P054 The effect of head up bed-tilt (HUT) on sleep disordered breathing (SDB) in patients with supine dominant sleep apnoea (SDOSA): an exploratory study

SDB severity is reduced in SDOSA when posture changes from supine to lateral. Sleeping with a head up bed-tilt(HUT) is known to reduce SDB in some OSA patients. In this exploratory study, we tested whether HUT could be used to reduce SDB in SDOSA patients who had refused continuous positive airway pressure therapy(CPAP). We studied 5 male patients (age: 60 to 72years, BMI: 25.8 to 32.2kg/m2). Standard, in-laboratory, overnight-polysomnography was performed (Compumedics Ltd, Australia). Posture was monitored, but not restricted, and bed position was set at horizontal(HB) for half the night and at 7° HUT for the remainder (randomised). Polysomnograms were scored by a sleep technician using AASM criteria. SDB severity was quantified using the apnoea hypopnoea index(AHI) and apnoea index(AI). For this analysis, we focus on periods of supine, stage 2 sleep (S2S) only. Participants spent 23 to 60minutes (range) in S2S with HB and 11 to 36minutes with HUT. AHI was 49 to 138events/hr with HB and 24 to 120events/hr with HUT, representing a fall of 2 to 62events/hr across all patients. AI was 19 to 111events/hr with HB and 0 to 48 events/hr with HUT, a fall of 15 to 96events/hr across all patients. In these CPAP non-compliant, SDOSA patients, S2S in HUT was associated with a reduction in SDB severity that varied between individuals. Notably apnoeic events were reduced in all patients and eliminated in two patients. We conclude that HUT warrants further investigation as a potential alternative therapy for SDOSA patients intolerant of CPAP.

Sleep During Menopausal Transition: A 10-year Follow-Up

Study Objectives A 10-year observational follow-up study to evaluate the changes in sleep architecture during menopausal transition. Methods Fifty-seven premenopausal women (mean age 46 years, SD 0.9) were studied at baseline and after a 10-year follow-up. At both time points, polysomnography (PSG) was performed, and the serum follicle-stimulating hormone (S-FSH) concentration measured. Linear regression models were used to study the effects of aging and menopause (assessed as change in S-FSH) on sleep. Results After controlling for body mass index, vasomotor, and depressive symptoms, higher S-FSH level was associated with longer sleep latency (B 0.45, 95 % CI 0.07 to 0.83). Aging of 10 years was associated with shorter sleep latency (B -46.8, 95 % CI -77.2 to -16.4), shorter latency to stage 2 sleep (B -50.6, 95 % CI -85.3 to -15.9), decreased stage 2 sleep (B -12.4, 95 % CI -21.4 to -3.4) and increased slow wave sleep (B 12.8, 95 % CI 2.32 to 23.3) after controlling for confounding factors. Conclusions This study suggests that PSG measured sleep of middle-aged women does not worsen over a 10-year time span due to menopausal transition. The observed changes seem to be rather age- than menopause-dependent.

Oral Dexmedetomidine Promotes Non-rapid Eye Movement Stage 2 Sleep in Humans

Background The administration of dexmedetomidine is limited to highly monitored care settings because it is only available for use in humans as intravenous medication. An oral formulation of dexmedetomidine may broaden its use to all care settings. The authors investigated the effect of a capsule-based solid oral dosage formulation of dexmedetomidine on sleep polysomnography. Methods The authors performed a single-site, placebo-controlled, randomized, crossover, double-blind phase II study of a solid oral dosage formulation of dexmedetomidine (700 mcg; n = 15). The primary outcome was polysomnography sleep quality. Secondary outcomes included performance on the motor sequence task and psychomotor vigilance task administered to each subject at night and in the morning to assess motor memory consolidation and psychomotor function, respectively. Sleep questionnaires were also administered. Results Oral dexmedetomidine increased the duration of non-rapid eye movement (non-REM) stage 2 sleep by 63 (95% CI, 19 to 107) min (P = 0.010) and decreased the duration of rapid eye movement (REM) sleep by 42 (5 to 78) min (P = 0.031). Overnight motor sequence task performance improved after placebo sleep (7.9%; P = 0.003) but not after oral dexmedetomidine–induced sleep (–0.8%; P = 0.900). In exploratory analyses, we found a positive correlation between spindle density during non-REM stage 2 sleep and improvement in the overnight test performance (Spearman rho = 0.57; P = 0.028; n = 15) for placebo but not oral dexmedetomidine (Spearman rho = 0.04; P = 0.899; n = 15). Group differences in overnight motor sequence task performance, psychomotor vigilance task metrics, and sleep questionnaires did not meet the threshold for statistical significance. Conclusions These results demonstrate that the nighttime administration of a solid oral dosage formulation of dexmedetomidine is associated with increased non-REM 2 sleep and decreased REM sleep. Spindle density during dexmedetomidine sleep was not associated with overnight improvement in the motor sequence task. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

