Sleep Maintenance Research Articles

1014 The PANDA Monster Under the Bed

Abstract Introduction Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) is an acute-onset constellation of symptoms including obsessive-compulsive disorder and concurrent neuropsychiatric symptoms including anxiety, emotional lability, and behavioral regression. Sleep disturbances are common in PANDAS, suspected of post-infectious inflammation that can decrease serotonin, increase dopamine, and prevent the production of melatonin. OCD fears and rituals can create may impede sleep onset and impair sleep maintenance. Abnormal motor manifestations during sleep include restlessness, stereotypies, paroxysms or periodic limb movements during sleep. This case report highlights the clinical time course of sleep disorders found in chronic PANDAS, refractory to immunomodulatory interventions. Report of case(s) We present the case of an 11-year-old male who presented with behavioral insomnia of childhood sleep-onset association type in the setting of personality changes and deterioration of school performance coinciding with streptococcus infection two months earlier. The patient was supported with prophylaxis antistreptococcal therapy as well as Omega-3 fatty acids. Parents noted heightened anxiety during the day, fear of obsessive and intrusive thoughts about becoming sick, and social seclusion but refusal to sleep alone and be away from home. He was also diagnosed with a tic disorder, chronic migraine, and postural orthostatic tachycardia syndrome (POTS), which likely exacerbated insomnia. The patient was referred for Cognitive behavior therapy utilizing exposure/response prevention ERP modality and psychoeducation. However, it was not until clonidine was introduced that the patient demonstrated a significant clinical response. Clonidine was initiated at 50ug and increased to 100ug QHS. It likely promotes sedation by decreasing norepinephrine release via negative feedback by agonism of the α2-adrenergic receptors at the level of the locus coeruleus. Conclusion Sleep disorders in PANDAS syndrome remain elusive and challenging to manage due to the lack of well-developed pharmacologic guidelines to treat insomnia in children. Our case illustrates the importance of the integration of pharmacologic treatments to augment behavioral strategies and promote better patient outcomes. More studies are needed to investigate the pharmacologic management of sleep ­disorders in children in general, but appraise the safety and efficacy of specific medications such, as clonidine, in particular. Support (if any)

0767 INSIGHT Responsive Infant Parenting Intervention and Child Sleep at Age 6 Years

Abstract Introduction The Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) responsive parenting (RP) intervention for first-time mothers resulted in more responsive bedtime parenting and longer infant sleep duration in the first year after birth. The current analysis evaluates intervention effects on parent-reported sleep behaviors and objectively-measured sleep at child age 6 years. Methods Mothers (n=279) were randomized to the RP or control intervention, delivered by nurses at home and clinic visits through child age 2.5 years. Sleep content focused on establishing bedtime routines, age-appropriate bedtimes, and promoting self-soothing at bedtime and after night wakings. At 6 years, children completed wrist actigraphy (Spectrum Plus) for 7 days during the school year. Children with ≥3 valid days were included in analyses (n=162). Mothers (n=173) completed the Children’s Sleep Wake Scale and Children’s Sleep Hygiene Scale. Study group differences for 10 sleep actigraphy variables (M/SD of onset, offset, and midpoint of sleep timing, sleep maintenance efficiency, and total sleep time), as well as survey scores, were examined. Results Children (mean age 6.7 years, 96% non-Hispanic White) slept on average 8.8 hours ± 33 minutes per night, with 40% meeting the minimum recommendation of 9 hours. The mean sleep onset time was 9:14 pm ± 50 minutes. There were no significant study group differences in any actigraphy variables. RP mothers reported higher scores for Total Sleep Quality (4.6 ± 0.5 vs. 4.4 ± 0.6, p=0.03), ‘Going to Bed’ subscale (4.3 ± 0.8 vs. 4.0 ± 0.9, p=0.03), which captures child compliance with bedtime, and ‘Reinitiating Sleep’ subscale (4.6 ± 0.9 vs. 4.2 ± 1.1, p=0.005), which captures the child’s ability to go back to sleep on their own after waking. Total Sleep Hygiene score did not differ between groups. Conclusion The INSIGHT intervention targeting sleep in infancy was associated with improved parental perception of bedtime stalling and self-soothing behaviors at age 6 years. However, this did not translate into differences in sleep duration, timing, or quality measured by actigraphy. Future research should examine strategies to maintain the impacts of the RP intervention on infant sleep into middle childhood. Support (if any) R01DK088244, KL2TR002015

