SLEEP · 2019-01-08 · SLEEP JOURNAL OF SLEEP AND SLEEP DISORDERS RESEARCH Volume 41 Supplement 1 | April 20, 2018 | Pages 1–475 Official publication of the Sleep Research Socitety

SLEEPVO

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E 41(S1) 2018 PAGES A

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Official Publication of the Sleep Research Society

SLEEP

32nd Annual

Meeting of the

Associated

Professional Sleep

Societies, LLC

VOLUME 41, 2018 | ABSTRACT SUPPLEMENT

SLEEPJOURNAL OF SLEEP AND SLEEP DISORDERS RESEARCH

Volume 41 Supplement 1 | April 20, 2018 | Pages 1–475

Official publication of the Sleep Research Socitety.

Editor-in-Chief

Ronald Szymusiak, PhD

Deputy Editors-in-Chief

Daniel J. Buysse, MD Naresh M. Punjabi, MD, PhD

Executive Director

John A. Noel

Associate Editors

Alon Avidan, MD, MPH

Mary A. Carskadon, PhD

Michael W. L. Chee, MD, PhD

Ronald D. Chervin, MD

Chiara Cirelli, MD, PhD

Ian M. Colrain, PhD

Luis de Lecea, PhD

Christopher Drake, PhD

Raffaele Ferri, MD

James E. Gangwisch, PhD

Namni Goel, PhD

Daniel J. Gottlieb, MD, MPH

David Gozal, MD

Martica Hall, PhD

David M. Hillman, MBBS

Kristen Knutson, PhD

Andrew D. Krystal, MD

Hans-Peter Landolt, PhD

Rachel Manber, PhD

Charles M. Morin, PhD

Sanjay R. Patel, MD

John Peever, PhD

Paul E. Peppard, PhD

Carlos H. Schenck, MD

Richard J. Schwab, MD

Eus J. W. Van Someren, PhD

Kenneth P. Wright Jr., PhD

Editorial Board

Daniel Aeschbach, PhD

Richard P. Allen, PhD

Monica L. Andersen, PhD

J. Todd Arnedt, PhD

Sara J. Aton, PhD

Rashmi Aurora, MD

M. Safwan Badr, MD

Siobhan Banks, PhD

David Barnes, MBBS, PhD

Celyne H. Bastien, PhD

Dean W. Beebe, PhD

Richard B. Berry, MD

Edward O. Bixler, PhD

Bjorn Bjorvatn, MD, PhD

Donald L. Bliwise, PhD

Orfeu Buxton, PhD

Julie Carrier, PhD

Peter Catcheside, PhD

Thien Thanh Dang-Vu, MD, PhD

Yves Dauvilliers, MD, PhD

Leslie C. Dort, MSc, DDS

Jeanne F. Duffy, PhD

Charmane Eastman, PhD

Bradley Edwards, PhD

Jeffrey M. Ellenbogen, MD

Julio Fernandez-Mendoza, PhD

Peter C. Gay, MD

Thomas J. Geller, MD

Sina A. Gharib, MD

Michael A. Grandner, PhD,

MTR, CBSM

Reut Gruber, PhD

Christian Guilleminault, MD

Monica Haack, PhD

Patrick Hanly, MD , D, ABDSM

Rosemary S. Horne, PhD

Reto Huber, PhD

Luca Imeri, MD

Shahrokh Javaheri, MD

Athanasios Kaditis, MD

Thomas S. Kilduff, PhD

Leila Kheirandish-Gozal, MD

Elizabeth B. Klerman, MD, PhD

Peretz Lavie, PhD

Miranda M. Lim, MD, PhD

Peter Y. Liu, MBBS, PhD

Steven W. Lockley, PhD

Mark Mahowald, MD

Bryce A. Mander, PhD

George Mashour, MD, PhD

W. Vaughn McCall, MD

Dennis J. McGinty, PhD

Thomas A. Mellman, MD

Ralph Mistlberger, PhD

Hawley Montgomery-Downs, PhD

Nirinjini Naidoo, PhD

David N. Neubauer, MD

Seiji Nishino, MD, PhD

Bruce O’Hara, PhD

Lyle Olson, MD

Jason C. Ong, PhD

Brian Palen, MD

Philippe Peigneux, PhD

Thomas Penzel, PhD

Michael L. Perlis, PhD

Dante Picchioni, PhD

Gina R. Poe, PhD

Thomas Pollmacher, MD

Govinda R. Poudel, PhD

Gregg S. Pressman, MD , FACC

Hengyi Rao, PhD

David M. Rapoport, MD

Renata L. Riha, RPSGT, MD

Timothy A. Roehrs, PhD

Paula K. Schweitzer, PhD

Kazue Semba, PhD

Paul J. Shaw, PhD

Priyattam J. Shiromani, PhD

Robert Stickgold, PhD

Kingman P. Strohl, MD

Deborah Suchecki, PhD

Ariel Tarasiuk, PhD

Robert J. Thomas, MD

Adrienne Tucker, PhD

Christa J. Van Dort, PhD

Sigrid C. Veasey, MD

Olivia J. Veatch, MS, PhD

Arthur S. Walters, MD

Nancy J. Wesensten, PhD

Jonathan P. Wisor, PhD

Amy R. Wolfson, PhD

James K. Wyatt, PhD

© 2018 Sleep Research Society.

EDITORIAL

Welcome to your preview of SLEEP 2018, the 32nd Annual Meeting of the Associated Professional Sleep Societies, which will be held in Baltimore, Maryland on June 2-6, 2018.

This abstract supplement unites the journal SLEEP, and the science of SLEEP 2018. All abstracts presented at SLEEP 2018 are included in this special issue. This year, 1,092 abstracts will be presented at the meeting. 200 will be presented in an oral presentation format, and the remainder will be presented in a poster format. Many authors of oral presentations will also be presenting their science in the poster hall, providing additional dedicated time to network with the authors of these important studies. In addition, this abstract supplement contains case reports submitted by individuals in Sleep Medicine Fellowship and other training programs.

Abstracts in this supplement are divided between basic and translational sleep science, and clinical sleep science and practice and then assigned to one of 26 subcategories. Each abstract has a unique four-digit number to facilitate identification and location both within this issue and at SLEEP 2018. The four-digit number in the abstract supplement matches the four-digit code published in the SLEEP 2018 Mobile App.

The SLEEP meeting fosters an environment in which members and attendees learn about the latest basic, translational and clinical science and technologies, promoting the continued growth of the field through the dissemination of new knowledge. We look forward to sharing in the success of this pivotal event and hope you consider joining the American Academy of Sleep Medicine and Sleep Research Society in Baltimore, Maryland in June.

Ronald Szymusiak, PhDEditor-in-Chief

iiSLEEP, Volume 40, Abstract Supplement, 2017

Table of Contents

Abstracts by Category (click on any section to jump to it)

A. Basic and Translational Sleep Science

I. Pharmacology and Biochemistry ........................ 1AbstrActs 0001-0009

II. Cell and Molecular Biology and Genetics .......... 5AbstrActs 0010-0037

III. Circadian Rhythms Mechanisms and Physiology ........................................................ 16AbstrActs 0038-0061

IV. Neurobiology .................................................... 26AbstrActs 0062-0081

V. Learning, Memory and Cognition .................... 34AbstrActs 0082-0115

VI. Physiology ......................................................... 46AbstrActs 0116-0139

VII. Sleep and Arousal ............................................. 55AbstrActs 0140-0160

VIII. Sleep and Circadian Interactions ...................... 63AbstrActs 0161-0168

IX. Behavior and Performance ................................ 67AbstrActs 0169-0210

X. Sleep Deprivation .............................................. 83AbstrActs 0211-0246

XI. Sleep and Development .................................... 96AbstrActs 0247-0268

XII. Sleep and Aging, Sleep and Gender ............... 104AbstrActs 0269-0289

XIII. Sleep and Neurodegeneration ......................... 112AbstrActs 0290-0305

XIV. Instrumentation and Methodology .................. 118AbstrActs 0306-0339

B. Clinical Sleep Science and Practice I. Insomnia ......................................................... 131

AbstrActs 0340-0442

II. Sleep-Related Breathing Disorders ................. 168AbstrActs 0443-0610

III. Hypersomnia ................................................... 227AbstrActs 0611-0636

IV. Circadian Rhythm Sleep-Wake Disorders ...... 237AbstrActs 0637-0659

V. RLS, Movement Disorders and Parasomnias ....245AbstrActs 0660-0690

VI. Adults: Sleep and Aging, Sleep and Gender ... 257AbstrActs 0691-0743

VII. Pediatrics ......................................................... 277AbstrActs 0744-0862

VIII. Sleep and Medical Disorders .......................... 321AbstrActs 0863-0925

IX. Sleep and Psychiatric Disorders ..................... 344AbstrActs 0926-1006

X. Sleep and Neurologic Disorders ..................... 374AbstrActs 1007-1044

XI. Healthcare Delivery and Education ................ 389AbstrActs 1045-1088

XII. Consumer Technology..................................... 405AbstrActs 1089-1092

C. Case ReportsCase Reports from Clinical Trainees .............. 407AbstrActs 1093-1158

IndexesAuthor Index ................................................... 428

Keyword Index ................................................ 463

iii SLEEP, Volume 41, Abstract Supplement, 2018

A1 SLEEP, Volume 41, Abstract Supplement, 2018

A. Basic and Translational Sleep Science I. Pharmacology and Biochemistry

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0001AN OREXIN 2 RECEPTOR-SELECTIVE AGONIST TAK-925 AMELIORATES NARCOLEPSY-LIKE SYMPTOMS IN OREXIN/ATAXIN-3 MICESuzuki M, Yukitake H, Ishikawa T, Kimura HTakeda Pharmaceutical Company Limited, Fijisawa, Kanagawa, JAPAN

Introduction: Narcolepsy is a severe neurological disorder character-ized by excessive daytime sleepiness (EDS) and cataplexy. Stimulants (e.g. modafinil) are effective for EDS and antidepressants (e.g. clo-mipramine) are used for cataplexy treatment. Sodium oxybate and pitolisant treat both EDS and cataplexy but do not completely address the full extent and spectrum of narcolepsy symptoms in clinical prac-tice. Type 1 narcolepsy is associated with the loss of orexin produc-ing neurons. An orexin receptor agonist, particularly an agonist acting at the orexin 2 receptor (OX2R), may provide better effectiveness for treatment of narcolepsy. In this study, we assessed the effect of TAK-925, an OX2R-selective agonist, on narcolepsy-like symptoms in orexin/ataxin-3 transgenic mice, a narcolepsy mouse model with orexin deficiency.Methods: TAK-925, modafinil or clomipramine was administered to orexin/ataxin-3 transgenic mice at zeitgeber time (ZT) 12, and sleep/wakefulness states were evaluated in vivo. The number of cat-aplexy-like episodes was determined by counting the number of dir-ect transitions from wakefulness to rapid eye movement (REM) sleep. TAK-925 effects on wakefulness were also evaluated for 3 hours after a single administration to orexin/ataxin-3 transgenic mice, and after 14 days of twice daily administration. (s.c., b.i.d., 3 hour interval).Results: Modafinil (30 mg/kg, p.o.) and clomipramine (15 mg/kg, i.p.) were effective in reducing sleepiness or cataplexy-like episodes only, respectively, in orexin/ataxin-3 transgenic mice. Under the same conditions, TAK-925 (≥1 mg/kg, s.c.) significantly increased wake-fulness time and also completely recovered wakefulness fragmenta-tion and cataplexy-like episodes in orexin/ataxin-3 transgenic mice. The wake-promoting effect of TAK-925 (3 mg/kg, s.c., b.i.d.) was not diminished after 14 days sub-chronic administration in orexin/ataxin-3 transgenic mice.Conclusion: TAK-925 may have the potential to treat a broad range of narcolepsy symptoms such as EDS, and cataplexy without causing OX2R desensitization.Support (If Any): This work was conducted by Takeda Pharmaceuticals.

