DMSO potentiates the suppressive effect of dronabinol on sleep apnea and REM sleep in rats.

INTRODUCTION: Dimethyl sulfoxide (DMSO) is an amphipathic molecule with innate biological activity that also is used to dissolve both polar and nonpolar compounds in preclinical and clinical studies. Recent investigations of dronabinol, a cannabinoid, dissolved in DMSO demonstrated decreased sleep apnea frequency and time spent in REM sleep in rats. Here, we tested the effects of dronabinol dissolved in 25% DMSO diluted in phosphate-buffered saline (PBS) to rule out potentiating effects of DMSO. METHODS: Sprague-Dawley rats were anesthetized and implanted with bilateral stainless steel screws into the skull for electroencephalogram recording and bilateral wire electrodes into the nuchal muscles for electromyogram recording. Each animal was recorded by polysomnography. The study was a fully nested, repeated measures crossover design, such that each rat was recorded following each of 8 intraperitoneal injections separated by three days: vehicle (25% DMSO/PBS); vehicle and CB1 antagonist (AM 251); vehicle and CB2 antagonist (AM 630); vehicle and CB1/CB2 antagonist; dronabinol (CB1/CB2 agonist); dronabinol and CB1 antagonist; dronabinol and CB2 antagonist; and dronabinol and CB1/CB2 antagonists. Sleep was manually scored into NREM and REM stages, and sleep apneas were quantified. RESULTS: Dronabinol dissolved in 25% DMSO did not suppress sleep apneas or modify sleep efficiency compared to vehicle controls, in contrast to previously published results. However, dronabinol did suppress REM sleep, which is in line with previously published results. CONCLUSIONS: Dronabinol in 25% DMSO partially potentiated dronabinol's effects, suggesting a concomitant biological effect of DMSO on breathing during sleep.

Comparing two pediatric sleep questionnaires: The Pediatric Sleep Questionnaire (PSQ) and a set of 6 hierarchically arranged questions (6Q).

OBJECTIVE: To compare the Pediatric Sleep Questionnaire (PSQ) and a less time-consuming set of 6 hierarchically arranged questions (6Q) as they relate to the pre-test probability for sleep apnea in pediatric patients. METHODS: Parents of 116 subjects between the ages of 7 and 17 answered two sleep questionnaires (the PSQ and the 6Q) distributed in random order before the subjects had sleep studies. Correlation coefficients were used for apnea-hypopnea index (AHI) prediction, while the area under the curve (AUC) was calculated for sleep apnea classification prediction. RESULTS: The 6Q showed statistical significance, while the more commonly used PSQ did not, both in terms of correlating with AHI (rho = 0.294, p = 0.001) and predicting moderate and severe sleep apnea (AUC = 0.650 and 0.788, respectively). CONCLUSION: Although additional field validation is required, these pediatric sleep questionnaires are sensitive and easy-to-use screening tools that can greatly help in the screening for pediatric sleep apnea.

Socioeconomic status impacts blood pressure response to positive airway pressure treatment.