0402 Factors associated with subjective sleep problem and treatment willingness in sleep clinic patients

Abstract Introduction Insomnia clinic physicians often encounter patients with discrepancy between subjective and objective sleep problem. This study aimed to investigate factors that attributed to patients’ perception of sleep disturbances and treatment willingness, which were practical in determining diagnostic and treatment direction. Methods This study was a cross-sectional study, data collected from November 2018 to October 2022 in sleep clinic of tertiary university-affiliated hospital. Adults older than 19 who underwent sleep questionnaires and polysomnography (PSG) were included (n=3,239). Demographic data and sleep-related factors (alcohol, caffeine, exercise, education, job, marital status, comorbidity) were collected. Subjects were categorized into four groups by questionnaire answers (Do you think you have sleep problem? Do you want treatment for sleep problem? -group 1, neither; group 2, no sleep problem but want treatment; group 3, yes sleep problem without treatment willing; group 4, both yes.) and compared. Results Group 2 had higher percentage of job, snoring, witnessed apnea, worry about sleep, sleep maintenance problem than group 1. Group 3 had less job, sleep maintenance problem, daytime dysfunction, worry about sleep than group 4 (p< 0.05). Majority of no sleep problem groups were revealed to be normal (group 1: 28.0%, 2: 28.5%) or OSA (group 1: 63,7%, 2: 63.1%), while yes sleep problem groups were relatively higher combined insomnia and OSA (COMISA) (group 3: 20.0%, 4: 23.8%) or insomnia (group 3: 11.1%, 4: 15.3%) by PSG. OSA patients in group 2 showed more witnessed apnea and worry about sleep than group 1. COMISA patients in group 3 had less daytime dysfunction than group 4. However, PSG parameters were not significantly different among groups. Conclusion This study found that social need and subjective sleep maintenance problem are key factors that lead patients to regard their sleep as problematic or seek for treatment. In particular, patients with suspected OSA need to be instructed to get sleep study since sleep apnea severity do not affect treatment willingness and they had the lowest insight of their sleep problem. For those complaining of no or mild problem yet seeks for treatment, focusing on relieving misperceived worries about sleep is needed. Support (if any)

1022 Two Teenagers with New Onset Insomnia post COVID

Abstract Introduction Sleep disturbances are increasingly seen in COVID-19 infection. Multiple reports have described the onset of insomnia, excessive daytime sleepiness, and fatigue in patients with both acute COVID infection and long COVID syndrome. Most of these are limited to adults. We report the cases of 2 teenagers with new onset chronic insomnia post COVID-19 infection. Report of case(s) The first patient is a 14-year-old male who presented with sleep onset and sleep maintenance insomnia, excessive daytime sleepiness, difficulty concentrating, fatigue, and chronic cough, with onset five months prior presentation to the sleep clinic. He developed these symptoms after testing positive for COVID-19. He had significant impairment with multiple school absences and tardies for which he required accommodation. He completed a 2-week actigraphy test which showed prolonged sleep latencies and insufficient sleep. He was scheduled for polysomnography (PSG) followed by a multiple sleep latency test (MSLT) but could not proceed to MSLT due to insufficient sleep the night before. The PSG did not reveal either obstructive sleep apnea or periodic limb movements of sleep. His laboratory testing was significant for a low ferritin level of 21. He was referred for IV iron infusion due to intolerance for oral iron. He was started on melatonin without benefit. He was offered clonidine and trazodone but declined. The second patient, a 17-year-old male, presented with insomnia of 3 months duration which started after an acute COVID infection. In addition to insomnia, he had comorbid mood symptoms. He went from being engaged in school and work to being unmotivated and listless. His actigraphy testing revealed he was having sufficient sleep on several days during which he reported not getting any sleep. He failed trials of multiple medications including melatonin, trazodone, hydroxyzine, and gabapentin. He also denied benefit with CBT-I. Conclusion These case reports link COVID 19 and chronic insomnia in pediatric patients. While it is yet unclear whether the development of sleep disturbances post COVID is as a result of an intrinsic characteristic of the COVID-19 virus or the biopsychosocial effects of the pandemic, it is important to develop and implement targeted interventions focused on recognizing and treating insomnia early. Support (if any)

0101 Greater Variability in Sleep Health is Associated with Obesogenic Appetitive Traits in 6-Year-Olds in the INSIGHT Study

Abstract Introduction Poor sleep health is associated with increased risk for childhood obesity, but the underlying mechanisms are unclear. Eating behaviors may play a role. We examined the association between appetitive traits and objectively-measured sleep variables in 6-year-old children. We hypothesized that poorer or more variable sleep health measures would be associated with higher levels of food approach traits (food responsiveness, enjoyment of food, emotional overeating, and desire to drink), and lower levels of satiety responsiveness. Methods Participants were from an observational long-term follow-up of INSIGHT, an RCT of a responsive parenting intervention for first-time mothers compared to a safety control intervention. At age 6 years, children wore wrist actigraphy (Spectrum Plus) for 7 days to assess sleep. Children with ≥3 valid days were included in analyses (n=167). Mothers completed the Children’s Eating Behavior Questionnaire to assess appetitive traits. Separate regression models examined the association between appetitive traits and sleep variables (M/SD of nighttime total sleep time (TST), onset, offset, and midpoint of sleep timing, and sleep maintenance efficiency), controlling for intervention group, child age, sex, and overweight status. Results Mean TST was unrelated to appetitive traits; greater variability (SD) in TST was associated with higher food responsiveness (B=0.008, p=0.03) and desire to drink (B=0.010, p=0.04). Mean sleep onset time was unrelated to appetitive traits, but greater variability in sleep onset time was associated with higher desire to drink (B=0.686, p=0.004). Higher mean sleep maintenance efficiency was associated with higher satiety responsiveness (B=0.035, p=0.04) and lower enjoyment of food (B=-0.053, p=0.008). Greater variability in sleep maintenance efficiency was associated with higher enjoyment of food (B=0.092, p=0.03) and lower satiety responsiveness (B=-0.089, p=0.01). Emotional overeating was unrelated to sleep variables, and sleep offset and midpoint were unrelated to appetitive traits. Conclusion Other than sleep efficiency, mean levels of sleep health appear unrelated to appetitive traits, but greater variability in sleep health measures were associated with higher levels of potentially obesogenic traits and lower levels of protective traits. Future studies should examine whether promotion of sleep regularity can improve regulation of eating behavior and reduce childhood obesity risk. Support (if any) R01DK088244, KL2TR002015