0002AN OREXIN 2 RECEPTOR-SELECTIVE AGONIST, TAK-925, SHOWS ROBUST WAKE-PROMOTING EFFECTS IN MICE AND NON-HUMAN PRIMATESYukitake H, Ishikawa T, Suzuki A, Shimizu Y, Nakashima M, Fujimoto T, Rikimaru K, Ito M, Suzuki M, Kimura HResearch, Takeda Pharmaceutical Company Limited, Fujisawa, JAPAN

Introduction: The orexin system is a critical regulator of sleep/wakefulness states, and the deficiency of orexin-producing neurons in lateral hypothalamus results in narcolepsy-like symptoms such as fragmentation of sleep/wakefulness and cataplexy-like episodes in other mammals, which are similar to those in patients. As narcolep-sy-like phenotypes such as wakefulness fragmentation were observed in orexin 2 receptor (OX2R) knockout mice, but not in orexin 1 recep-tor (OX1R) knockout mice, activation of OX2R could be expected to promote wakefulness. In this study, we describe the pharmacological

and electrophysiological characterization of an orexin 2 receptor-se-lective agonist TAK-925 in vitro and in vivo in wild-type mice and non-human primates.Methods: To determine the agonist activity of TAK-925, an in vitro calcium influx assay was conducted using Chinese hamster ovary cells stably expressing ProLink-tagged human OX2R and β-arres-tin2-β-gal-EA fusion protein (hOX2R/CHO-EA cells). The effect of TAK-925 on OX2R downstream signals was evaluated in hOX2R/CHO-EA cells. Next, the effect of TAK-925 on endogenous OX2R was evaluated using whole-cell patch-clamp techniques in hista-minergic neurons in mouse tuberomamillary nucleus (TMN). Last, the effect of TAK-925 on sleep/wakefulness states was evaluated in mice, common marmosets, and cynomolgus monkeys during their sleep phase.Results: TAK-925 activated OX2R (EC

50 = 5.5 nM) in in vitro cal-

cium influx assays with > 5,000-fold selectivity against OX1R (EC50

> 30,000 nM). An electrophysiological study revealed that TAK-925 activated physiological OX2R in histaminergic neurons in mouse TMN. TAK-925 significantly increased wakefulness time in wild-type mice (≥ 1 mg/kg, s.c.), common marmosets (≥ 0.1 mg/kg, s.c.), and cynomolgus monkeys (≥ 1 mg/kg, s.c.), but not in OX2R knockout mice, during their sleep phase.Conclusion: We demonstrated that OX2R-selective activation by TAK-925 induced wake-promoting effects in mice and nonhuman primates.Support (If Any): This work was conducted by Takeda Pharmaceuticals.

0003EFFECTS OF A NOVEL GABA

B RECEPTOR POSITIVE

ALLOSTERIC MODULATOR, ASP8062, ON SLEEP AND ELECTROENCEPHALOGRAM ACTIVITY IN RATSMurai N, Kondo Y, Akuzawa S, Mihara T, Shiraishi N, Kakimoto S, Matsumoto MAstellas Pharma Inc., Tsukuba Ibaraki, JAPAN

Introduction: The GABAB receptor agonists such as baclofen and gam-

ma-hydroxybutyrate (GHB) showed effects on sleep and electroenceph-alogram (EEG) activity. However, the use of GABA

B receptor agonists is

limited by their undesirable side-effects. One possible alternative approach to avoid GABA

B receptor agonist-induced side-effects is positive allo-

steric modulation approach. To clarify whether GABAB receptor positive

allosteric modulator (PAM) has effects on sleep and EEG activity, we investigated the potential of a novel GABA

B receptor PAM, ASP8062.

Methods: Male SD rats were surgically prepared for EEG and elec-tromyography (EMG) electrodes. GABA

B receptor PAM ASP8062 (1,

3 and 10 mg/kg, p.o.) and GABAB receptor agonist baclofen (3 mg/

kg, i.p.) were administrated. EEG and EMG were recorded and the percentage of each sleep stage [non-rapid eye movement (REM) sleep, REM sleep and wakefulness] versus total duration, frequency of sleep interruptions and frequency analysis (EEG power spectra) in non-REM and REM sleep were calculated at 0 to 2 h after administration during the light period.Results: ASP8062 significantly decreased the percentage of REM sleep time and frequency of sleep interruptions. Baclofen significantly decreased the percentage of REM sleep time. ASP8062 increased the power in delta frequency during non-REM sleep. ASP8062 and baclofen slightly increased the power in theta frequency during REM sleep.Conclusion: ASP8062, a novel GABA

B receptor PAM, has potential

to exert effects on sleep and EEG activity.Support (If Any):

A2SLEEP, Volume 41, Abstract Supplement, 2018

0004SALIDROSIDE AMELIORATES CHRONIC INTERMITTENT HYPOXIA-INDUCED ENDOTHELIAL INSULIN RESISTANCE VIA SUPPRESSION OF ERK1/2 ACTIVATIONLi L, Yang Y, Ma X, Wei Y, Qin YKey Laboratory of Upper Airway Dysfunction-related Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, CHINA

Introduction: Obstructive sleep apnea (OSA), a condition leading to chronic intermittent hypoxia (CIH), is an independent risk factor for cardiovascular disease and type 2 diabetes and is correlated with insulin resistance. Insulin stimulates production of nitric oxide (NO) in vascular endothelial cells through the IRS-1/PI3K/Akt/eNOS path-way (IRS-1, insulin receptor substrate 1; PI3K, phosphatidylinosi-tol 3-kinase; eNOS, endothelial NO synthase). We wondered if CIH that mimic OSA affects insulin signalling/action both in the aortas of C57BL/6J mice and in the human umbilical vein endothelial cells (HUVECs), and whether salidroside (Sali), a major active constituent of Rhodiola sachalinensis, could reverse this inhibitory effect.Methods: Forty male C57BL/6J mice were randomly divided into four groups (n=10/group): (1) control (intermittent air), (2) CIH (21%-5%, 90 s/cycle, 10 h/day), (3) CIH+50 mg/kg Sali, (4) CIH+100 mg/kg Sali, 7 weeks intervention. HUVECs were treated with 10 uM or 100 uM of Sali and exposed to CIH (21%-5%, 1 h/cycle) for 24 h or 48 h with or without insulin. Blood pressure, endothelium-dependent relaxation (EDR) and insulin-stimulated activation of signal molecules were assessed.Results: We observed that CIH increased systolic blood pressure and impaired EDR of aortas in C57BL/6J mice. CIH increased IRS-1 phosphorylation at Ser307 and Ser612, impaired insulin-stimulated phosphorylation of IRS-1 at Tyr896 and Akt/eNOS pathway in aortas. In addition, CIH increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Treatment of C57BL/6J mice with Sali dose-dependently ameliorated theses deleterious effects of CIH. In vitro, CIH impaired IRS-1/PI3K/Akt/eNOS pathway that resulted in reduced insulin-stimulated NO production in HUVECs. These events were accompanied by elevated ERK1/2 phosphorylation and were reversed by ERK1/2 inhibition. Sali improved endothelial insulin resistance by inhibition of ERK1/2 activation, leading to positive regulation of serine/tyrosine phosphorylation of IRS-1 and restoration of downstream Akt/eNOS activation and insulin-mediated NO production.Conclusion: Our data suggest that CIH may cause endothelial insu-lin resistance by dysregulation of IRS-1 serine/tyrosine phosphoryla-tion via ERK1/2. Salidroside is effective in ameliorating CIH-induced insulin resistant endothelial dysfunction by inhibition ERK1/2 activa-tion and beneficial regulation of IRS-1 function.Support (If Any): N/A.

0005EFFICACY OF SM-1 IN A TRANSIENT INSOMNIA MODELDahl T1, Roth T2, Zammit G3, Ahmad M3, Chen L11Sequential Medicine Ltd, Taipei, TAIWAN, 2Henry Ford Hospital Sleep Disorders and Research Center, Detroit, MI, 3Clinilabs Inc., New York, NY

Introduction: The 1983 National Institutes of Health Consensus Conference distinguished between transient and chronic insomnia. They stated “Transient insomnia refers to insomnia related to situa-tional stress. The most frequent use of hypnotics is for short-term use. Despite this, transient insomnia has not been systematically studied

in clinical trials. Hence the safe and effective treatment for transient insomnia represents an unmet need. This study assessed the effects of SM-1 vs. Placebo on PSG-defined Total Sleep Time (TST) in a 5-hour phase advance model of transient insomnia.Methods: This was a randomized, double-blind, three-way cross-over study assessing the efficacy of a single dose of SM-1 (50 mg diphen-hydramine, 5 mg delayed-release zolpidem and 0.5 mg delayed-release lorazepam) versus an active comparator (5 mg delayed-release zolpi-dem and 0.5 mg delayed-release lorazepam) and placebo after a 5-hour phase advance in healthy subjects reporting a past history of transient insomnia. Subjects slept in the laboratory for 8 hours having gone to bed 5 hours before their habitual bedtime on each of the 3 treatment days. Upon awakening subjects filled out a post-sleep questionnaire.Results: Mean TST treatment with SM-1 was 382.9 minutes, an increase 126.7 minutes over placebo (256.2 minutes; p


assessed with a word list test at 1, 2, 4, 6, 8, 10 and 12 hours after the dose administration. Electroencephalographic (EEG) recording were carried out prior to and at the following time points after the dose: 1, 2, 4, 6, 8, 10 and 12 hours, for off-line analysis of the proportion of beta frequency amplitude in the EEG spectrum.Results: The drug combination was well tolerated, as evidenced by similar number and severity of adverse events following administration of SM-1 and placebo. The pharmacodynamic profile of SM-1 showed onset of activity, as determined by subjective, performance, and EEG surrogates for sedation, at 0.5–1 hour post-dose, lasting about 7–7.5 hours. Pharmacokinetic profiles showed that the shapes of the plasma concentration curves for the two delayed-release components were altered compared with published data with unmodified drugs, while for all three agents the exposure values obtained with the combination product are in good agreement with published or historical values of the drugs given individually.Conclusion: Support (If Any):