STUDY OBJECTIVES: Positive airway pressure (PAP) treatment of obstructive sleep apnea reduces blood pressure (BP). Retrospective data suggest that African Americans (AA), a group at high-risk for hypertensive organ dysfunction, may have a greater BP response to PAP therapy than European Americans (EA). We examined the difference in 24-hour BP response to 3 months of PAP treatment between AA and EA. METHODS: Participants (n = 259, 161 AA and 98 EA) with apnea-hypopnea index ≥ 15 events/h from 2 prospective cohorts were included. t-Tests and multiple linear regression were used to examine BP outcomes in AA vs EA, adjusting for PAP adherence, socioeconomic status, and baseline characteristics. RESULTS: Participants were middle aged (mean ± SD, 53.8 ± 9.3 years), 86% (227) men, apnea-hypopnea index 35.6 ± 19.2 events/h, and PAP adherence of 3.36 ± 2.24 h/day. The reductions in 24-hour systolic and diastolic BP (mm Hg) were not different in AA vs EA (systolic = -1.13 ± 12.1 vs -0.61 ± 12.8, P = .80 and diastolic = -0.74 ± 7.9 vs -0.80 ± 7.4, P = .96), and race was not a predictor of 24-hour systolic or diastolic BP reduction (P = .75 and 0.54). Socioeconomic status and PAP adherence demonstrated a significant interaction; low socioeconomic status was associated with an increase in 24-hour systolic BP (ß = 19.3, P = .03) in the absence of PAP use but a greater reduction in 24-hour systolic BP with higher PAP adherence (ß = -3.96, P = .03). CONCLUSIONS: Twenty-four hour BP response to PAP treatment is similar in AA and EA. Adherence to PAP treatment is more effective in improving 24-hour systolic BP in those with low SES. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Race and CPAP Effectiveness (RACE); URL: https://clinicaltrials.gov/ct2/show/NCT01960465; Identifier: NCT01960465 and Registry: ClinicalTrials.gov; Name: The Effects of Treating Obese and Lean Patients with Sleep Apnea (PISA); URL: https://clinicaltrials.gov/ct2/show/NCT01578031; Identifier: NCT01578031. CITATION: Imayama I, Gupta A, Yen PS, et al. Socioeconomic status impacts blood pressure response to positive airway pressure treatment. J Clin Sleep Med. 2022;18(5):1287-1295.

Relating three-dimensional airway measurements to the apnea-hypopnea index in pediatric sleep apnea patients.

OBJECTIVES: (a) To evaluate three-dimensional radiographic airway analysis as it relates to the pre-test probability for sleep apnea in pediatric patients, and (b) to develop cut-off values for measurements showing promising results. SETTING AND SAMPLE POPULATION: A consecutive series of pediatric patients between the ages of 7 and 17 years, referred for a sleep study were recruited. Cone beam computed tomography (CBCT) scans were acquired for 103 subjects within one month following the sleep study. METHODS: Three-dimensional airway analysis was performed including volumetric, area and linear measurements. Correlations with the apnea-hypopnea index (AHI) and receiver operating characteristic (ROC) curves were constructed. Sensitivity and specificity were calculated for prediction of AHI ≥ 5 and AHI ≥ 10. RESULTS: 99 CBCT scans were included (median age = 11 years). The nasopharyngeal volume (NPV) significantly correlated with AHI (rho≈-0.4, P < .05). In subjects aged 7-11 years, proposed cut-off values for NPV are 2400mm3 and 1600mm3 for AHI ≥ 5 and AHI ≥ 10, respectively. In subjects aged 12-17 years, proposed cut-off values for NPV are 3500mm3 and 2700mm3 for AHI ≥ 5 and AHI ≥ 10, respectively. Oropharyngeal cross-sectional area (OCSA) demonstrated significant predictive value in ROC curve analysis, and cut-off values for this airway measure are also proposed. CONCLUSIONS: Contrary to findings in adults, the NPV shows promise when screening for sleep apnea in children when CBCT scans are available. The OCSA might also be of value when screening for sleep apnea especially in older children.

Relationships between objective sleep parameters and inflammatory biomarkers in pregnancy.