0364 The Effect of Lemborexant on Polysomnographic Sleep Parameters in Adults with Mild, Moderate, or Severe Obstructive Sleep Apnea

Abstract Introduction Several commonly prescribed hypnotics may worsen respiratory function, especially in the elderly. Lemborexant (LEM) is a dual-orexin-receptor-antagonist approved to treat adults with insomnia. In Studies 102 (NCT03471871) and 113 (NCT04647383), LEM demonstrated respiratory safety in subjects with mild, moderate, or severe obstructive sleep apnea (OSA) who did not report insomnia. The current analyses evaluated sleep variables from these studies. Methods Studies 102 and 113 were double-blind, placebo (PBO)-controlled, crossover studies in adults with untreated mild (apnea-hypopnea-index [AHI] ≥5 to < 15), moderate (AHI≥15 to < 30), or severe (AHI≥30) OSA, without insomnia. Subjects were randomized to two 8-night periods (separated by ≥14 days) treated with LEM 10mg (LEM10) or PBO. Latency to persistent sleep (LPS), sleep efficiency (SE), and wake after sleep onset (WASO) were assessed using polysomnography on Days 1 (D1) and 8 (D8). Results The analysis set comprised 39, 13, and 20 subjects with mild, moderate, or severe OSA, respectively. On both days, LPS was not statistically different from PBO in any group. Compared with PBO, SE was significantly greater on D1 in subjects with mild (LEM10, 90.43; PBO, 80.31; P< 0.0001), moderate (LEM10, 88.83; PBO, 84.02; P=0.016), and severe (LEM10, 87.76; PBO, 77.84; P< 0.0001) OSA. On D8, SE was significantly greater in subjects with mild (LEM10, 86.65; PBO, 80.59; P=0.003) and moderate (LEM10, 88.45; PBO, 80.70; P=0.004) OSA, with a trend towards significance in subjects with severe (LEM10, 85.60; PBO, 80.63; P=0.055) OSA. WASO was significantly lower (improved) on D1 in subjects with mild (LEM10, 33.30; PBO, 76.76; P< 0.0001), moderate (LEM10, 44.26; PBO, 64.71; P=0.008), and severe (LEM10, 42.03; PBO, 91.49; P< 0.0001) OSA. On D8, WASO was significantly lower in subjects with mild (LEM10, 51.74; PBO, 70.52; P=0.015) and moderate (LEM10, 49.16; PBO, 75.15; P=0.008) but not severe (LEM10, 59.85; PBO, 74.46; P=0.161) OSA. LEM was well-tolerated. Conclusion In untreated OSA subjects without insomnia, irrespective of OSA severity, LEM improved sleep maintenance versus PBO. LPS did not differ between treatments since such patients may not report sleep onset difficulties. These findings support the use of LEM for patients with comorbid insomnia and sleep apnea (COMISA). Support (if any) Eisai, Inc.

0410 Lavender essential oil and sleep hygiene as therapeutic options for insomniac postmenopausal women: a randomized clinical trial

Abstract Introduction Menopausal transition and postmenopause often bring sleep complaints and insomnia, a common sleep disorder. In addition, women at this stage also experience vasomotor symptoms, which can compromise sleep maintenance and quality of life. This study aimed to observe the effect of an intervention with aromatherapy and sleep hygiene in the quality of life, self-related sleep pattern and hot flashes record in postmenopausal women with insomnia diagnosis. Methods This pilot study is a double-blind randomized clinical trial. Of the 135 women interested in participating in the study, 34 postmenopausal women met the inclusion criteria and completed the protocol. Volunteers were clinically diagnosed with insomnia and distributed in two groups: Aroma Group (Lavandula angustifolia essential oil) (n=17) and Placebo Group (sunflower oil) (n=17), both inhaled before bedtime for 29 days. The groups received sleep hygiene guidelines and were monitored weekly. To assess the effect of the intervention, the Menopause-Specific Quality-of-Life Questionnaire, intervention version (MENQOL-I), and Epworth Sleepiness Scale (ESS) were used. With data from the sleep diary, we evaluated sleep onset latency (SLO), total sleep time (TST) and sleep efficiency (SE) daily. Additionally, participants who complained of vasomotor symptoms were invited to fill out a hot flashes form, reporting the presence or absence of these symptoms, daily amount, and its intensity. Results The therapeutic approaches in this study benefited participants in both groups in almost all domains of quality of life and self-rated sleep patterns such as TST and SE. Particularly, the lavender essential oil intervention provided significant improvement in the overall quality of life score over time. No differences were observed considering the hot flashes record and sleepiness. Conclusion The aromatherapy intervention was effective in improving overall quality of life in the Aroma group. Furthermore, strategies such as sleep hygiene and a sleep diary helped participants to self-assess their sleep routine and improve it. Support (if any) This research was supported by fellowships from Associação Fundo de Incentivo à Pesquisa (AFIP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) - Finance Code 001, and Conselho Nacional de Pesquisa (CNPq). Laszlo (essential oils, books, foods, and aromatherapy products) donated the necessary oils for this project.