0007MULTIPLE-ASCENDING-DOSE STUDY OF ACT-541468, A NOVEL DUAL OREXIN RECEPTOR ANTAGONIST: CHARACTERIZATION OF ITS MULTIPLE-DOSE PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY, AND TOLERABILITYMuehlan C1, Brooks S2, Zuiker R2, van Gerven J2, Dingemanse J11Idorsia Pharmaceuticals Ltd, Allschwil, SWITZERLAND, 2Centre for Human Drug Research (CHDR), Leiden, NETHERLANDS, 3Idorsia Pharmaceuticals Ltd, Allschwil, SWITZERLAND

Introduction: The orexin system regulates sleep and arousal. Following entry-into-humans with ACT-541468, a dual orexin recep-tor antagonist, multiple-ascending oral dose pharmacokinetics (PK) including dose-proportionality and accumulation, pharmacodynamics (PD), safety, and tolerability were investigated.Methods: Double-blind, placebo-controlled, randomized, multi-ple-ascending dose study in 30 healthy male and female subjects (10, 25, and 75 mg once daily (o.d.) in the morning for 5 consecutive days, 8/2 active/placebo per group). PK, PD (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual ana-log scales (VAS), Karolinska Sleepiness Scale (KSS), VAS Bowdle for assessment of psychedelic effects), safety, and tolerability were assessed.Results: Following administration of 10, 25, or 75 mg of ACT-541468 o.d. the drug was rapidly absorbed, with a median tmax of 1.0–2.0 h. The geometric mean elimination half-life on Day 5 was between 5.6 and 8.5 h, and the exposure (area under the curve (AUC)) showed dose proportionality, while the maximum plasma concentration increased slightly less than proportionally to the dose administered. No relevant accumulation (based on AUC) was observed. No influence of sex on the multiple-dose PK parameters of ACT-541468 was observed. PD were assessed for 10 h on Days 1 and 5. There were no effects at 10 mg. At 25 and 75 mg, distinct effects on psychomotor functions (SPV, adaptive tracking, body sway) were observed. Onset of effects was within 1 h, maximum effects at 2 h, and return to baseline at approximately 4–10 h post-dose. Subjective alertness decreased dose-dependently. An increase in the KSS score was observed with 25 and 75 mg, and VAS Bowdle showed small increases at 75 mg.Conclusion: Multiple-dose PK/PD of ACT-541468 are compatible with a drug for the treatment of insomnia and support further develop-ment in patients with insomnia disorders.

Support (If Any): Clemens Muehlan and Jasper Dingemanse are employees at Idorsia, the sponsor of the clinical study. The investiga-tors Joop van Gerven, Rob Zuiker, and Sander Brooks are employees of CHDR. The authors disclosed no other relevant affiliations or finan-cial interest.

0008NIGHT-TIME ADMINISTRATION OF ACT-541468, A NOVEL DUAL OREXIN RECEPTOR ANTAGONIST: CHARACTERIZATION OF ITS PHARMACOKINETICS, NEXT-DAY RESIDUAL EFFECTS, SAFETY, AND TOLERABILITYMuehlan C1, Brooks S2, Zuiker R2, van Gerven J2, Dingemanse J11Idorsia Pharmaceuticals Ltd, Allschwil, SWITZERLAND, 2Centre for Human Drug Research (CHDR), Leiden, NETHERLANDS, 3Idorsia Pharmaceuticals Ltd, Allschwil, SWITZERLAND

Introduction: ACT-541468 is a potent dual orexin receptor antagon-ist. The orexin system regulates sleep and arousal and is targeted by ACT-541468. Night-time pharmacokinetics (PK), next-day residual effects, safety, and tolerability following evening administration of ACT-541468 were investigated.Methods: Double-blind, placebo-controlled, randomized, repeat-ed-dose study in 20 young adult healthy male and female subjects (16/4 active/placebo) following evening administration of 25 mg ACT-541468 for 7 days. PK were assessed in the evening (trough), in the morning (8 h post-dose), and on Day 8 with a PK profile during the elimination phase of the drug to determine the half-life (t½). Four subjects had an additional 8th study drug administration to determine PK parameters at night. Next-day pharmacodynamic (PD) effects (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analog scale (VAS), Digit Symbol Substitution Test (DSST), Simple Reaction Time Test (SRTT), Karolinska Sleepiness Scale (KSS), Leeds Sleep Evaluation Questionnaire (LSEQ), and VAS Bowdle for evaluation of psyche-delic effects) were assessed in the morning. During the night sub-jects were not disturbed.Results: Plasma concentrations reached steady-state on Day 3 with-out relevant accumulation. The geometric mean t½ on Day 8 was 6.0 h. The night-time median time to maximum plasma concentration, geometric mean t½, geometric mean maximum plasma concentration, and area under the curve from zero to 24 h were 1.5 h, 6.1 h, 475 ng/mL, and 3729 ng·h/mL, respectively. No relevant effects on any of the PD variables, neither objective (SPV, adaptive tracking, body sway, DSST, SRTT) nor subjective (VAS Bond and Lader, KSS, LSEQ, VAS Bowdle) were observed.Conclusion: Evening administration of ACT-541468 was well tol-erated with no apparent next-day impairment of motor and cognitive functions which supports the further development of ACT-541468 in insomnia disorders.Support (If Any): Clemens Muehlan and Jasper Dingemanse are employees at Idorsia, the sponsor of the clinical study. The investiga-tors Joop van Gerven, Rob Zuiker, and Sander Brooks are employees of CHDR. The authors disclosed no other relevant affiliations or finan-cial interest.

0009A COMPARISON OF THE EFFECTS OF GABOXADOL AND SLEEP RESTRICTION ON SLEEP DEPTH ASSESSED BY THE ODDS-RATIO-PRODUCTWalsh JK1, Schweitzer PK1, Griffin KS1, Younes M2,3

A. Basic and Translational Sleep Science I. Pharmacology and Biochemistry


1Sleep Medicine and Research Center, St. Luke’s Hospital, Chesterfield, MO, 2Sleep Disorders Centre, University of Manitoba, Winnipeg, MB, CANADA, 3YRT Ltd, Winnipeg, MB, CANADA

Introduction: Several studies have shown dose-related increases in SWS and low frequency EEG power and reduced wake time and awak-enings with gaboxadol (GBX). These changes are similar to those seen with sleep loss, suggesting that GBX may enhance sleep depth. Odds-Ratio-Product (ORP) is a unit-less continuous measure of the relative power in four EEG frequency bands, with values ranging from 0 (deep sleep) to 2.5 (full wakefulness). Excellent correlation was reported between current ORP and probability of arousal in the next 30 seconds (r2=0.98), suggesting that ORP is related to sleep depth. We evaluated the effects of sleep restriction (SR) alone or with GBX on sleep depth using ORP.Methods: Forty-one subjects underwent two baseline PSGs followed by four SR nights (5h) with either placebo (21 subjects) or 15 mg GBX (20 subjects). We compared the change from baseline night 2 (first 5h) to SR night 1 and SR night 4 using two measures: ORP during TST and arousal index.Results: During the first SR night, ORP and arousal index did not change with SR alone (-0.01 ± 0.09 and 0.2 ± 3.0/h for ORP and arousal index, respectively; P>.6 for both), but decreased signifi-cantly with GBX (-0.11 ± 0.09 and -3.7 ± 5.2/h; P


0010A PUTATIVE BIOMARKER FINGERPRINT OF INSUFFICIENT SLEEP DERIVED FROM THE HUMAN PLASMA METABOLOMEDepner CM1, Markwald RR1, Cruickshank-Quinn C2, Quinn K2, Melanson EL3, Reisdorph N2, Wright KP11University of Colorado Boulder, Integrative Physiology, Boulder, CO, 2University of Colorado School of Pharmacy, Aurora, CO, 3University of Colorado Denver School of Medicine, Division of Endocrinology, Metabolism and Diabetes, Aurora, CO

Introduction: Developing an objective and easily assessed biomarker of insufficient sleep has great potential to enhance clinical assessment of overall sleep health, and improve our diagnostic capacity to identify individuals with poor sleep health. Such a biomarker would also con-tribute to personalized medicine with the potential of advancing clin-ical care. We analyzed the plasma metabolome in humans undergoing experimental sleep restriction to identify small molecule biomarkers associated with insufficient sleep.Methods: We conducted a randomized cross-over 14–15 day in-lab-oratory study where 16 (8M/8F) healthy participants aged 22.4 ± 4.8y (mean±SD) completed three baseline days (9h scheduled sleep oppor-tunity/night) followed by five days of insufficient (5h /night), and adequate (9h /night) sleep conditions. Blood was collected every 4h across 24h on the final day of baseline, insufficient, and adequate sleep conditions, and plasma was analyzed by untargeted liquid chromatography/mass-spectrometry.Results: After filtering out metabolites not present in at least fifty per-cent of all samples, we detected 3,995 metabolites. Using variable impor-tance scores derived from partial least squares discriminant modeling with 50 repeated cross-validations where one-third of all samples were randomly withheld, we identified a metabolite biomarker of insufficient sleep that consists of 34 metabolites forming a single biomarker finger-print. We calculated a receiver operator curve (ROC) to assess the range of sensitivity and specificity of this biomarker fingerprint. The ROC area under the curve for insufficient sleep versus baseline is 0.856 (95% con-fidence interval 0.788–0.936), suggesting this 34 metabolite biomarker fingerprint has “good” performance as a biomarker of insufficient sleep.Conclusion: Under controlled laboratory conditions, we identified a preliminary biomarker fingerprint of insufficient sleep consisting of 34 plasma metabolites measured in parallel. Such a biomarker fingerprint has the potential to provide a more accurate assessment of overall sleep health compared to self-report questionnaires. This preliminary bio-marker fingerprint of insufficient sleep sets the stage for future studies to confirm and improve biomarker performance using larger sample sizes and at risk populations.Support (If Any): NIH R01HL085705, R01HL109706, R01HL132150, F32DK111161, and UL1TR000154; and Sleep Research Society Foundation 011-JP-16.

0011ACUTE SLEEP LEADS TO TISSUE-SPECIFIC EPIGENETIC AND TRANSCRIPTIONAL RESPONSES IN HEALTHY HUMANSCedernaes J1, Orzechowski Westholm J2, Benedict C11Department of Neuroscience, Uppsala University, Uppsala, SWEDEN, 2Department of Biochemistry and Biophysics, Stockholm University, Stockholm, SWEDEN

Introduction: Sleep loss and circadian misalignment alter energy metabolism and promote adverse weight gain in humans, but the tis-sue-specific mechanisms remain largely unknown.