0951 Sleep Stabilization Patterns Define Pediatric CNS Hypersomnia Conditions

Introduction Narcolepsy type 1 (NT1) is caused by loss of hypocretins, neuropeptides that promote consolidated nocturnal sleep and sustain daytime wakefulness. In mouse models of NT1, sleep in the light period is characterized by more brief wake bouts, fewer long wake bouts, and longer REM sleep bouts. It is unknown if this sleep pattern is present in NT1 patients and whether it can distinguish NT1 sleep from other CNS hypersomnia conditions [narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH)]. Methods Participants (6-18 years of age, drug -naïve or drug free) had diagnostic PSG/MSLT testing at Boston Children’s Hospital between 2009-2018. PSG records were rescored blinded to diagnosis. We calculated Kaplan Meier survival curves for nocturnal wake and sleep stages extracted from the nocturnal PSGs. To adjust for differences in survival related to age, sex, and race, we used Cox proportional hazards models. In total, we performed survival analysis and compared wake/sleep stages for 4 groups: NT1 (n=46), NT2 (n=12), IH (n=18) and subjective sleepy controls (n=48). Results NT1 patients had worse survival of wake bouts compared to controls (p<0.001). In addition, NT1 patients had decreased survival of both NREM 2 and REM sleep bouts compared to all groups (all p<0.001), and, the survival of REM sleep bouts decreased with age (p=0.006). Compared to controls, NREM 2 bouts survived longer in IH patients and whereas NREM 1 bouts survived longer in the NT2 group (p’s<0.006). There were no group effects for NREM 3, but survival of NREM 3 was less in the older IH patients compared to older controls (p<0.02). Conclusion Pediatric NT1 patients have unique sleep fragmentation characterized by unstable wake, NREM 2 and REM bouts. Though less severe as NT1, NT2 patients sustain lighter sleep. In contrast, IH patients show overly stable NREM stage 2 sleep and plausibly this contributes to their characteristic sleep inertia. Further research is needed to determine if sleep stability patterns can be used to diagnose CNS hypersomnia conditions and differentiate treatment responsiveness. Support K23 National Institutes of Health (NINDS, K23 NS104267-01A1) and Investigator Initiated Research grants from Jazz Pharmaceuticals, Inc. (Dr. Maski)

1008 Brain Age Based on Sleep Encephalography is Elevated in HIV+ Adults on ART

Introduction Sleep EEG is a promising tool to measure brain aging in vulnerable populations such as people with HIV, who are high risk of brain aging due to co-morbidities, increased inflammation, and antiretroviral neurotoxicity. Our lab previously developed a machine learning model that estimates age from sleep EEG (brain age, BA), which reliably predicts chronological age (CA) in healthy adults. The difference between BA and CA, the brain age index (BAI), independently predicts mortality, and is increased by cardiovascular co-morbidities. Here, we assessed BAI in HIV+ compared to matched HIV- adults. Methods Sleep EEGs from 43 treated HIV+ adults were gathered and matched to controls (HIV-, n=284) by age, gender, race, alcoholism, smoking and substance use history. We compared BAI between groups and used additional causal interference methods to ensure robustness. Individual EEG features that underlie BA prediction were also compared. We performed a sub-analysis of BAI between HIV+ with or without a history of AIDS. Results After matching, mean CA of HIV+ vs HIV- adults were 49 and 48 years, respectively (n.s.). The mean HIV+ BAI was 3.04 years higher than HIV- (4.4 vs 1.4 yr; p=0.048). We found consistent and significant results with alternative causal inference methods. Several EEG features predictive of BA were different in the HIV+ and HIV- cohorts. Most notably, non-REM stage 2 sleep (N2) delta power (1-4Hz) was decreased in HIV+ vs. HIV- adults, while theta (4-8Hz) and alpha (8-12Hz) power were increased. Those with AIDS (n=19, BAI=4.40) did not have significantly different BAI than HIV+ without AIDS (n=23, BAI=5.22). HIV+ subjects had higher rates of insomnia (56% vs 29%, p<0.001), obstructive apnea (47% vs 30%, p=0.03), depression (49% vs 23%, p<0.001), and bipolar disorder (19% vs 4%, p<0.001). Conclusion HIV+ individuals on ART have excess sleep-EEG based brain age compared to matched controls. This excess brain age is partially due to reduction in delta power during N2, suggesting decreased sleep depth. These results suggest sleep EEG could be a valuable brain aging biomarker for the HIV population. Support This research is supported by the Harvard Center for AIDS Research HU CFAR NIH/NIAID 5P30AI060354-16.

Abnormal Sleep Spindles, Memory Consolidation, and Schizophrenia

There is overwhelming evidence that sleep is crucial for memory consolidation. Patients with schizophrenia and their unaffected relatives have a specific deficit in sleep spindles, a defining oscillation of non-rapid eye movement (NREM) Stage 2 sleep that, in coordination with other NREM oscillations, mediate memory consolidation. In schizophrenia, the spindle deficit correlates with impaired sleep-dependent memory consolidation, positive symptoms, and abnormal thalamocortical connectivity. These relations point to dysfunction of the thalamic reticular nucleus (TRN), which generates spindles, gates the relay of sensory information to the cortex, and modulates thalamocortical communication. Genetic studies are beginning to provide clues to possible neurodevelopmental origins of TRN-mediated thalamocortical circuit dysfunction and to identify novel targets for treating the related memory deficits and symptoms. By forging empirical links in causal chains from risk genes to thalamocortical circuit dysfunction, spindle deficits, memory impairment, symptoms, and diagnosis, future research can advance our mechanistic understanding, treatment, and prevention of schizophrenia.