Six multidimensional sleep health facets in older adults identified with factor analysis of actigraphy: Results from the Einstein Aging Study

ObjectivesThe concept of multi-dimensional sleep health, originally based on self-report, was recently extended to actigraphy in older adults, yielding five components, but without a hypothesized rhythmicity factor. The current study extends prior work using a sample of older adults with a longer period of actigraphy follow-up, which may facilitate observation of the rhythmicity factor. MethodsWrist actigraphy measures of participants (N = 289, Mage = 77.2 years, 67% females; 47% White, 40% Black, 13% Hispanic/Others) over 2 weeks were used in exploratory factor analysis to determine factor structures, followed by confirmatory factor analysis on a different subsample. The utility of this approach was demonstrated by associations with global cognitive performance (Montreal Cognitive Assessment). ResultsExploratory factor analysis identified six factors: Regularity: standard deviations of four sleep measures: midpoint, sleep onset time, night total sleep time (TST), and 24-hour TST; Alertness/Sleepiness (daytime): amplitude, napping (mins and #/day); Timing: sleep onset, midpoint, wake-time (of nighttime sleep); up-mesor, acrophase, down-mesor; Efficiency: sleep maintenance efficiency, wake after sleep onset; Duration: night rest interval(s), night TST, 24-hour rest interval(s), 24-hour TST; Rhythmicity (pattern across days): mesor, alpha, and minimum. Greater sleep efficiency was associated with better Montreal Cognitive Assessment performance (β [95% confidence interval] = 0.63 [0.19, 1.08]). ConclusionsActigraphic records over 2 weeks revealed that Rhythmicity may be an independent factor in sleep health. Facets of sleep health can facilitate dimension reduction, be considered predictors of health outcomes, and be potential targets for sleep interventions.

Sleep in Gerstmann-Straüssler-Scheinker disease

BackgroundGerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known in other prion diseases such as fatal familial insomnia and Creutzfeldt-Jakob disease, information on sleep is limited in GSS. MethodsWe evaluated sleep in three genetically confirmed GSS cases using clinical history, sleep scales and video-polysomnography. In addition, patients underwent neurological assessment, neurological scales, neuropsychological testing, lumbar puncture, brain MRI and brain 18F-FDG-PET. ResultsTwo patients reported sleep maintenance insomnia attributed to leg stiffness and back pain while the remaining patient did not report sleep problems. Video-polysomnography showed normal sleep staging in all of them. Findings such as reduced sleep efficiency in two patients, a confusional arousal in one patient, obstructive apneas in one patient, and periodic legs movements in sleep in two patients were observed. ConclusionsIn contrast to fatal familial insomnia, the normal sleep staging in GSS may suggest dissimilar involvement of the neuronal structures that regulate sleep. We found non-specific sleep alterations in GSS such as obstructive apneas and periodic leg movements in sleep which are of unknown origin and of uncertain clinical relevance. Studies including a larger number of patients, serial sleep evaluations and incorporating neuropathological assessment will further help to understand sleep in GSS.

Impairment in sleep health in young adults with chronic pain: a modifiable risk factor

BackgroundImpairments in sleep health are associated with the development or worsening of chronic pain. Further, chronic pain can cause sleep health disruption by impacting sleep onset, sleep maintenance, sleep quality, and causing daytime somnolence. However, the association between chronic pain and sleep disturbances in the young adult population is unclear.AimWe describe our initial experience in establishing and running a clinic for managing sleep health and chronic pain in young adults. We also describe the prevalence and the pattern of sleep disruption as well as its relationship with self-efficacy in pain management, depression, and quality of life in this cohort.MethodsAfter approval from the Institutional Review Ethics board, chart review and data extraction were conducted for patients who presented at the Young Adult Clinic (YAC) at Women’s College Hospital from March 1, 2018 to April 30, 2019.ResultsMedical charts of 55 patients were reviewed with the majority being females (71%). Chronic widespread pain was the most common pain syndrome diagnosed in our patients. Insomnia was the most common sleep-health related diagnosis in our patients. Patients with disorders of sleep were more likely to report lower self-efficacy for managing pain as compared to those with no sleep disorders (p = 0.023) but there was no significant difference between these two groups as regards risk for pain-related catastrophizing.ConclusionImpairments in sleep health may be an important modifiable risk factor for alleviating pain in young adults with chronic pain. Sleep disorders should be evaluated and addressed in this population.