Methods: In a randomized, 2-session, 2-condition, crossover clinical study involving 15 healthy young men, skeletal muscle and adipose tis-sue biopsies were collected in the morning fasting state following one night of sleep loss and following one night of sleep (8.5 hrs). The sam-ples were analyzed using genome-wide DNA methylation and RNA sequencing, as well as by qPCR for target validation.Results: After acute sleep loss compared with sleep, only adipose tis-sue exhibited changes in DNA methylation, predominantly in regions near transcription start sites, and notably in genes linked to obesity and lipid metabolism. Whereas inflammatory signatures were upregulated across tissues at the transcriptomic level in response to acute sleep loss, adipose tissue and skeletal muscle also exhibited highly tissue-specific responses, and metabolic transcriptional pathways downstream of the circadian clock were only altered in skeletal muscle.Conclusion: Opposite genome-wide effects in skeletal muscle and adipose tissue provide evidence that metabolic pathways are tis-sue-specifically affected by sleep loss in humans, in what may con-stitute circadian misalignment across metabolic tissue. Epigenetic alterations in adipose tissue may promote more long-term adverse metabolic effects of acute sleep loss. In sum, we uncover potential genomic mechanisms through which chronic sleep loss and circadian misalignment may increase the risk of metabolic disease and adverse weight gain.Support (If Any): Work from the authors’ laboratory is supported by the Swedish Brain Foundation, Åke Wiberg Foundation, NovoNordisk Foundation, Bissen Brainwalk Foundation, the Swedish Society of Medicine and the Swedish Research Council.

0012PERIPHERAL MICRORNAS ARE ALTERED BY TOTAL SLEEP DEPRIVATION AND PSYCHOLOGICAL STRESS AND PREDICT COGNITIVE PERFORMANCE IN HUMANSZajko MJ1, Taylor DM1, Pearson-Leary J2, Bhatnagar S2, Goel N31Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 2Department of Anesthesiology, The Children’s Hospital of Philadelphia, Philadelphia, PA, 3Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

Introduction: Sleep loss is associated with cancer, cardiovascu-lar disease, and Alzheimer’s disease and psychiatric disorders, and also impairs cognitive performance, although there are individual differences in such deficits. MicroRNAs (miRNAs), small non-cod-ing RNAs that are important regulators of gene expression, typi-cally repress expression of their target mRNAs. It remains unknown whether sleep deprivation or the adverse combination of sleep depriv-ation and psychological stress affect miRNA responses in humans, and whether these responses predict cognitive performance during sleep deprivation.Methods: Thirty-two healthy adults (ages 27–53; mean±SD, 35.1 ± 7.1y; 14 women) participated in a five-day experiment con-sisting of two 8h time-in-bed (TIB) baseline nights, followed by 39h of total sleep deprivation (TSD) and two 8h-10h TIB recovery nights. A modified Trier Social Stress Test was conducted on the day after TSD to induce psychological stress. The Psychomotor Vigilance Test (PVT), Digit Symbol Substitution Task (DSST), and Digit Span Task (DS), were administered throughout the experiment. Blood samples were taken at 6 time points and miRNAs from plasma were analyzed via Affymetrix microarrays. Linear mixed models with Z-score log2 fold change cutoffs of ±1.645 and greater (FDR


Results: Compared to the pre-study time point, 10 miRNAs showed fold changes with TSD alone and 18 miRNAs showed fold changes with TSD and psychological stress; these miRNAs targeted 2309 and 2823 genes, respectively, with 700 overlapping targets. Notably, at pre study, 14 miRNAs predicted PVT lapses and errors during TSD, 7 miRNAs predicted DSST performance and 10 miRNAs predicted DS performance.Conclusion: For the first time we show that peripheral miRNAs can track responses to total sleep deprivation and its detrimental combin-ation with psychological stress and predict individual differences in cognitive performance. As such, peripheral miRNAs are viable epigen-etic biomarkers of sleep deprivation, psychological stress, and cogni-tive vulnerability in humans.Support (If Any): This work was supported by NASA NNX14AN49G (NG).

0013GENOME-WIDE ASSOCIATION ANALYSIS IDENTIFIES >75 GENETIC LOCI ASSOCIATED WITH SLEEP DURATION IN UK BIOBANK PARTICIPANTSDashti HS1, Jones S2, Lane JM1, Wang H3, Song Y1, Patel K1, Gill S1, Gottlieb D3, Tiemeier H4, Ray DW5, Frayling TM2, Rutter MK5, Weedon MN2, Saxena R11Massachusetts General Hospital, Boston, MA, 2University of Exeter Medical School, Exeter, UNITED KINGDOM, 3Brigham and Women’s Hospital, Boston, MA, 4Harvard Chan School of Public Health, Boston, MA, 5The University of Manchester, Manchester, UNITED KINGDOM

Introduction: Sleep disturbances, including short and long sleep durations, have negative consequences on health. Yet, molecular mech-anisms regulating sleep and underlying the link to diseases remain poorly understood. Genome-wide association studies (GWAS) for sleep duration have thus far identified PAX8 and VRK2 signals associ-ated with sleep duration at genome-wide significance.Methods: We performed GWAS of self-reported sleep duration (n=446,118) and separately for short (8 hours/night; n=34,184 cases) sleep using linear/logistic regression adjusting for age, sex, 10 principal components of ancestry, and genotyping array of ~11m imputed variants in partici-pants of European ancestry in the UK Biobank.Results: Trait heritability was 9.8% for sleep duration, 7.9% for short sleep, and 4.7% for long sleep. We identified 78, 27 and 8 independent genome-wide significant (P


0015BIOLOGICAL AND CLINICAL INSIGHTS FROM GENETICS OF INSOMNIA SYMPTOMSLane JM1, Jones S2, Dashti HS1, Wood A2, Van Hees V2, Spiegelhalder K3, Wang H4, Bowden J5, Kyle SD6, Ray D7, Frayling TM2, Lawlor DA5, Rutter MK7, Weedon M2, Saxena R11Massachusetts General Hospital, Boston, MA, 2Genetics of Complex Traits, University of Exeter Medical School, Exeter, UNITED KINGDOM, 3Uni Freiburg, Freiburg, GERMANY, 4Brigham and Women’s Hospital, Boston, MA, 5University of Bristol, Bristol, UNITED KINGDOM, 6University of Oxford, Oxford, UNITED KINGDOM, 7University of Manchester, Manchester, UNITED KINGDOM

Introduction: Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying patho-physiological processes and causal relationships with disease are poorly understood.Methods: We performed a genome-wide association study using 453,379 participants of European ancestry with self-reported insomnia symptoms in the UK Biobank using BOLT-LMM. We measured herit-ability and performed association tests adjusting for age, sex, genetic ancestry and genotyping array (~14 million variants). We performed follow-up analysis stratified by sex. We performed tissue-based and pathway enrichment analyses using FUMA, Magma, and Pascal. Pair-wise genetic correlation analyses to 224 traits were performed using LDSC. Two-sample Mendelian randomization (MR) was performed in MR-base.Results: We identified 57 genome-wide significant loci for self-re-ported insomnia symptoms (n=453,379) and confirmed their impact on self-reported insomnia symptoms in the HUNT study (n=14,923 cases, 47,610 controls), physician diagnosed insomnia in the Partners Biobank (n=2,217 cases, 14,420 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n=83,726). Our results show enrichment of genes involved in ubiqui-tin-mediated proteolysis, phototransduction and muscle development and enrichment of genes expressed in specific brain regions, skeletal muscle and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, cardio-metabolic traits, neuroticism, smoking behavior, depressive symptoms/disorder, cognitive measures, subjective well-being, proxy longevity measures and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary heart disease, depressive symptoms and subjective well-being (p


genetic regulation. Here, we examined intra-individual variation in targeted single-nucleotide polymorphisms (SNPs) associated with: a) resistance to sleep deprivation (ADORA2A [7 variants]; TNF-alpha, ADA1); b) morning preference (PER1, PER2); c) sleep intensity (BDNF); and d) daytime sleepiness (COMT) under one of the longest regimens of TSD conducted in sleep research.Methods: 12 subjects (6 males) underwent three cycles of 48 h of TSD separated by three days of recovery sleep (8 h, TIB). During TSD, caffeine was administered every 12 h at 13:00 and 01:00 (0 mg, 200 mg, and 300 mg) concurrently with the psychomotor vigilance test (PVT) to examine neurobehavioral performance.Results: There was no significant association between the targeted SNPs and neurobehavioral responses to sleep deprivation (p> 0.05, all). One ADORA2A SNP (rs2298383) did show a trend towards association with PVT lapses (p=0.049, non-adjusted) and reaction time (p=0.066, non-adjusted). There was no significant association between the tar-geted SNPs and caffeine preservation of neurobehavioral performance under sleep deprivation. One CYP1A SNP (rs762551) did show a trend towards association with PVT lapses (p=0.08, Bonferroni-adjusted).Conclusion: We observed that targeted SNPs associated with sleep resiliency and caffeine sensitivity are loosely associated with neurobe-havioral impairment under repeated cycles of TSD and possession of a unique SNP may not be enough to overcome the deleterious effects of total sleep deprivation. However, given that the trends observed agree with previous work, repetition with a larger cohort is warranted.Support (If Any): Department of Defense Military Operational Medicine Program.

0018WHOLE GENOMIC ASSOCIATIONS OF TRANSCRIPTION FACTOR NETWORKS WITH SLEEP DISORDERED BREATHING TRAITS IN TRANS-OMICS FOR PRECISION MEDICINE (TOPMED)Cade BE1, Lee J2, Sofer T1, Wang H1, Chen H3, Gharib SA4, Mei H5, Ochs-Balcom HM6, Patel SR7, Saxena R1, Shah NA8, Zhu X9, Gottlieb DJ1, Lin X10, Redline S11Brigham and Women’s Hospital / Harvard Medical School, Boston, MA, 2Brigham and Women’s Hospital, Boston, MA, 3University of Texas Health Science Center, Houston, TX, 4University of Washington, Seattle, WA, 5University of Mississippi Medical Center, Jackson, MS, 6University at Buffalo, Buffalo, NY, 7University of Pittsburgh, Pittsburgh, PA, 8Icahn School of Medicine at Mount Sinai, New York, NY, 9Case Western Reserve University, Cleveland, OH, 10Harvard T.H. Chan School of Public Health, Boston, MA.

