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STUDY OBJECTIVES: Sleep spindles, a defining feature of stage N2 sleep, are maximal at central electrodes and are found in the frequency range of the electroencephalogram (EEG) (sigma 11-16 Hz) that is known to be heritable. However, relatively little is known about the heritability of spindles. Two recent studies investigating the heritability of spindles reported moderate heritability, but with conflicting results depending on scalp location and spindle type. The present study aimed to definitively assess the heritability of sleep spindle characteristics. METHODS: We utilized the polysomnography data of 58 monozygotic and 40 dizygotic same-sex twin pairs to identify heritable characteristics of spindles at C3/C4 in stage N2 sleep including density, duration, peak-to-peak amplitude, and oscillation frequency. We implemented and tested a variety of spindle detection algorithms and used two complementary methods of estimating trait heritability. RESULTS: We found robust evidence to support strong heritability of spindles regardless of detector method (h2 > 0.8). However not all spindle characteristics were equally heritable, and each spindle detection method produced a different pattern of results. CONCLUSIONS: The sleep spindle in stage N2 sleep is highly heritable, but the heritability differs for individual spindle characteristics and depends on the spindle detector used for analysis.
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Eletroencefalografia , Fases do Sono , Algoritmos , Polissonografia , SonoRESUMO
BACKGROUND: Extreme phenotypes of OSA have not been systematically defined. RESEARCH QUESTION: This study developed objective definitions of extreme phenotypes of OSA by using a multivariate approach. The utility of these definitions for identifying characteristics that confer predisposition toward or protection against OSA is shown in a new prospective sample. STUDY DESIGN AND METHODS: In a large international sample, race-specific liability scores were calculated from a weighted logistic regression that included age, sex, and BMI. Extreme cases were defined as individuals with an apnea-hypopnea index (AHI) ≥ 30 events/hour but low likelihood of OSA based on age, sex, and BMI (liability scores > 90th percentile). Similarly, extreme controls were individuals with an AHI < 5 events/hour but high likelihood of OSA (liability scores < 10th percentile). Definitions were applied to a prospective sample from the Sleep Apnea Global Interdisciplinary Consortium, and differences in photography-based craniofacial and intraoral phenotypes were evaluated. RESULTS: This study included retrospective data from 81,338 individuals. A total of 4,168 extreme cases and 1,432 extreme controls were identified by using liability scores. Extreme cases were younger (43.1 ± 14.7 years), overweight (28.6 ± 6.8 kg/m2), and predominantly female (71.1%). Extreme controls were older (53.8 ± 14.1 years), obese (34.0 ± 8.1 kg/m2), and predominantly male (65.8%). These objective definitions identified 29 extreme cases and 87 extreme controls among 1,424 Sleep Apnea Global Interdisciplinary Consortium participants with photography-based phenotyping. Comparisons suggest that a greater cervicomental angle increases risk for OSA in the absence of clinical risk factors, and smaller facial widths are protective in the presence of clinical risk factors. INTERPRETATION: This objective definition can be applied in sleep centers throughout the world to consistently define OSA extreme phenotypes for future studies on genetic, anatomic, and physiologic pathways to OSA.
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Apneia Obstrutiva do Sono/classificação , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Fenótipo , Fotografação , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Apneia Obstrutiva do Sono/etnologiaRESUMO
Study Objectives: A recent study of patients with moderate-severe obstructive sleep apnea (OSA) in Iceland identified three clinical clusters based on symptoms and comorbidities. We sought to verify this finding in a new cohort in Iceland and examine the generalizability of OSA clusters in an international ethnically diverse cohort. Methods: Using data on 972 patients with moderate-severe OSA (apnea-hypopnea index [AHI] ≥ 15 events per hour) recruited from the Sleep Apnea Global Interdisciplinary Consortium (SAGIC), we performed a latent class analysis of 18 self-reported symptom variables, hypertension, cardiovascular disease, and diabetes. Results: The original OSA clusters of disturbed sleep, minimally symptomatic, and excessively sleepy replicated among 215 SAGIC patients from Iceland. These clusters also generalized to 757 patients from five other countries. The three clusters had similar average AHI values in both Iceland and the international samples, suggesting clusters are not driven by OSA severity; differences in age, gender, and body mass index were also generally small. Within the international sample, the three original clusters were expanded to five optimal clusters: three were similar to those in Iceland (labeled disturbed sleep, minimal symptoms, and upper airway symptoms with sleepiness) and two were new, less symptomatic clusters (labeled upper airway symptoms dominant and sleepiness dominant). The five clusters showed differences in demographics and AHI, although all were middle-aged (44.6-54.5 years), obese (30.6-35.9 kg/m2), and had severe OSA (42.0-51.4 events per hour) on average. Conclusions: Results confirm and extend previously identified clinical clusters in OSA. These clusters provide an opportunity for a more personalized approach to the management of OSA.