Treatment strategy for insomnia disorder: Japanese expert consensus.

There is a lack of evidence regarding answers for clinical questions about treating insomnia disorder. This study aimed to answer the following clinical questions: (1) how to use each hypnotic and non-pharmacological treatment differently depending on clinical situations and (2) how to reduce or stop benzodiazepine hypnotics using alternative pharmacological and non-pharmacological treatments. Experts were asked to evaluate treatment choices based on 10 clinical questions about insomnia disorder using a nine-point Likert scale (1 = "disagree" to 9 = "agree"). The responses of 196 experts were collected, and the answers were categorized into first-, second-, and third-line recommendations. The primary pharmacological treatment, lemborexant (7.3 ± 2.0), was categorized as a first-line recommendation for sleep initiation insomnia, and lemborexant (7.3 ± 1.8) and suvorexant (6.8 ± 1.8) were categorized as the first-line recommendations for sleep maintenance insomnia. Regarding non-pharmacological treatments for primary treatment, sleep hygiene education was categorized as the first-line recommendation for both sleep initiation (8.4 ± 1.1) and maintenance insomnia (8.1 ± 1.5), while multicomponent cognitive behavioral therapy for insomnia was categorized as the second-line treatment for both sleep initiation (5.6 ± 2.3) and maintenance insomnia (5.7 ± 2.4). When reducing or discontinuing benzodiazepine hypnotics by switching to other medications, lemborexant (7.5 ± 1.8) and suvorexant (6.9 ± 1.9) were categorized as first-line recommendations. Expert consensus indicates that orexin receptor antagonists and sleep hygiene education are recommended as first-line treatments in most clinical situations to treat insomnia disorder.

Disturbance of sleep maintenance, but not sleep duration, activates nuclear factor-κB and signal transducer and activator of transcription family proteins in older adults: sex differences.

Disturbances of sleep maintenance and sleep duration are common in older adults and associated with an increased risk for age-related mortality and morbidity. Converging evidence implicates inflammation as an underlying mechanism, especially in females. However, it is unknown what specific aspects of sleep disturbance impact inflammatory mechanisms in older adults. Using data from community-dwelling older adults who participated in the Sleep Health and Aging Research (SHARE) field study (n = 262, mean age 71.9 ± 8.0 years), we conducted a secondary analysis to examine whether disturbance of sleep maintenance (i.e. greater amount of wake time after sleep onset [WASO]) and sleep duration (i.e. shorter total sleep time [TST]) assessed by sleep diary and actigraphy are associated with greater activation of nuclear factor (NF)-κB and signal transducer and activator of transcription (STAT) family proteins STAT1, STAT3, and STAT5 in peripheral blood monocytic cells. In addition, moderation effects of sex were explored. Data were available for sleep diary (n = 82), actigraphy (n = 74), and inflammatory signaling and transcriptional measures (n = 132). As assessed by sleep diary, greater amount of WASO (β = 0.39, p < 0.01), but not TST, was associated with higher levels of NF-κB. Whereas diary-assessed sleep measures were not associated with STAT family proteins, a moderation analysis revealed that greater diary-assessed WASO was associated with higher levels of STAT1 (p < 0.05), STAT3 (p < 0.05), and STAT5 (p < 0.01) in females, but not in males. Actigraphy-assessed sleep measures were not associated either with NF-κB or STAT activation. In older adults, self-reported disturbance of sleep maintenance assessed by sleep diary was uniquely associated with higher levels of NF-κB, along with higher levels of STAT family proteins in females, but not in males. Our data suggest that improvingself-reported sleep maintenance might mitigate age-related increases in inflammatory signaling and transcriptional pathways, possibly more strongly in females, with the potential to reduce mortality risk in older adults.

Why so slangry (sleepy and angry)? Shorter sleep duration and lower sleep efficiency predict worse next-day mood in adolescents.

The goal of this study was to evaluate the relationships of actigraphic nighttime sleep duration and quality with next-day mood among urban adolescents using a micro-longitudinal design. A subsample (N = 525) of participants from the Fragile Families & Child Wellbeing Study (mean age: 15.4 years; 53% female; 42% Black non-Hispanic, 24% Hispanic/Latino, 19% White non-Hispanic) in the United States between 2014 and 2016 concurrently wore a wrist actigraphic sleep monitor and rated their daily mood in electronic diaries for about 1 week. Multilevel models tested the within-person temporal associations of nightly sleep duration and sleep maintenance efficiency with next-day reports of happiness, anger, and loneliness. The models also tested the between-person associations of sleep variables and mood. Models adjusted for sociodemographic and household characteristics, weekend, and school year. After nights when adolescents obtained longer sleep duration than their usual, they reported lower ratings of anger (B = -.03, p < .01) the next day. After nights when adolescents had higher sleep maintenance efficiency than their usual, they reported higher ratings of happiness (B = .02, p < .01) the next day. Adolescents who had longer average sleep duration reported lower ratings of anger (B = -.08, p < .01) and loneliness (B = -.08, p < .01) compared to others. There was no within-person association of sleep duration or efficiency with loneliness. Sleep duration was not associated with happiness between adolescents, and sleep maintenance efficiency was not associated with any mood measure between adolescents. Improvements to nightly sleep may help increase happiness and decrease anger the following day in adolescents. Promoting sleep health is recommended to improve mood.