We examined the relationships between sleep and inflammatory biomarkers during late pregnancy. Seventy-four women underwent an overnight sleep assessment by polysomnography. Blood samples were collected before bedtime and again within 1 h upon awakening to measure C-reactive protein (CRP), interleukin (IL)-6, and IL-6 soluble receptor. Sleep parameters included variables characterizing sleep architecture and sleep continuity. The participants were 32.2 (SD = 4.1) years old, and the average gestational age was 32.8 (3.5) weeks. Controlling for covariates, evening CRP was negatively associated with N3 sleep (ß = -0.30, P = 0.010). N3 sleep was also negatively associated with morning CRP (ß = -0.26, P = 0.036), with a higher percentage of N3 sleep associated with a lower level of morning CRP. Contrarily, there was a tendency for a positive association between stage N2 sleep and morning CRP (ß = 0.23, P = 0.065). Stage N1 sleep was associated with morning IL-6 (ß = 0.28, P = 0.021), with a higher percentage of N1 sleep associated with a higher morning IL-6. No significant associations were found between morning inflammatory biomarkers and sleep continuity parameters. In conclusion, increased light sleep was associated with increased inflammatory biomarkers, whereas more deep sleep was associated with decreased inflammatory biomarkers. These findings further support the interactions between sleep and the immune system during late pregnancy.

Obstructive Sleep Apnea Is Associated with Newly Diagnosed Gestational Diabetes Mellitus.

Rationale: Sleep-disordered breathing (SDB) is associated with increased risk of adverse pregnancy outcomes, including gestational diabetes mellitus (GDM). GDM is a significant cause of maternal and infant morbidities. Assessing these risk factors concurrently may facilitate both the identification of women at GDM risk and the initiation of GDM prevention strategies.Objectives: To investigate whether SDB events, including SDB in rapid eye movement (REM) sleep and other sleep parameters, are associated with increased risk of GDM and to evaluate the performance of the models investigating associations between breathing and sleep parameters and GDM risk.Methods: In this case-control study, 46 women with newly diagnosed GDM and 46 healthy control subjects, who were individually matched for age, gestational age, body mass index, race, and parity, completed overnight polysomnographic studies and sleep questionnaires after being screened for GDM during the late-second to mid-third trimesters. Conditional logistic regression analysis was used to identify models investigating associations between risk factors and GDM risk. The Bayesian information criterion (BIC) was employed to compare models; the model with the lowest BIC is preferred.Results: Obstructive sleep apnea (OSA; defined as an apnea-hypopnea index [AHI] >5 events/h) was present in 22% of subjects with GDM and 9% of control subjects (P < 0.001). Women with OSA had a higher GDM risk (odds ratio [OR], 4.71; 95% confidence interval [CI], 1.05-21.04). In individual models, GDM risk was also significantly higher among women with higher overall AHI (events/h OR, 1.81; 95% CI, 1.01-3.27), higher AHI in REM (events/h OR, 2.09; 95% CI, 1.02-4.31), higher oxygen desaturation index greater than or equal to 4% (ODI4; events/h OR, 2.21; 95% CI, 1.03-4.73), and higher Sleep Apnea Symptom Score (OR, 2.72; 95% CI, 1.11-6.69). The percentage of non-REM sleep was significantly associated with decreased risk of GDM (percentage of non-REM sleep OR, 0.88; 95% CI, 0.78-0.99). The BIC supports the conclusion that there is a strong association between AHI in REM and GDM risk compared with the other significant models.Conclusions: SDB events, including REM-related OSA, are linked to increased GDM risk. GDM risk is also influenced by intercorrelated sleep variables.

Validation of the MediByte Portable Monitor for the Diagnosis of Sleep Apnea in Pediatric Patients.