Introduction: The genetic architecture of sleep disordered breath-ing (SDB) traits in humans remains largely unknown. Transcription factors such as HIF1A regulate gene expression, facilitate transcrip-tional programs, and respond to environmental signals. Identifying how variations in transcription factor binding sites (TFBS) across the genome associate with SDB phenotypes may help identify com-mon mechanisms underlying the pathogenesis of SDB and its cardi-ometabolic consequences. As part of our ongoing genetic analysis of SDB traits at sequence-level resolution, we examined TFBS net-work mutations in individuals participating in the NHLBI TOPMed Consortium.Methods: We analyzed 3,525 individuals from 5 NHLBI research cohort studies (892 African-, 206 Asian-, 2013 European-, and 414 Hispanic/Latino-Americans) with overnight objective recordings of average and minimum oxyhemoglobin saturation (SpO

2) during sleep, percent sleep

with SpO2 0.5) across the genome were tested together in set-based analyses using MM-SKAT.Results: The lead transcription factor associations were with CTCF (average SpO

2 and Per90 SKAT p = 6.5 × 10–15 and 2.3 × 10–8 respec-

tively), ERG (minimum SpO2 p = 7.8 × 10–22), and TAL1 (AHI

p = 5.9 × 10–22). CTCF, FOXA1 and MYC were among the top 5 transcription factors in 3 analyses (average SpO

2, minimum SpO

2 and

Per90), while PPARG, RELA, and TAL1 were among the top 5 tran-scription factors in 2 analyses.Conclusion: Important regulators of cell cycles (FOXA1, MYC), transcriptional insulation (CTCF), inflammation (RELA, PPARG), lipid metabolism (PPARG), and hematopoesis (ERG, TAL1) are asso-ciated with SDB traits through altered transcription factor binding sites throughout the genome. These results provide further insight into the genetic regulation of traits associated with SDB.Support (If Any): American Thoracic Society Foundation, K01 HL135405, R35 HL135818, R01 HL113338.

0019EXTREME TRAIT NEXT GENERATION SEQUENCING IDENTIFIES AHDC1 AS A NOVEL CANDIDATE GENE IN OBSTRUCTIVE SLEEP APNEAQin Y, Yang S, Li K, Wei YBeijing An Zhen Hospital, Capital Medical University, Beijing, CHINA

Introduction: Obstructive sleep apnea (OSA) (OMIM: 107650) is a common disorder characterized by recurrent episodes of partial or com-plete upper airway obstruction that lead to sleep fragmentation, day-time sleepiness, and repeated episodes of chronic intermittent hypoxia. OSA may be a clinical symptom of Mendelian diseases, such as auric-ulocondylar syndrome, Costello syndrome, Xia-Gibbs syndrome, and Marfan syndrome, suggesting a genetic basis for this disease. Genetic susceptibility to OSA remains incompletely characterized. This study was performed to identify rare variation by whole-exome sequencing and targeted sequencing in unrelated Chinese Han patients with OSA.Methods: We identified 30 severe patients with obstructive sleep apnea and 21 samples from controls in a case-control study included 165 patients with obstructive sleep apnea and 62 control individuals. We filtered whole-genome sequencing results to include only rare variants. Targeted sequencing of 8 candidate genes (PPARG, LEPR, SLC6A4, PHOX2B, TNF, AHDC1, HIF1A, and ADIPOQ) was con-ducted in 68 samples from patients with moderate to severe obstruc-tive sleep apnea and 58 samples from controls to in another cohort to validate novel rare variants. Deleterious effects of each variant were assessed by various algorithms. Luciferase reporter assay was used to validate the effect of variation on genes.Results: We detected one probably deleterious missense mutation (AHDC1:p.G1484D) and one rare variant (c.-781C>G) in the 5′-UTR of AHDC1 in two patients who had a higher apnea-hypopnea index and lower oxygen saturation. All variants identified by sequencing were confirmed by Sanger sequencing. Luciferase reporter assay results show that the variant (c.-781C>G) in the 5′-UTR of AHDC1 affect the expression of gene.Conclusion: AHDC1 is a novel candidate gene in patients with severe obstructive sleep apnea, and the variant (c.-781C>G) in the 5′-UTR of AHDC1 is a previously unreported rare variant contributing to obstructive sleep apnea susceptibility.

A. Basic and Translational Sleep Science II. Cell and Molecular Biology and Genetics


Support (If Any): This study was supported by the National Natural Science Foundation of China (Grant No. 81670331, 81470567); International Science & Technology Cooperation Program of China No. 2015DFA30160; Beijing Medical Project (2016-4); Beijing Municipal Science & Technology Commission No. Z141100006014057.

0020TLR4 GENOTYPE IS ASSOCIATED WITH NOCTURNAL SLEEP DURATION AND CONSOLIDATIONSherazi NA1,2, Riedy SM1,2, Satterfield BC1,3, Schmidt MA1,2, Wisor JP1,2, Van Dongen H1,21Sleep and Performance Research Center, Washington State University, Spokane, WA, 2Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, 3Department of Psychiatry, College of Medicine, University of Arizona, Oro Valley, AZ

Introduction: Toll-like receptor 4 (TLR4) is a cell membrane sensor for the pro-inflammatory membrane component, lipopolysaccharide. TLR4 activation results in synthesis and release of sleep-promot-ing cytokines known to be upregulated during sleep deprivation. In a rodent genetic model, TLR4 was found to modulate the electroen-cephalographic response to sleep loss. Thus, TLR4 activation may be involved in sleep regulation. In humans, we investigated whether a rare single nucleotide polymorphism (SNP) of the TLR4 gene, A896G (Asp299Gly), affects sleep duration under laboratory baseline conditions.Methods: N=49 healthy normal sleepers (27.2 ± 5.2y; 21 females) participated in one of three laboratory studies. Subjects had a 10-hour nocturnal, baseline sleep opportunity (22:00-08:00) recorded pol-ysomnographically. Blood samples obtained prior to the study were assayed for TLR4 genotype using polymerase chain reaction (PCR) with restriction enzyme digestion. 44 subjects were homozygous for the A allele, 5 subjects were heterozygous, and none were homozy-gous for the G allele. The G allele occurs at a population frequency of just 5%, and the sample was in Hardy-Weinberg equilibrium (χ2=0.14, p=0.71). Genotype effects on total sleep time (TST), wake after sleep onset (WASO), and sleep latency (SL) were analyzed using mixed-ef-fects ANOVA, accounting for study and subjects’ age.Results: Baseline PSG revealed no sleep disorders in any of the sub-jects. TST was significantly greater (F

1,44=8.49, p=0.006) in heterozy-

gous (A/G) subjects (572.3 ± 18.6min) than in homozygous (A/A) subjects (515.2 ± 6.3min). WASO was significantly less (F

1,44=6.49,

p=0.014) in heterozygous subjects (17.6 ± 14.0min) compared to homozygous subjects (55.1 ± 4.8min). There was a trend for smaller SL (F

1,44=3.66, p=0.062) in heterozygous subjects (9.8 ± 9.7min) com-

pared to homozygous subjects (29.4 ± 3.3min).Conclusion: Subjects with the relatively rare A/G genotype of the TLR4 A896G SNP exhibited longer and more consolidated baseline sleep compared to subjects with the A/A genotype. These data are con-sistent with the idea that TLR4 is involved in the regulation of sleep.Support (If Any): ONR grants N00014-13-C-0063 and N00014-13-1-0302, CDMRP grants W81XWH-05-1-0099 and W81XWH-16-1-0319, NIH grant R01HL105768, and FAA grant DTFAAC-11-A-00003.

0021EARLY LIFE SLEEP DEPRIVATION BY ENHANCING NEURONAL EXPRESSION OF MKP1 CAUSES LATER LIFE BEHAVIORAL DEFICITS IN RATSAtrooz F, Salim SUniversity of Houston, Houston, TX

Introduction: Early life sleep deprivation has been linked to devel-opment of later life psychiatric symptoms. Using an animal model of early life sleep deprivation, we found that early life sleep deprivation in rats, at postnatal-day 19 (PND19), induced anxiety-like behavior at early life, PND32 and PND60. However, during adult stage at PND90, anxiety-like behavior disappeared and depression-like behavior devel-oped instead.Methods: Rats, at postnatal day (PND) 19 were subjected to sleep deprivation for 14 days, (6–8 hours/day) using Pinnacle automated sleep deprivation system. Corticosterone level in blood and the expres-sion level of stress response proteins in the brain of rats were measured at PND35 and PND90.Results: We found that corticosterone levels were higher in sleep deprived (SD) rats as compared to control (CON) rats at PND35 but not at PND90. This was associated with anxiety-like behavior at the same developmental stage. At PND90, corticosterone levels were normalized and anxiety-like behavior disappeared. Interestingly, Sleep deprivation induced expression of mitogen activated protein kinase phosphatase 1 (MKP1) in the prefrontal cortex and amygdala regions of SD rats. MKP1 is well known to regulate neuronal activ-ity and structural integrity of neurons in a MAP Kinases-dependent manner.Conclusion: Preliminary evidence suggests that early life sleep deprivation by enhancing MKP1 expression causes alteration in neu-ronal structure, and alters neuronal circuit formation during develop-ment resulting in later onset of depression-like behavior at adult stage.Support (If Any): NIH grant awarded to Samina Salim: 2R15MH093918-02.

0022ASSOCIATION OF AHDC1 AND PPARG GENE POLYMORPHISM WITH OBSTRUCTIVE SLEEP APNEA IN CHINESE HANQin Y, Yang S, Li K, Wei YBeijing An Zhen Hospital, Capital Medical University, Beijing, CHINA

Introduction: Obstructive sleep apnea (OSA) is a common dis-order characterized by recurrent episodes of partial or complete upper airway obstruction.OSA is influenced by multiple factors. Having a first-degree relative with OSA increases the risk of OSA by more than 1.5-fold.Genetic susceptibility to OSA remains incompletely characterized.Several genome-wide linkage and association studies have identified at least 50 genes/loci linked to obstructive sleep apnea susceptibility. This study was performed to identify novel genetic variants in unrelated Chinese Han patients with obstructive sleep apnea.Methods: This case-control study included 165 patients with obstruc-tive sleep apnea and 62 control individuals. Polysomnography was used to diagnose obstructive sleep apnea and determine its severity. Targeted sequencing of 8 candidate genes (PPARG, LEPR, SLC6A4, PHOX2B, TNF, AHDC1, HIF1A, and ADIPOQ) was conducted in 68 samples from patients with moderate to severe obstructive sleep apnea and 58 samples from controls to identify novel associated variants. The associations between variants and obstructive sleep apnea traits were determined by multivariate regression analysis.Results: After adjusting for age, sex, and body mass index, we iden-tified three variants associated with obstructive sleep apnea compared with wild-type carriers: rs13073869, rs13306747, and rs373096508. Additionally, phenotype analysis showed that rs13073869 in PPARG was positively associated with the apnea-hypopnea index. All var-iants identified by targeted sequencing were confirmed by Sanger sequencing.