0600 Subjective reporting of Disrupted Nighttime Sleep and Associated Functional Outcomes in NT1 Youth

Abstract Introduction In people with NT1, Disrupted Nighttime sleep (DNS) can be measured using the Wake/N1 Index, the number of transitions from sleep to wake or N1 sleep per hour of sleep. However, it remains unknown if this DNS measure correlates with sleep quality and daytime symptom burden. We compared the Wake/N1 Index with perceptions of sleep quality in young NT1 patients and healthy controls (HC) and determined its relationships with subjective sleep quality, daytime behavior, and cognition across groups. Methods 25 HC (mean age 13.4 years) and 23 NT1 participants (mean age 15.8 years) completed a 15-item survey after sleeping a minimum of 6 hours during an in-lab polysomnogram. The survey included questions from validated surveys on habitual sleep quality, fatigue, sleepiness and cognitive function. We dichotomized survey responses into frequent or infrequent concerns. We compared responses using Fisher Exact tests and logistic regression to determine associations with the Wake/N1 Index. NT1 participants could take SSRI/SNRI medication for cataplexy but were weaned off wake-promoting medications and excluded if on an oxybate. Results Compared to HC, NT1 participants reported more frequent restless sleep, nighttime moaning/groaning/talking, tossing and turning, and waking more than once during the night (p’s &amp;lt; 0.02) and showed a trend for more leg kicking during sleep (p=0.06). NT1 and HC groups did not differ in falling asleep quickly and returning back to sleep quickly after waking. NT1 subjects reported more frequent fatigue, difficulty keeping thoughts focused, difficulty thinking clearly and making decisions, problems remembering things, and dozing/napping inadvertently. Across groups and controlling for age, the Wake/N1 Index was associated with subjective reporting of waking more than once (OR=3.2) as well as problems with daytime alertness (OR 1.5) and fatigue (OR 1.4). Conclusion Young NT1 patients describe DNS as a multi-factorial complaint comprising problems with sleep maintenance, restless sleep, parasomnia-like behaviors, and periodic limb movements. The Wake/N1 Index is associated with perceptions of waking at night as well as daytime alertness and fatigue across groups. This work suggests that Wake/N1 Index could be a useful measure of sleep instability and inform future research on DNS impact on daytime function. Support (if any) NIH 5K23NS104267-2, Jazz Pharmaceuticals

0679 Do Individuals with ADHD and Sleep Disorders Symptoms Exhibit Worse Executive Function?

Abstract Introduction Sleep disorders in individuals with Attention Deficit Hyperactivity Disorder (ADHD) are more prevalent than in people without ADHD. Given that sleep disorders (e.g., insomnia and OSA) impact daytime function (e.g., mood, memory, motivation, attention, executive function [EF], etc.), it is reasonable to wonder if these domains interact. Thus, the aim of the present analysis was to evaluate subjects diagnosed with ADHD who were also symptomatic for insomnia or OSA on a self-report measure of executive function. The hypothesis for the analysis being: subjects with insomnia would show more severe executive function deficits as compared to subjects without symptoms of insomnia and/or subjects with OSA. Methods This analysis includes data from 149 subjects diagnosed with ADHD (38% female, Mage 32.8±13.2yrs). Sleep disorder and EF data was provided by the Penn ADHD Treatment and Research Program. Database assessments were gathered from intakes, which included the SDS-CL-25 (a comprehensive screener for sleep disorders) and the BDEFS-LF (a self-report measure of EF deficit). In order to type individuals as “symptom positive” for insomnia or OSA, subjects were required to score &amp;gt;3 for any item within each category. These groups were then compared for their scores on the BDEFS-LF (total score and for three factor scores: self-restraint score [BDEFS-SR], self-regulation of emotions score [BDEFS-SRM], and self-motivation score [BDEFS-SM]). Results Subjects with-and-without insomnia symptoms were not found to significantly differ on the BDEFS-T, or any of the three sub-scales. In contrast, subjects with-and-without OSA symptoms significantly differed on the BDEFS-T (p=0.0328), and on two of the three sub-scales (BDEFS-SR [p=0.0183] &amp; BDEFS-SRM [p=0.0032]). Conclusion Contrary to our hypothesis, it was the symptom positive OSA group that showed the most deficits on executive function (as measured by the BDEFS-T). This suggests that, in people with ADHD, sleep fragmentation and/or hypoxia may be more associated with EF deficits than problems with sleep initiation or maintenance. This said, it is also possible that other measures of insomnia that better represent sleep insufficiency and/or total nocturnal wakefulness may be more associated with executive functioning deficits, alone or in combination with the sleep sequela of OSA. Support (if any)