STUDY OBJECTIVES: Polysomnography (PSG) is considered the gold standard in the diagnosis of sleep apnea. In pediatric patients, because of limited availability and access to laboratory-based PSG, there can be significant delays in the diagnosis and management of sleep apnea that can result in progressive associated comorbidities. The main objective of the current study was to test the diagnostic value of a portable sleep monitor (PM), the MediByte, in comparison with laboratory PSG in pediatric patients wearing both setups simultaneously. METHODS: A consecutive series of pediatric patients referred to the University of Illinois Sleep Science Center wore the MediByte during simultaneous PSG. The apnea-hypopnea index (AHI) was calculated for PSG and both manual and autoscoring functions of the PM. Pearson correlation and Bland-Altman plots were assessed. RESULTS: A total of 70 patients successfully completed simultaneous PSG and PM studies (median age 10.8 years). The AHI obtained both manually and automatically scored PM studies strongly correlated with the AHI obtained from the PSG (r ≥ .932, P < .001). The oxygen saturation obtained by the PM showed significant correlation with that obtained by PSG among children aged 12 to 17 years (P < .001), but not among children aged 7 to 11 years (P ≥ .24). The sensitivity and specificity for detection of severe sleep apnea diagnosed by PSG (AHI ≥ 10 events/h) using both PM scoring methods was very high (> 93% for both). CONCLUSIONS: Although PSG is still recommended for the diagnosis of sleep apnea, PMs can play a valuable role in diagnosing moderate and severe sleep apnea, especially in older pediatric patients. COMMENTARY: A commentary on this article appears in this issue on page 685.

Changes in sleep and airway variables in patients with obstructive sleep apnea after mandibular advancement splint treatment.

INTRODUCTION: Obstructive sleep apnea (OSA) is an extensive public health problem that imposes considerable morbidity. Mandibular advancement splint (MAS) therapy is a well tolerated treatment, but success rates are difficult to predict. Our objective was to investigate the relationship of oropharyngeal airway dimensions, sleep characteristics, patient biometrics, and treatment response within an OSA patient sample. METHODS: Records of 33 adults were assessed retrospectively with the use of Dolphin 3D and Image J to measure the airway on pretreatment supine cone-beam computed tomography images and derived lateral cephalograms. The patients used Somnodent (Somnomed; Crows Nest, Australia) MAS appliances, which were titrated over 6-8 weeks. Appliance titration measurements and pre- and posttreatment polysomnograms were assessed. Respiratory disturbance index (RDI), absolute and percentage changes in RDI, non-rapid eye movement (NREM) RDI, rapid eye movement (REM) RDI, supine and nonsupine NREM and REM RDI, and minimal blood-oxygen saturation variables were evaluated. The associations of measurements from 2D and 3D minimal anterior-posterior linear distance and 3D airway variables with MAS treatment response were estimated. RESULTS AND CONCLUSIONS: Combined effects of baseline total airway volume, body mass index, neck circumference, location of minimal cross sectional area, and OSA severity were associated with treatment response. Patients with higher initial OSA and more superiorly located airway constriction showed enhanced treatment response to MAS therapy. Airway constriction due to maxillofacial disproportions rather than soft tissue obstruction also showed better treatment response. No significant relationships were found in lateral cephalogram measurements.

Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea.

Study Objectives: There remains an important and unmet need for fully effective and acceptable treatments in obstructive sleep apnea (OSA). At present, there are no approved drug treatments. Dronabinol has shown promise for OSA pharmacotherapy in a small dose-escalation pilot study. Here, we present initial findings of the Phase II PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial, a fully blinded parallel groups, placebo-controlled randomized trial of dronabinol in people with moderate or severe OSA. Methods: By random assignment, 73 adults with moderate or severe OSA received either placebo (N = 25), 2.5 mg dronabinol (N = 21), or 10 mg dronabinol (N = 27) daily, 1 hour before bedtime for up to 6 weeks. Results: At baseline, overall apnea-hypopnea index (AHI) was 25.9 ± 11.3, Epworth Sleepiness Scale (ESS) score was 11.45 ± 3.8, maintenance of wakefulness test (MWT) mean latency was 19.2 ± 11.8 minutes, body mass index was 33.4 ± 5.4 kg/m2, and age was 53.6 ± 9.0 years. The number and severity of adverse events, and treatment adherence (0.3 ± 0.6 missed doses/week) were equivalent among all treatment groups. Participants receiving 10 mg/day of dronabinol expressed the highest overall satisfaction with treatment (p = .04). In comparison to placebo, dronabinol dose-dependently reduced AHI by 10.7 ± 4.4 (p = .02) and 12.9 ± 4.3 (p = .003) events/hour at doses of 2.5 and 10 mg/day, respectively. Dronabinol at 10 mg/day reduced ESS score by -3.8 ± 0.8 points from baseline (p < .0001) and by -2.3 ± 1.2 points in comparison to placebo (p = .05). MWT sleep latencies, gross sleep architecture, and overnight oxygenation parameters were unchanged from baseline in any treatment group. Conclusions: These findings support the therapeutic potential of cannabinoids in people with OSA. In comparison to placebo, dronabinol was associated with lower AHI, improved self-reported sleepiness, and greater overall treatment satisfaction. Larger scale clinical trials will be necessary to clarify the best potential approach(es) to cannabinoid therapy in OSA.