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Internacionalidade , Apneia Obstrutiva do Sono/classificação , Apneia Obstrutiva do Sono/diagnóstico , Adulto , Idoso , Índice de Massa Corporal , Doenças Cardiovasculares/classificação , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Análise por Conglomerados , Estudos de Coortes , Comorbidade , Diabetes Mellitus/classificação , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Distúrbios do Sono por Sonolência Excessiva/classificação , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/epidemiologia , Feminino , Humanos , Hipertensão/classificação , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Apneia Obstrutiva do Sono/epidemiologiaRESUMO
Study objectives: Debate persists as to whether obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. The purpose of this study was to compare carotid intima-media thickness (IMT), an early sign of atherosclerosis, in obese and nonobese adults with OSA before and following positive airway pressure (PAP) treatment. Methods: A total of 206 adults newly diagnosed with OSA with an apnea-hypopnea index (AHI) of 15-75 events/hour and 53 controls with AHI <10 were studied. Waist circumference was used to classify participants as obese and nonobese. Bilateral common carotid artery B-mode ultrasound was performed at baseline to assess IMT, arterial diameter, arterial-wall mass, and circumferential wall stress. Measurements were repeated in 118 participants with OSA who completed a 4-month PAP treatment and had an average daily use over that period of ≥4 hours/day. Results: No significant differences in carotid IMT, diameter, or arterial-wall mass were present at baseline between participants with OSA and controls stratified by waist circumference, after adjusting for other cardiovascular risk factors. In participants with OSA, who had adequate PAP adherence over the 4-month treatment, carotid artery diameter significantly increased (mean change [95% confidence interval] = 0.13 [0.06, 0.20] mm; p = .0004), but no significant changes in carotid IMT, arterial-wall mass, and circumferential stress were observed in obese and nonobese participants. Conclusions: Regardless of obesity status, carotid IMT is not increased in adults with moderate to severe OSA versus controls and does not change following 4 months of PAP treatment.
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Artérias Carótidas , Espessura Intima-Media Carotídea , Obesidade/complicações , Respiração com Pressão Positiva , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/terapia , Adulto , Idoso , Aterosclerose/complicações , Aterosclerose/fisiopatologia , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Fatores de Risco , Apneia Obstrutiva do Sono/fisiopatologia , Circunferência da CinturaRESUMO
Introduction: In mammals, there is evidence that glutamate has a role as a wake-active neurotransmitter. So using video-based analysis of Drosophila behavior, we undertook a study to examine if glutamate, which has been previously shown to have an excitatory role in neuromuscular junctions in Drosophila, may have a conserved wake-active role in the adult brain. Aims and Methods: Using 6- to 9-day-old female flies, we examined the effect of perturbations of the glutamatergic signaling on total wakefulness and wake bout architecture. We increased and decreased neuronal activity of glutamatergic neurons in the brains of adult flies using Upstream Activating Sequence (UAS) NaChBac and UAS EKO, respectively. We blocked neurotransmission from glutamatergic neurons in adult flies using the UAS-driven temperature-sensitive dynamin mutation shibirets. We examined the behavior of flies with loss of function mutations of individual subunits of brain-specific ionotropic glutamate receptors. Results: Increasing the activity of glutamatergic neurons in the adult brain led to a significant increase in wakefulness compared to the control groups both in the daytime and nighttime and decreasing the activity of these same neurons reduced wakefulness in the nighttime. Blocking neurotransmitter release in glutamatergic neurons significantly reduced wake in the nighttime. The ionotropic receptor mutants had significantly less wake in the nighttime than their respective genetic background controls. Conclusion: The results show the following: glutamate is indeed a wake-active neurotransmitter in Drosophila; there is a major time of day effect associated with loss of glutamatergic neurotransmission; and it is a major wake-active neurotransmitter in the nighttime.