0105 INSIGHT Study associations between sleep health and child behavior at age 6 years

Abstract Introduction Sub-optimal sleep duration, quality and timing are associated with the presence of disruptive behaviors in childhood. Previous studies have largely utilized parent-/teacher-report of children’s behaviors and focused on mean sleep duration and quality measures, ignoring sleep variability. This analysis uses actigraphy and standardized laboratory behavioral tasks to examine the associations of average levels and variability (SD) of sleep duration, timing, and quality with child behavior. Methods The Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) Study randomized families with firstborn newborns to a responsive parenting intervention or a safety control shortly after delivery. At age 6 years, children wore a wrist actigraphy device (Spectrum Plus) for 7 days to measure sleep and completed frustration (Transparent Box) and parent-child interaction (Picture Frame) tasks. Tasks were recorded and coded using global behavioral coding schemes; inter-rater reliability was sufficient (Transparent Box ICCs=.83-.97; Picture Frame=.83-1). Children with data on sleep (≥3 valid days) and both behavioral tasks were included in this secondary data analysis (n=143). Separate linear regression models examined associations between 10 sleep variables (M/SD of onset, offset, and midpoint of sleep timing, sleep maintenance efficiency, and total sleep time) and 4 behavioral variables (Transparent Box: emotion regulation, impulsivity; Picture Frame: prosocial and antisocial behavior). Models controlled for child sex and age, household income, and study group. Results Children were aged 6.7 ± 0.3 years and predominantly White, non-Hispanic (95%). Sleep onset (timing) variability was positively associated with impulsivity (B=.85, p=.004) and negatively associated with emotion regulation (B=-.65, p=.01). Sleep midpoint (timing) variability was positively associated with impulsivity (B=.80, p=.03). Mean sleep timing, sleep duration, and sleep maintenance efficiency were not associated with any of the behavioral variables. Conclusion The regularity of sleep timing (onset and midpoint) at age 6 had a greater role in behavioral and emotional regulation than duration and quality of sleep. These findings support existing literature that highlight the importance of parents implementing consistent routines (e.g., consistent bedtime) and how such routines play a key role in socioemotional outcomes among children. Support (if any) R01DK088244

Structure and Function of Neuronal Circuits Linking Ventrolateral Preoptic Nucleus and Lateral Hypothalamic Area.

To understand how sleep-wakefulness cycles are regulated, it is essential to disentangle structural and functional relationships between the preoptic area (POA) and lateral hypothalamic area (LHA), since these regions play important yet opposing roles in the sleep-wakefulness regulation. GABA- and galanin (GAL)-producing neurons in the ventrolateral preoptic nucleus (VLPO) of the POA (VLPOGABA and VLPOGAL neurons) are responsible for the maintenance of sleep, while the LHA contains orexin-producing neurons (orexin neurons) that are crucial for maintenance of wakefulness. Through the use of rabies virus-mediated neural tracing combined with in situ hybridization (ISH) in male and female orexin-iCre mice, we revealed that the vesicular GABA transporter (Vgat, Slc32a1)- and galanin (Gal)-expressing neurons in the VLPO directly synapse with orexin neurons in the LHA. A majority (56.3 ± 8.1%) of all VLPO input neurons connecting to orexin neurons were double-positive for Vgat and Gal Using projection-specific rabies virus-mediated tracing in male and female Vgat-ires-Cre and Gal-Cre mice, we discovered that VLPOGABA and VLPOGAL neurons that send projections to the LHA received innervations from similarly distributed input neurons in many brain regions, with the POA and LHA being among the main upstream areas. Additionally, we found that acute optogenetic excitation of axons of VLPOGABA neurons, but not VLPOGAL neurons, in the LHA of male Vgat-ires-Cre mice induced wakefulness. This study deciphers the connectivity between the VLPO and LHA, provides a large-scale map of upstream neuronal populations of VLPO→LHA neurons, and reveals a previously uncovered function of the VLPOGABA→LHA pathway in the regulation of sleep and wakefulness.SIGNIFICANCE STATEMENT We identified neurons in the ventrolateral preoptic nucleus (VLPO) that are positive for vesicular GABA transporter (Vgat) and/or galanin (Gal) and serve as presynaptic partners of orexin-producing neurons in the lateral hypothalamic area (LHA). We depicted monosynaptic input neurons of GABA- and galanin-producing neurons in the VLPO that send projections to the LHA throughout the entire brain. Their input neurons largely overlap, suggesting that they comprise a common neuronal population. However, acute excitatory optogenetic manipulation of the VLPOGABA→LHA pathway, but not the VLPOGAL→LHA pathway, evoked wakefulness. This study shows the connectivity of major components of the sleep/wake circuitry in the hypothalamus and unveils a previously unrecognized function of the VLPOGABA→LHA pathway in sleep-wakefulness regulation. Furthermore, we suggest the existence of subpopulations of VLPOGABA neurons that innervate LHA.