The pedunculopontine tegmentum controls renal sympathetic nerve activity and cardiorespiratory activities in nembutal-anesthetized rats.

Elevated renal sympathetic nerve activity (RSNA) accompanies a variety of complex disorders, including obstructive sleep apnea, heart failure, and chronic kidney disease. Understanding pathophysiologic renal mechanisms is important for determining why hypertension is both a common sequelae and a predisposing factor of these disorders. The role of the brainstem in regulating RSNA remains incompletely understood. The pedunculopontine tegmentum (PPT) is known for regulating behaviors including alertness, locomotion, and rapid eye movement sleep. Activation of PPT neurons in anesthetized rats was previously found to increase splanchnic sympathetic nerve activity and blood pressure, in addition to altering breathing. The present study is the first investigation of the PPT and its potential role in regulating RSNA. Microinjections of DL-homocysteic acid (DLH) were used to probe the PPT in 100-µm increments in Nembutal-anesthetized rats to identify effective sites, defined as locations where changes in RSNA could be evoked. A total of 239 DLH microinjections were made in 18 rats, which identified 20 effective sites (each confirmed by the ability to evoke a repeatable sympathoexcitatory response). Peak increases in RSNA occurred within 10-20 seconds of PPT activation, with RSNA increasing by 104.5 ± 68.4% (mean ± standard deviation) from baseline. Mean arterial pressure remained significantly elevated for 30 seconds, increasing from 101.6 ± 18.6 mmHg to 135.9 ± 36.4 mmHg. DLH microinjections also increased respiratory rate and minute ventilation. The effective sites were found throughout the rostal-caudal extent of the PPT with most located in the dorsal regions of the nucleus. The majority of PPT locations tested with DLH microinjections did not alter RSNA (179 sites), suggesting that the neurons that confer renal sympathoexcitatory functions comprise a small component of the PPT. The study also underscores the importance of further investigation to determine whether sympathoexcitatory PPT neurons contribute to adverse renal and cardiovascular consequences of diseases such as obstructive sleep apnea and heart failure.

Effects of Cannabinoid Agonists and Antagonists on Sleep and Breathing in Sprague-Dawley Rats.

Study Objectives: There are no pharmacological treatments for obstructive sleep apnea syndrome, but dronabinol showed promise in a small pilot study. In anesthetized rats, dronabinol attenuates reflex apnea via activation of cannabinoid (CB) receptors located on vagal afferents; an effect blocked by cannabinoid type 1 (CB1) and/or type 2 (CB2) receptor antagonists. Here, using a natural model of central sleep apnea, we examine the effects of dronabinol, alone and in combination with selective antagonists in conscious rats chronically instrumented to stage sleep and measure cessation of breathing. Methods: Adult male Sprague-Dawley rats were anesthetized and implanted with bilateral stainless steel screws into the skull for electroencephalogram recording and bilateral wire electrodes into the nuchal muscles for electromyogram recording. Each animal was recorded by polysomnography on multiple occasions separated by at least 3 days. The study was a fully nested, repeated measures crossover design, such that each rat was recorded following each of 8 intraperitoneal injections: vehicle; vehicle and CB1 antagonist (AM 251); vehicle and CB2 antagonist (AM 630); vehicle and CB1/CB2 antagonist; dronabinol; dronabinol and CB1 antagonist; dronabinol and CB2 antagonist; and dronabinol and CB1/CB2 antagonist. Results: Dronabinol decreased the percent time spent in rapid eye movement (REM) sleep. CB receptor antagonists did not reverse this effect. Dronabinol also decreased apneas during sleep, and this apnea suppression was reversed by CB1 or CB1/CB2 receptor antagonism. Conclusions: Dronabinol's effects on apneas were dependent on CB1 receptor activation, while dronabinol's effects on REM sleep were CB receptor-independent.