Conclusion: AHDC1 is a novel candidate gene in Chinese Han patients with obstructive sleep apnea, and rs13073869 in PPARG is a previously unreported polymorphism contributing to apnea-hypopnea index.Support (If Any): Project 81670331 supported by the National Natural Science Foundation of China (NSFC); Project 81470567 supported by the NSFC; Project 91439127 supported by the NSFC; International Science & Technology Cooperation Program of China No. 2015DFA30160; Beijing Medical Project (2016-4); Beijing Municipal Science & Technology Commission No. Z141100006014057.

0023CANDIDATE METABOLITE COULD PREDICT SEVERITY OF OBSTRUCTIVE SLEEP APNEALee P1, Kuo C2, Kuo T3, Chen G2, Huang Y4, Lin M1, Wang T4, Chen J5, Tseng Y61Center of Sleep Disorder, National Taiwan University Hospital, Taipei, TAIWAN, 2Department of Pharmacy, Metabolomics Group, National Taiwan University, Taipei, TAIWAN, 3Drug Research Center, College of Medicine & The Metabolomics Core Laboratory, Center of Genomic Medicine, Taipei, TAIWAN, 4Department of Internal Medicine, National Taiwan University Hospital, Taipei, TAIWAN, 5Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, TAIWAN, 6Department of Computer Science and Information Engineering, National Taiwan University, Taipei, TAIWAN

Introduction: Obstructive sleep apnea (OSA) would result in chronic intermittent hypoxia and sleep fragmentation. Metabolomics has been increasingly applied to explore the biologic pathways at hypoxic envir-onment but only a few studies investigated the metabolomic profile in OSA. The present study aimed to identify candidate metabolites pre-dictive of OSA severity.Methods: Total 200 adult male patients were recruited from refer-rals for suspect sleep apnea including 50 patients in each of no (apnea-hypopnea index, AHI


to hypoxia, we hypothesized that hepatocyte knockout of HIF-1 would cause gene expression differences yielding observed pheno-typic variations.Methods: Eight-week-old mice with hepatocyte-specific HIF-1α knockout (Hif1aF/FAlb-Cre+/+), and Hif1aF/FAlb-Cre-/- mice serving as wild-type controls, were all fed a high trans-fat diet for six months to mimic human NAFLD, inducing profound steatohepatitis. Upon sacrifice, livers were assessed for fibrosis by Sirius red staining and hydroxyproline assay. RNA was extracted from liver tissue; highest quality samples were used to generate RNA sequencing libraries. Libraries were sequenced with 50 bp single end reads to a depth of approximately 50 million reads/sample. The edgeR and limma pack-ages were used to direct differential expression analysis. Functional enrichment of the differentially expressed genes was performed using the ToppGene Suite.Results: Knockout mice had a 56% reduction in liver fibrosis as measured by hydroxyproline content (liver collagen in knockout: 2.67 ± 0.40 μg/mg, versus wild-type: 1.17 ± 0.21 μg/mg, p=0.028). Samples had a sufficient number of unique aligned reads (44.0–49.7 million). Based on 12,530 gene expression comparisons, 17 genes were differentially expressed with statistical significance (p


0028GABA

A RECEPTORS OF THE THALAMIC RETICULAR

NUCLEUS REGULATE SLEEP SPINDLES: AN IN VIVO INVESTIGATION BY CRISPR-CAS9 GENETIC ABSCISSIONUygun DS, Yang C, Miwa H, McKenna JT, McNally JM, Katsuki F, Strecker RE, Brown RE, Basheer RHarvard Medical School-VA Boston Healthcare System, West Roxbury, MA

Introduction: The GABAergic neurons of the thalamic reticular nucleus (TRN) are critical in regulating thalamocortical oscillations, particularly the waxing and waning 10-15Hz spindle-oscillations of non-rapid-eye-movement (NREM) sleep. Spindles are important for sleep-dependent memory consolidation and are impaired in neu-ropsychiatric disorders such as schizophrenia. Thus, there is consid-erable interest in understanding their regulation. TRN neurons receive inhibitory inputs from the basal forebrain and hypothalamus, acting on GABA

A receptors containing the α3-subunit. However, their func-

tional role remains unclear. Here we use the cutting-edge gene editing CRISPR-Cas9 technique to selectively delete α3-subunits in the par-valbumin (PV)-expressing TRN neurons, and examined the effect on sleep spindles.Methods: We crossed lox-stop-lox-Cas9 and PV-Cre mice to generate mice that express the endonuclease Cas9 in PV neurons, and delivered AAV encoding short-guide-RNA (AAV-sgRNA) targeting the α3-sub-unit into TRN bilaterally via an implanted cannula. A skull electrode implanted above frontal cortex recorded electroencephalogram, and nuchal muscle electrode recorded electromyographic activity. Spindles were detected by a custom-built automated algorithm. Knock down of functional α3-subunits was validated by examining the changes in spontaneous-inhibitory-postsynaptic-currents (sIPSCs) recorded from individual TRN-PV neurons with in vitro electrophysiology.Results: NREM spindle density (spindles/min) was reduced 15% from 6.5 ± 2.1 to 5.4 ± 0.8 (n=3) four weeks after AAV-sgRNA admin-istration, compared to pre-AAV condition. TRN-PV neurons with AAV-sgRNA transfection showed a significant reduction in sIPSC (1.01 ± 0.53 Hz, n=5), compared to TRN-PV neurons without AAV transfection (3.47 ± 0.75 Hz, n=6; t-test, p=0.03).Conclusion: Our results suggest that in vivo, cell-type and region-spe-cific CRISPR-Cas9 technology is an effective method to probe the role of individual genes in sleep physiology, circumventing the devel-opmental confounds associated with other types of genetic manipu-lations. Deletion of α3-GABA

A receptors from TRN PV neurons

reduced NREM sleep spindle density suggesting that selective phar-macological antagonism of α3 receptors may be beneficial in disorders where spindle density is reduced, such as schizophrenia.Support (If Any): VA I01BX001404, I01BX001356, I01BX002774, IK2BX002130; NIMH R01-MH039683, R03-MH107650; T32-HL007901. JTM received partial salary from Merck MISP, no COI with this work.

0029ABERRANT SLEEP, SPINDLE, AND EEG POWER IN MGLUR5 KNOCKOUT MICEAguilar DD, Strecker RE, Basheer R, McNally JMVABHS / Harvard Medical School, West Roxbury, MA

Introduction: The type 5 metabotropic glutamate receptor (mGluR5) is implicated in the etiology of schizophrenia (Sz) as a potential risk gene. Increasing mGluR5 activity may represent a novel therapeutic treatment to rescue NMDA hypofunction associated with this disorder. mGluR5 knockout (KO) mice demonstrate a variety of Sz-like symptoms,

including abnormal sleep (Ahnaou et al 2015). Recent clinical work has sparked interest in sleep spindles, 8–15 Hz rhythmic oscillatory events which are decreased in Sz and have been implicated in deficits in cogni-tion and memory. We thus examined sleep/wake and sleep spindle activ-ity of mGluR5 KO mice at baseline and after sleep deprivation (SD). We hypothesized mGluR5 KO mice would demonstrate increased NREM sleep and a Sz-like decrease in sleep spindle density.Methods: Adult male and female wild type C57BL/6 and mGluR5 KO mice (n=6 per group) were used for in vivo frontal EEG/EMG record-ings. After 48 hours of tethered habituation, sleep/wake and spindle analysis was performed across a 24 hour control period, and then during SD (6 hours at light onset) and 18 hours recovery sleep. Analysis of EEG power and spindle activity was performed using custom Matlab scripts.Results: mGluR5 KO mice exhibited significantly decreased wake and increased NREM sleep over both light and dark phases. These changes coincide with increased delta power and decreased theta power across all vigilance states. Knockout mice had significantly fewer NREM sleep spindles per minute at the onset of the dark cycle (~17% decrease) and demonstrated a dampening of the circadian rhythm with respect to spindle density and power spectral density.Conclusion: Our data confirm mGluR5 KO mice spend increased time in NREM sleep, replicating previous work. Novel findings include Sz-like abnormalities in sleep spindle density and delta power.Support (If Any): VA CDA IK2BX002130, VA Merit Awards I01BX001356, I01BX002774, I01BX001404, NIMH R01MH39683 & NIMH T32MH016259.

0030INVOLVEMENT OF REGULATORY FACTOR X4 IN NARCOLEPSYLuo GStanford University Center for Sleep Sciences, Palo Alto, CA

Introduction: Type 1 narcolepsy is 98% associated with human leu-kocyte antigen (HLA) class II haplotype DQA1*01:02/DQB1*06:02 (DQ0602) and highly associated with T cell receptor (TCR) alpha locus polymorphism and other immune regulatory loci. During 2009–2010, a number of narcolepsy cases appeared linked to Pandemrix® vaccina-tion, strongly suggesting that narcolepsy is an autoimmune disorder. In spite of all the indirect evidence, the identification of the autoanti-gens involved remains elusive. Here we studied whether autoimmun-ity directed toward the transcription regulatory factor X4 (RFX4), a protein co-localized with hypocretin, is involved in narcolepsy cases.Methods: Anti-RFX4 variant 3 (RFX4_v3) autoantibodies were detected using flow cytometry and confirmed using western blotting and cell-based assay in 86 narcolepsy cases and 88 DQ0602 positive controls. T cell reactivity was examined using RFX4 peptide-DQ0602 tetramers, after screening of an overlapping peptide library for strong binders to DQ0602. RFX4 peptide-DQ0602 tetramer staining of all strong DQ0602 binders was conducted in 16 DQ0602 positive subjects (3 early onset patients, 7 post-Pandemrix® patients, and 6 post-Pan-demrix® controls). PBMCs were stimulated and cultured for 10 days with Pandemrix® or single peptides and stained with each tetramer.Results: Anti RFX4_v3 antibodies were found in in 2 of 86 narcolepsy patients and 1 of 88 controls. Tetramer positive cells were observed after single peptide but not Pandemrix cultures. RFX4-specific CD4+ T cells were detected in 2 post Pandemrix® narcolepsy cases using tetramer DQ0602-RFX4-95. Staining with tetramer DQ0602-RFX4-86 was observed In 2 of 7 post-Pandemrix® narcolepsy cases and 2 of 6 con-trols, both unaffected post Pandemrix family members. Both RFX4-86 and RFX4-95 were recognized by one patient. RFX4-60 showed positive tetramer staining in one early onset (non post-Pandemrix) narcolepsy



patient. Tetramer positive cells were not CD25/CD127/FoxP3 posi-tive, thus unlikely to be regulatory T cells. No visible enrichment was observed in baseline PBMC samples (without pre-culture), suggesting that tetramer positive autoreactive cells are rare.Conclusion: RFX4 CD4+ T cell auto-reactivity may be involved in narcolepsy, although staining was also observed in two controls. An extended dataset with TCR sequencing is needed to address significance.Support (If Any): No.