Effect of Lemborexant on Early Morning Awakening in Elderly Subjects with Severe Problems with Waking Too Early (S6.010)

<h3>Objective:</h3> Evaluate treatment with lemborexant (LEM) in subjects age ≥65y reporting “problems waking up too early” on the Insomnia Severity Index (ISI) Item-3 as assessed by wake after sleep onset in the second half of the night (WASO2H). <h3>Background:</h3> LEM is a competitive dual orexin receptor antagonist approved in several countries for the treatment of adults with insomnia. In Study 304 (NCT02783729), LEM improved sleep onset and sleep maintenance as measured by WASO2H. <h3>Design/Methods:</h3> Study 304 was a 1-month, placebo (PBO)-controlled and active-comparator (zolpidem extended-release 6.25mg [ZOL]) study of LEM 5mg (LEM5) and 10mg (LEM10). Subjects whose baseline ISI Item-3 scores were ≥3 (severe/very severe) and were age ≥65y were included in this post-hoc analysis. WASO2H was measured at Nights 1/2 (NT1/2) and 29/30 (NT29/30) using polysomnography and averaged across consecutive nights. <h3>Results:</h3> “Early morning awakening” treatment groups were LEM5 (n=68), LEM10 (n=53), ZOL (n=60) and PBO (n=48). Baseline WASO2H (minutes) mean (SD) ranged from 83.7–91.1 (30.9–41.0) across treatment groups. In these subjects, by NT1/2, WASO2H mean (SD) change from baseline improved significantly with LEM5 (−42.4[37.1]) and LEM10 (−45.2[31.4]) versus both ZOL (−22.3[36.7]) and PBO (−9.5[31.4]; all P&lt;0.001). Improvements were maintained through NT29/30: LEM5 (−33.4[38.9]), LEM10 (−34.4[31.7]), ZOL (−18.46[32.5]), and PBO (−10.4 [32.5]) (LEM5 and LEM10: P&lt;0.05 versus ZOL and P&lt;0.001 versus PBO). ISI Item-3 decreased (improved) from 4 (“very severe”) at baseline to 0 (“no problem”) or 1 (“mild problem”) at NT29/30 in a greater percentage of subjects receiving LEM (LEM5, 56%; LEM10, 50%) versus ZOL (25%) or PBO (33%). <h3>Conclusions:</h3> Treatment with LEM provided significant improvement in WASO2H compared with ZOL and PBO at both NT1/2 and NT29/30 in subjects aged ≥65y with severe/very severe problems waking too early. Improvements reported for ISI Item-3 for LEM-treated subjects support this benefit. <b>Disclosure:</b> Dr. Lundwall has received personal compensation for serving as an employee of Eisai. Margaret Moline has received personal compensation for serving as an employee of EISAI, INC.. Margaret Moline has received intellectual property interests from a discovery or technology relating to health care. Margaret Moline has received personal compensation in the range of $0-$499 for serving as a review, loan repayment program with NIH. Dr. Zee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi-Aventis. Dr. Zee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Harmony Biosciences. Dr. Zee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz Pharmaceuticals Inc.. Dr. Zee has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. The institution of Dr. Zee has received research support from National Institutes of Health. The institution of Dr. Zee has received research support from Vanda. Dr. Zee has received intellectual property interests from a discovery or technology relating to health care. Dr. Zee has received intellectual property interests from a discovery or technology relating to health care. Dr. Zee has received publishing royalties from a publication relating to health care. Dinesh Kumar has received personal compensation for serving as an employee of Eisai. Dr. Pappadopulos has received personal compensation for serving as an employee of Eisai Inc.

Lemborexant (Dayvigo)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses lemborexant (Dayvigo), 5 mg per tablet and 10 mg per tablet, oral.&#x0D; Indication: For the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.&#x0D;

Chronic Sleep Disturbances Alters Sleep Structure and Tau Phosphorylation in AβPP/PS1 AD Mice and Their Wild-Type Littermates.

Emerging evidence indicates that sleep disorders are the common non-cognitive symptoms of Alzheimer's disease (AD), and they may contribute to the pathogenesis of this disease. In this study, we aim to investigate the effect of chronic sleep deprivation (CSD) on AD-related pathologies with a focus on tau phosphorylation and the underlying DNA methylation regulation. AβPPswe/PS1ΔE9 AD mice and their wild-type (WT) littermates were subjected to a two-month CSD followed by electroencephalography and electromyography recording. The mice were examined for learning and memory evaluation, then pathological, biochemical, and epigenetic assessments including western blotting, immunofluorescence, dot blotting, and bisulfite sequencing. The results show that CSD caused sleep disturbances shown as sleep pattern change, poor sleep maintenance, and increased sleep fragmentation. CSD increased tau phosphorylation at different sites and increased the level of tau kinases in AD and WT mice. The increased expression of cyclin-dependent kinase 5 (CDK5) may result from decreased DNA methylation of CpG sites in the promoter region of CDK5 gene, which might be associated with the downregulation of DNA methyltransferase 3A and 3B. CSD altered AD-related tau phosphorylation through epigenetic modification of tau kinase gene. The findings in this study may give insights into the mechanisms underlying the effects of sleep disturbances on AD pathology and provide new therapeutic targets for the treatment of this disease.