany Sleep Society), EPFL Pavilions, European Biological Rhythms Society, Gordon Research Conference, Santa Fe Research Institute, Sleep Research Society, and World Conference of Chronobiology; and being on the Scientific Advisory Board (unpaid) for Chronsulting. Other: Partner is founder, director, and chief scientific officer of Chronsulting., (Copyright © 2024 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Genome-wide profiling of rhythmic gene expression has offered new avenues for studying the contribution of circadian clock to diverse biological processes. Sleep has been considered one of the most important physiological processes that are regulated by the circadian clock, however, the effects of chronic sleep loss on rhythmic gene expression remain poorly understood. In the present study, we exploited Drosophila sleep mutants insomniac 1 ( inc 1 ) as models for chronic sleep loss. We profiled the transcriptomes of head tissues collected from 4-week-old wild type flies, wide awake D2 ( wake D2 compared to wild type flies, with most of the affected genes common to both mutants. The disruption of gene oscillation was not due to changes in average gene expression levels. We also identified a subset of genes whose loss of rhythmicity was shared among animals with chronic sleep loss and old flies, suggesting a contribution of aging to chronic, sleep-loss-induced disruption of gene oscillation.inc 1 and wake D2 at timepoints around the clock. Analysis of gene oscillation revealed a substantial loss of rhythmicity in inc 1 and wake D2 compared to wild type flies, with most of the affected genes common to both mutants. The disruption of gene oscillation was not due to changes in average gene expression levels. We also identified a subset of genes whose loss of rhythmicity was shared among animals with chronic sleep loss and old flies, suggesting a contribution of aging to chronic, sleep-loss-induced disruption of gene oscillation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Lincoln, Nguyen, Li and Young.)

This study addressed a rarely studied question of self-perceptions of performance and overall functional state during cumulative sleep restriction and the ensuing recovery period. Twenty healthy male volunteers, aged 19-29 years, were divided into a sleep restriction group ( n = 13) and a control group ( n = 7). On the first 2 nights, the sleep restriction group had an 8-h sleep opportunity that was restricted to 4 h for the next 5 nights, and then restored to 8 h for the last 2 nights. The control group had an 8-h sleep opportunity each night. Each day participants accomplished 50-min multitask sessions and gave self-ratings in their connection. Similar to our previous findings on multitasking performance, self-perceived task performance, sleepiness and mental fatigue impaired during the sleep restriction and returned to baseline during the recovery phase. Self-perceived mental effort, tension, task difficulty and task pace showed no sensitivity to the sleep restriction. We concluded that sleep-restricted individuals can probably make use of some self-perceptions when assessing their 'fitness for duty'. However, at the individual level these measures seem to be inaccurate in revealing actual performance impairments. [ABSTRACT FROM AUTHOR]

Currently, over 44 million people worldwide suffer from Alzheimer's disease (AD). A common feature of AD is disrupted sleep. Sleep is essential for many psychological and physiological functions, though 35.3% of adults report getting less than 7 hours per night. The present research examined whether chronic sleep restriction would elevate hippocampal amyloid-beta 1–42 expression or alter cognitive ability in adult C57BL/6 mice. Chronic sleep restriction was associated with cognitive impairment and increased hippocampal amyloid-beta. Thus, chronic sleep loss may have a detrimental effect upon cognitive function, in part, via increasing amyloid-beta levels in the hippocampus, even in non-genetically modified mice. [ABSTRACT FROM AUTHOR]

Society has a rapidly growing accumulative sleep debt due to employment obligations and lifestyle choices that limit sleep opportunities. The degree to which poor sleep may set the stage for adverse symptom outcomes among more than 1.7 million persons who will be diagnosed with cancer is not entirely understood. Paclitaxel (PAC), a commonly used chemotherapy agent, is associated with painful, debilitating peripheral neuropathy of the hands and feet, which may persist long after adjuvant therapy is completed. The aims of this preclinical study were to determine the accumulative and sustained effects of sleep restriction on PAC-induced mechanical sensitivity in animals and whether there are male-female differences in mechanical sensitivity in PAC-injected animals. Sixty-two adult Sprague-Dawley rats (n = 31 females) were assigned to three cycles of intraperitoneal injections of PAC (1 mg/kg) versus vehicle (VEH; 1 ml/kg) every other day at light onset for 7 days, followed by seven drug-free days and to sleep restriction versus unperturbed sleep. Sleep restriction involved gentle handling to maintain wakefulness during the first 6 hr of lights on immediately following an injection; otherwise, sleep was unperturbed. Mechanical sensitivity was assessed via von Frey filaments, using the up-down method. Mechanical sensitivity data were Log10 transformed to meet the assumption of normality for repeated measures analysis of variance. Chronic sleep restriction of the PAC-injected animals resulted in significantly increased mechanical sensitivity that progressively worsened despite sleep recovery opportunities. If these relationships hold in humans, targeted sleep interventions employed during a PAC protocol may improve pain outcomes., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2014.)