0031NLRP3 INFLAMMASOME MEDIATES IL-18 AND IL-18 RECEPTOR RESPONSES TO SLEEP LOSSJohnston AM, Niznikiewicz MM, Gerashchenko D, Strecker RE, Basheer R, Zielinski MRBoston VA Healthcare System, West Roxbury, MA

Introduction: Interleukin (IL)-18 is a pro-inflammatory cytokine involved in immunity, behavior, and enhancing sleep. The nucleo-tide-binding domain leucine rich family pyrin containing 3 (NLRP3) inflammasome is a protein complex that activate the enzyme caspase-1, which converts the pro-forms of IL-18 and IL-1beta into their active forms. We previously found that the expression of NLRP3 inflammas-ome components, caspase-1 activity, and IL-1beta protein is enhanced in the somatosensory cortex by sleep deprivation. Herein, we determined the effects of sleep deprivation on IL-18 gene expression in the brain.Methods: NLRP3 knockout (KO) and wild-type (WT) control mice were sleep deprived for 6 h prior to dark onset or allowed to sleep ad libitum. Thereafter, mice were either perfused and brains were collected and processed for immunohistochemistry or rapidly dissected and somatosensory cortex, thalamus, and brain-stem regions were flash frozen. Brain sections were double-labeled with anti-IL-18 and neuronal and glial-markers [anti-glial fibrillary acidic protein (astrocytes), and anti-CD11b (microglia)]. Percent change in the number of IL-18 immuno-reactive astrocytes and microglia were determined between treatments. Frozen tissues were processed and analyzed for IL-18, IL-18 receptor accessory protein (IL-18RAP), and IL-18 receptor 1 (IL-18R1) mRNA by real-time polymerase chain reaction.Results: IL-18 mRNA expression in the somatosensory cortex, thalamus, and brainstem was enhanced in WT (p



but not NLRP3 KO mice. KO mice had responses after sleep deprivation that was similar to their control responses. For example, NLRP3 KO mice also did not demonstrate the significant enhanced percentage of time spent immobilized during the tail suspension test (an indicator of increased depressive-like behavior) found in WT mice (p



Data were analyzed using multiple linear regression, and all models controlled for age, gender, and BMI. Effect sizes were evaluated by examining squared semi-partial correlations (sr2).Results: Contrary to our hypothesis, inflammatory cytokines did not mediate the relationship between TST and TL. Instead, TST and AHI both directly predicted TL independent of covariates (TST: b = 892.11, p < .01; AHI: b = 117.07, p < .01). However TST had a stronger effect (sr2= .55) on TL than age (sr2 = .42), gender (sr2 = .06), BMI (sr2 = .19), and AHI (sr2 = .23). PTSD, combat status, perceived stress, and sleep quality did not predict TL. Greater levels of fatigue predicted higher hsCRP (b = 0.02, p < .01, sr2 = .41), but neither fatigue nor hsCRP was associated with TL.Conclusion: This study was the first to examine inflammation as a mediator between sleep and TL in veterans. Results suggest that objec-tively measured TST is the most robust predictor of telomere length, independent of several health related and psychosocial variables. The AHI-TL relationship may be complex. Results should be replicated in a larger sample, but this pilot study suggests the need for further research examining sleep duration as a unique risk factor for premature aging in veteran populations.Support (If Any): Metropolitan Detroit Research and Education Foundation.

0037MOLECULAR MARKERS OF BIOLOGICAL AGING IN PREDICTED SHORT-LIVED FLIESLisse J1, Fiebelman C1, Wang L1, Ercal N1, Samaranayake V1, Olbricht G1, Thimgan M21Missouri University of Science and Technology, Rolla, MO, 2Missouri S&T, Rolla, MO

Introduction: Inadequate sleep has been associated with numerous health problems, including diabetes, cardiovascular disease, obesity, and may lead to a reduced lifespan. It is yet unknown why inadequate sleep leads to these various health problems, but it is likely due to a problem at the molecular level. These consequences are often the result of repeated bouts of insufficient sleep rather than a single night of sleep loss. Therefore, we decided to use the model organism, Drosophila melanogaster, to track the sleep and wake bouts through-out the lifespan of the animal to relate the characteristics of sleep and wakefulness to the lifespan of the animal.Methods: We recorded the sleep and wakefulness patterns for the entire lifespan of 477 male wild-type Canton S male Drosophila melanogaster. Flies were maintained on standard yeast and molasses diet and changed twice a week. We derived a model using multi-ple linear regression model that can predict the lifespan of the flies from ~30 different variables and the predictions compared to actual lifespan. We then binned flies based on 30 days’ worth of data to test glutathione levels with HPLC and polyubiquinated proteins using western blot.Results: Using 30 days data, the model separated flies into long- and short-lived flies. Predicted long-lived flies lived for an average of 10 days longer. In addition, predicted short-lived flies had elevated lev-els of Amylase transcript in their heads, indicating elevated sleep drive. Predicted short-lived flies exhibited changes consistent with increased biological aging. For one, short-lived flies exhibited decreased levels of the antioxidant, glutathione. Moreover, predicted short-lived flies had increased levels of polyubiquinated proteins.Conclusion: Sleep and wake transitions can be used to describe lifespan and bin flies into short and long-lived flies based on sleep and wake char-acteristics with 30 days’ of data. The model has identified biologically older flies with less capacity to deal with oxidative stress and increased

ubiquination. Thus, our approach can separate flies according to biolog-ical age in a non-invasive manner to determine molecular connections between inadequate sleep and cellular environment.Support (If Any): R15-GM117507.


A. Basic and Translational Sleep Science III. Circadian Rhythms Mechanisms and Physiology

0038SEPARATING CIRCADIAN- AND BEHAVIOR-DRIVEN METABOLITE RHYTHMS IN SIMULATED SHIFT WORKVan Dongen H1,2, Gaddameedhi S1,3, Chowdhury NR4, Skornyakov E1,5, Gajula RP3, Middleton B4, Satterfield BC1,6, Porter K3, Skene DJ41Sleep and Performance Research Center, Washington State University, Spokane, WA, 2Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, 3College of Pharmacy, Washington State University, Spokane, WA, 4Faculty of Health and Medical Sciences, University of Surrey, Guildford, UNITED KINGDOM, 5Department of Physical Therapy, Eastern Washington University, Spokane, WA, 6Department of Psychiatry, College of Medicine, University of Arizona, Oro Valley, AZ

Introduction: Shift work causes misalignment between internal cir-cadian rhythmicity and externally imposed behavioral schedules, which has been implicated in elevated risk of metabolic disorders. We investigated the metabolic consequences of misaligned shift schedules using a metabolomics approach.Methods: N=14 healthy subjects (25.8 ± 3.2y, 4f) participated in a 7-day in-laboratory study in dim light. Following a baseline day, sub-jects were randomized (50% chance) to either a 3-day simulated day shift schedule (sleep: 22:00-06:00) or, after a transition nap (sleep: 14:00-18:00), to a 3-day simulated night shift schedule (sleep: 10:00-18:00). This was followed by a 24h constant routine protocol, and then a recovery day. During the constant routine, blood was sampled every 3h through an intravenous catheter. Plasma was analyzed for circa-dian rhythm markers of the central pacemaker: melatonin, cortisol, and PER3 mRNA expression. Additionally, 132 metabolites were assayed using targeted LC/MS metabolomics. Data were analyzed using mixed-effects cosinor analysis.Results: Melatonin, cortisol, and PER3 rhythms maintained approxi-mately the same phase alignment relative to clock time during constant routine after the day versus night shift schedules. Of the 132 circulating metabolites analyzed, 65 showed significant 24h rhythmicity (p90% of the circulating metabolites assessed during constant routine, 24h rhythmicity was not locked to the central cir-cadian pacemaker. Rather, their rhythmicity aligned with the behav-ioral timing of the prior 3-day simulated shift schedule, providing a window onto peripheral oscillators and metabolic pathways potentially involved in elevated risk of metabolic disorders in shift work.Support (If Any): College of Pharmacy, Washington State University, and in part by CDMRP award W81XWH-16-1-0319, NIH grant R00ES022640, U.K. BBSRC grant BB/I019405/1, and EU FP7-HEALTH-2011 EuRhythDia grant 278397.

0039SEX DIFFERENCES IN THE EFFECTS OF CIRCADIAN MISALIGNMENT ON APPETITE HORMONES AND SUBSTRATE UTILIZATIONQian J1,2, Caputo R1,3, Morris CJ1,2, Wang W1,2, Scheer FA1,21Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA,

2Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA, 3Division of Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, NETHERLANDS

Introduction: Shift work is known to cause circadian misalignment and increase the risk for weight gain and obesity. While emerging evi-dence indicates some characteristics of the human circadian system and energy metabolism to differ between men and women, little is known about whether sex modulates the effects of circadian misalign-ment on energy homeostasis. Here we explore the sex differences in the effects of circadian misalignment on appetite hormones, energy expenditure, and substrate utilization.Methods: Fourteen healthy young adults (mean age ± SD, 28 ± 9 y; BMI, 25.4 ± 2.6 kg/m2; 8 men) each underwent two highly con-trolled 8-day laboratory protocols: a circadian alignment protocol and circadian misalignment protocol in a randomized, cross-over design. Participants consumed an isocaloric diet per 24 h. Identical test meals were given 1 h and 13 h following wake time. Indirect calorimetry measurements were assessed for these test meals sessions. Hourly lep-tin and active ghrelin concentrations were assessed for 24 h on the first and third test day.Results: The effects of circadian misalignment on the 24-h aver-age level of the satiety hormone leptin differed significantly between women and men (P



elucidated. We therefore examined circulating FFA, glucose and insu-lin during an inpatient simulated night shiftwork protocol.Methods: 14 healthy adults (6M; aged 26.4 ± 1.2y, BMI 22.7 ± 0.5 kg/m2; mean±SD) participated in the study. Blood was sampled every 2 hours for 24 hours during circadian alignment and circadian misalignment and every 30 minutes after each meal for 2 hours. Blood was assayed for FFA, insulin and glucose. Participants were provided with a 3-day energy balance diet prior to study admis-sion and the diet was continued inpatient. Diet was designed with the same meals each day.Results: Circadian misalignment was induced by our simulated nightshift work protocol, as evidenced by the melatonin rhythm which did not adapt to the nightshift schedule. Mean FFA levels were significantly elevated during wake (+41 ± 18%, p


These findings may have implications for diagnosis or treatment of impaired glucose tolerance.Support (If Any): NIH R01-HL125893, KL2TR002370-01, F32-HL131308, MRF of Oregon, Ford Foundation, and CTSA grant (UL1TR000128).