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Drosophila melanogaster/fisiologia , Ácido Glutâmico/fisiologia , Neurotransmissores/fisiologia , Sono/fisiologia , Vigília/fisiologia , Animais , Animais Geneticamente Modificados , Encéfalo/fisiologia , Feminino , Locomoção/fisiologia , Mutação/fisiologia , Neurônios/fisiologia , Transdução de Sinais/fisiologia , Gravação em VídeoRESUMO
Objectives: To determine if the large and highly reproducible interindividual differences in arousal intensity and heart rate response to arousal (ΔHR) during non-REM sleep are heritable. Methods: Polysomnograms of 55 monozygotic (14 male and 41 female pairs) and 36 dizygotic (15 male and 21 female pairs) same-sex twin pairs were analyzed. Arousals were scored using the 2012 American Academy of Sleep Medicine criteria. Arousal intensity was scaled (between 0 and 9) using an automatic algorithm based on the change in electroencephalogram time and frequency characteristics. The ΔHR was determined at each arousal. We calculated average arousal duration, average arousal intensity, average overall ΔHR, average ΔHR at a given arousal intensity, slope of ΔHR per arousal intensity, and arousal intensity threshold of ΔHR. Results: The intraclass correlations among monozygotic and dizygotic twin pairs were 0.663 and 0.146, respectively, for average arousal intensity, and 0.449 and 0, respectively, for arousal intensity threshold of ΔHR controlling for age, sex, and race. These values imply large broad sense heritability (H2) for these traits. This evidence was confirmed by a robust maximum likelihood-based variance components estimation approach, with an additive genetic heritability of 0.64 (95% confidence interval: 0.48 to 0.80) for average arousal intensity and a combined additive and dominance genetic heritability and of 0.46 (0.25 to 0.68) for arousal intensity threshold of ΔHR. Results also suggested significant additive genetic effects for average arousal duration, ΔHR at arousal intensity scale 4 and the overall average ΔHR. Conclusion: Genetic factors explain a significant fraction of the phenotypic variability for average arousal intensity and arousal intensity threshold of ΔHR. Results suggest that the duration of arousals and specific average ΔHR values may also be heritable traits. Clinical trial registration: NCT02827461.
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Nível de Alerta/fisiologia , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Gêmeos Monozigóticos/genética , Adulto , Algoritmos , Nível de Alerta/genética , Eletroencefalografia , Feminino , Humanos , Funções Verossimilhança , Masculino , Fenótipo , PolissonografiaRESUMO
OBJECTIVES: Accumulating evidence has shown that there is a genetic contribution to obstructive sleep apnea (OSA).The objectives were to use magnetic resonance imaging (MRI) cephalometry to (1) confirm heritability of craniofacial risk factors for OSA previously shown by cephalometrics; and (2) examine the heritability of new craniofacial structures that are measurable with MRI. DESIGN: A sib pair "quad" design examining apneics, apneic siblings, controls, and control siblings. The study design used exact matching on ethnicity and sex, frequency matching on age, and statistical control for differences in age, sex, ethnicity, height, and weight. SETTING: Academic medical center. PATIENTS: We examined 55 apneic probands (apnea-hypopnea index [AHI]: 46.8 ± 33.5 events/h), 55 proband siblings (AHI: 11.1 ± 15.9 events/h), 55 controls (AHI: 2.2 ± 1.7 events/h), and 55 control siblings (AHI: 4.1 ± 4.0 events/h). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Five independent domains reflecting different aspects of the craniofacial structure were examined. We confirmed heritability of sella-nasion-subspinale (38%, P = 0.002), saddle angle (55%, P < 0.0001), mandibular length (24%, P = 0.02) and lower facial height (33%, P = 0.006) previously measured by cephalometry. In addition, the current study added new insights by demonstrating significant heritability of mandibular width (30%, P = 0.005), maxillary width (47%, P < 0.0001), distance from the hyoid bone to the retropogonion (36%, P = 0.0018) and size of the oropharyngeal space (31%, P = 0.004). Finally, our data indicate that heritability of the craniofacial structures is similar in normal patients and those with apnea. CONCLUSIONS: The data support our a priori hypothesis that the craniofacial structures that have been associated with obstructive sleep apnea (OSA) are heritable. We have demonstrated heritability for several intermediate craniofacial phenotypes for OSA. Thus, we believe that future studies should be able to identify genes associated with these intermediate craniofacial phenotypes.