0043INSUFFICIENT SLEEP INDUCES MORNING CIRCADIAN MISALIGNMENT AND IMPAIRS ORAL GLUCOSE TOLERANCEMorton SJ, Marbas E, Knauer O, Depner CM, Wright KP, Broussard JLUniversity of Colorado Boulder, Boulder, CO

Introduction: We previously reported that short sleep schedules with an early wake-time induce morning circadian misalignment and impair insulin sensitivity under ad libitum food intake conditions. However, the impact of insufficient sleep on circadian alignment and insulin sensitivity under controlled feeding conditions is unknown. Therefore, the aim of this study was to investigate whether short sleep schedules with wake-time kept constant at habitual time induces morning cir-cadian misalignment and impairs insulin sensitivity under isocaloric food intake conditions.Methods: 18 lean, healthy, adult (10F, aged 24.4 ± 3.8y, BMI=22.3 ± 1.9kg/m2; mean±SD) participated in the study. An oral glucose tolerance test (OGTT) was conducted to assess insulin sensitivity at baseline and after 3 nights of 5h sleep opportunity/night achieved by delaying bedtime by 4h without a change to habitual wake-time. Salivary melatonin was collected hourly for 6h at baseline and after insufficient sleep to assess the dim light (


for human P301L mutation of the microtubule-associated protein tau gene, and double wild-type (WT) controls from the same genetic background. We assessed aggressive propensity using resident intruder tests at four time points, and LMA rhythms using biotelemetry, at ages known to be relevant milestones in the development of neuropathol-ogy. We are examining the effects of this neuropathology on the SCN-SPZ-VMH circuit.Results: Preliminary findings show TAPP mice exhibit increased aggression during the early daytime compared to WT controls and blunted nighttime LMA. These behavioral abnormalities are similar to that seen following SPZ GABAergic disruption, suggesting the SCN-SPZ-VMH pathway may be compromised in TAPP mice.Conclusion: TAPP mutants and mice with SPZ GABAergic disruption show increased aggression during the early resting phase (morning for mice), which is temporally consistent with increased aggressive symptoms reported in patients who display sundowning. This suggests the SCN-SPZ-VMH pathway could be a promising therapeutic target for treating circa-dian dysfunction and aggression in dementia and AD patients.Support (If Any): Alzheimer’s Association AARF-16-443613.

0046REDUCED DAILY RHYTHM OF FRACTAL CARDIAC DYNAMICS IS ASSOCIATED WITH WEIGHT LOSS RESISTANCE IN OVERWEIGHT/OBESE WOMENYang H1,2, Lo M2, Garaulet M3, Hu K4,51National Taiwan University, Taipei City, TAIWAN, 2Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, TAIWAN, 3Department of Physiology, Faculty of Biology, University of Murcia, Murcia, SPAIN, 4Assistant Professor of Medicine, Harvard Medical School, Boston, MA, 5Associate Physiologist, Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA

Introduction: Weight loss in response to dietary interventions shows huge inter-individual variations, which cannot be explained by diet and exercise levels. A possible contributing factor is sleep/circadian regu-lation that may affect body weight and metabolism via its influences on autonomic function. Evidence indicates a delicate interplay between sympathetic and vagal outflows, generating fractal temporal correla-tions in heartbeat fluctuations that change with sleep/wake states and circadian phases. Here we tested whether the daily rhythm of fractal cardiac dynamics is linked to weight loss resistance, and whether the rhythm is altered in people carrying genetic variant CLOCK (Circadian Locomotor Output Cycles Kaput) 3111C allele who have increased weight loss resistance.Methods: Forty overweight/obese Caucasian women (BMI>25) com-pleted an obesity dietary treatment (up to 30 weeks) and a cardiac assessment in which heartbeat intervals were continuously recorded for ~3.5 days. The sample included 20 C carriers (CC and TC) and 20 non-carriers with matched age, BMI, energy intake, and physical activ-ity levels. Fractal correlations in heartbeat fluctuations were quanti-fied in each 1-h bin, and 24-h rhythmicity was estimated using cosinor analysis.Results: Subjects lost 9.8%±0.9%[SE] of the initial weight during the treatment. There were more Low Responders (weigh loss 10% (0.150 ± 0.012, 16% reduction, p


NORWAY, 5Department of Psychology, Norwegian University of Science and Technology, Trondheim, NORWAY, 6Section for Applied Clinical Research, Norwegian University of Science and Technology, Trondheim, NORWAY, 7Faculty of Architecture and Design, Norwegian University of Science and Technology, Trondheim, NORWAY, 8Norwegian University of Science and Technology, Department of Mental Health, Trondheim, NORWAY

Introduction: We have built a new psychiatric intensive care unit to optimize patients circadian rhythms using a tunable light system. All light sources in half the unit (patient rooms, bathrooms, corridors, and common areas) are depleted of blue light between 1830h to 0700h, at other times the light is normal. The other half has normal light at all times. We aimed to test the effect of living in the evening blue-depleted hospital environ-ment on melatonin suppression and melatonin onset phase shift.Methods: In a randomized crossover trial, 12 healthy participants were admitted for 10 days, 5 days in each light environment. Hourly saliva samples were collected from 19:00h to 23:00h on five evenings. The evening before admission (baseline), and the evening after each condition, melatonin was assessed in dim light (4pg/ml) between the last assessment and the baseline assessment. The effect of ‘condi-tion’ on suppression and time for melatonin onset was estimated using a linear mixed model. The combination of assessment, condition and time was taken as the fixed effect and participant as the random effect.Results: Melatonin levels were less suppressed in the blue-depleted environment, by 15% (95% CI -2% - 34%) compared to 45% (95% CI 33% - 59%) in the normal environment (p = 0.007). Melatonin onset was phase advanced by 1:45h (95% CI 1:25 - 2:04) after living in the blue-depleted environment compared to 0:35h (95% CI 0:11 - 1:04) after the normal environment (p < 0.001).Conclusion: It is possible to create a hospital environment that has an impact on melatonin secretion and the circadian clock. This may improve treatment outcomes in patient groups with disrupted circadian rhythms, and may be important for how inpatient units are designed.Support (If Any): N/A.

0049

The Role Of Environmental Light Exposure And Circadian Phase In Seasonal Affective DisorderDuPont CM1, Hasler BP2, Miller MA1, Longinotti S1, Fletcher ME3, Roecklein KA11Department of Psychology, University of Pittsburgh, Pittsburgh, PA, 2Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 3University of Pittsburgh Medical Center, Pittsburgh, PA

Introduction: Seasonal affective disorder (SAD) is a recurrent depression that occurs in the winter and remits in spring. The phase shift hypothesis suggests that a later sunrise in winter promotes a cir-cadian phase delay and subsequent depressive symptoms in SAD. As the circadian system is most sensitive to blue wavelengths of light, the current study aims to investigate whether circadian phase mediates the relationship between blue light exposure and depression severity in SAD. Thus, we hypothesize that a later timing of blue light exposure is associated with a delayed circadian phase and greater depressive symptoms in SAD.

Methods: Adults (N = 58; 81% women) with SAD, subsyndromal SAD, and non-depressed controls were assessed in winter. Blue light was measured by an Actiwatch Spectrum and quantified as the mean timing and duration of light exposure above 1.0x1011 photons/cm2/sec. Depressive symptoms were assessed during a structured clinical inter-view and circadian phase was determined by dim light melatonin onset (3 pg/ml threshold). Age and gender were covariates in all analyses.Results: The timing of blue light exposure was not associated with cir-cadian phase (β = 0.27, t(57) = 1.98, p = 0.05), or depressive symptoms (β = 0.05, t(57) = 0.35, p = 0.73). A longer duration of blue light expos-ure was associated with a later circadian phase (β = 0.44, t(57) = 3.27, p = 0.002), but circadian phase was not associated with depressive symp-toms (β = -0.23, t(57) = -1.79, p = 0.08). When women were analyzed separately, circadian phase mediated the relationship between light expos-ure and depressive symptoms (B = -0.04; SE = 0.02; 95% CI = -0.09 - -0.005), such that a shorter duration of blue light exposure was associated with an earlier circadian phase and greater depressive symptoms.Conclusion: Contrary to the hypothesis, our results indicate that reduced blue light exposure predicts greater depressive symptoms, as mediated by more advanced circadian phase. Thus, future studies should investigate potential sex differences in the association between phase and depressive symptoms in SAD.Support (If Any): R01MH103313 (K.R.).

0050SHIFT WORK AND SYMPTOMS OF ANXIETY AND DEPRESSION AMONG CHINESE PRACTICE NURSES: A PROSPECTIVE STUDYChen X, Fan F, Shi XSouth China Normal University, Guangzhou, CHINA

Introduction: Shift work is associated with sleep problems and psycholog-ical health outcomes. The main aim of the present study was to investigate shift work-related sleep problems change in depression as well as anxiety following a transition to a shifts work schedule using a longitudinal design.Methods: This is a longitudinal study with two waves of data col-lection. A total of 664 nurses(all females;17.83 ± 1.56 years)were assessed at baseline, prior to commencing shift work. They were re-as-sessed during the follow-up sessions within the first half a year of shift work exposure after approximately 3 months of rotating shift work. Participants reported demographic characteristics and whether suffer-ing Insomnia. They also completed the Patient Health Questionnaire, the Generalized anxiety disorder-7, Composite Morningness Questionnaire, Circadian Type Inventory-11, Epworth Sleepiness Scale and some questions concerning shifting work.Results: The prevalence of depression at follow-up was 10.4% and anxiety was 16%.Logistic regression analyses showed significant risks of being depression at follow-up and the following variables measured at baseline after controlling the baseline depression, demo-graphic characteristics and other items about shift work: languidity (OR = 1.15, 95% CI = 1.01–1.30), Insomnia symptoms(OR = 3.20, 95% CI = 1.37–7.47) and sleepiness(OR = 1.14, 95% CI = 1.03–1.26); as well, Insomnia symptoms(OR =3.35, 95% CI = 1.69–6.97) and sleepiness(OR = 1.19, 95% CI = 1.10–1.30) may associated with a significantly risk of anxiety at follow-up.Conclusion: The prevalence of depression and anxiety after shifting work were relatively high among these shift nurses. Individuals with shift work-related sleep problems: languidity, insomnia and sleepi-ness were more suffering depression. Those who reported insomnia and sleepiness symptoms were more experiencing anxiety. This sug-gests that shift work-related sleep problems may exacerbate individual depression and anxiety.Support (If Any): no.



0051SOCIAL JETLAG IS ASSOCIATED WITH GREATER DEPRESSIVE SYMPTOMS AMONG FEMALE ADOLESCENTSMathew GM1, Buxton O1,2,3,4, Hale L5, Chang A11Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, 2Division of Sleep Medicine, Harvard Medical School, Boston, MA, 3Sle

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SLEEP · 2019-01-08 · SLEEP JOURNAL OF SLEEP AND SLEEP DISORDERS RESEARCH Volume 41 Supplement 1 | April 20, 2018 | Pages 1–475 Official publication of the Sleep Research Socitety