Glucose Variations and Activity Are Strongly Coupled in Sleep and Wake in Young Adults With Type 1 Diabetes.

BACKGROUND: Glucose variations are common throughout sleep and wakefulness in people with type 1 diabetes mellitus (T1DM). The objective of this investigation was to characterize the time-varying coupling between glucose and unstructured physical activity over a 60-hr period in young adults with T1DM. The hypothesis was that coupling would differ during sleep versus wakefulness and would exhibit circadian variations. METHOD: Young adults with T1DM treated with an insulin pump participated in the study. Glucose variations were monitored with a continuous glucose monitoring system, and activity was assessed using an activity-monitoring band worn on the nondominant wrist. Simultaneous glucose and physical activity data across a continuous 60-hr period were used for analysis. Wavelet coherence analysis was employed to quantify the coupling between physical activity and glucose. Cosinor analysis was used to assess whether glucose/activity coherence exhibited significant circadian variations. RESULTS: Participants comprised 23 adults, aged 18-30 years, with T1DM. Coherence analysis demonstrated substantial coupling between physical activity and glucose variations during both wakefulness and sleep. For rapid (10-30 min) fluctuations, mean coherence was higher during sleep than wakefulness ( F = 10.86, p = .003). Rapid glucose variations consistently led to changes in activity ( p = .001) during sleep but not during wake. Cosinor analysis revealed significant circadian modulation of glucose/activity coupling, especially for fluctuation periods 2-4 hr. CONCLUSIONS: Unstructured physical activity and glucose variations demonstrated strong time- and frequency-dependent coupling over a 60-hr period in young adults with T1DM, with sleep/wake differences and circadian modulation evident in this relationship.

Validity of Actigraphy in Measurement of Sleep in Young Adults With Type 1 Diabetes.

STUDY OBJECTIVES: Accurate objective measurement of sleep, an important health behavior, is needed. Individuals with type 1 diabetes mellitus (T1DM) have altered sleep architecture and reduced sleep quality in comparison with healthy controls. The aim of this investigation was to compare a commonly used actigraphy device, Actiwatch2, with polysomnography (PSG)-based measures of sleep in young adults with T1DM, and to determine which Actiwatch2 threshold setting provides the best correspondence. METHODS: Subjects age 18-30 years with T1DM wore the Actiwatch2 while simultaneously undergoing in-laboratory PSG. Sleep parameters were derived from the Actiwatch2 using the three different sensitivity thresholds (low, medium, and high) provided by the manufacturer and compared with sleep parameters from PSG. Statistical analysis included intraclass correlation coefficients and Bland-Altman plots for comparison of sleep parameters. Cohen kappa and the prevalence-adjusted and bias-adjusted kappa (PABAK) were calculated to determine agreement between epoch-by-epoch sleep and wake data measured by the PSG versus Actiwatch2. RESULTS: Twenty-seven subjects were included in the analysis. The low threshold setting provided the greatest agreement and least bias in comparison with PSG for sleep parameters (intraclass correlation coefficient range 0.38 to 0.77). Mean differences between the low setting and PSG were nonsignificant (P > .65) for all sleep parameters except sleep onset latency (P = .04). All three settings provided approximately equivalent and moderate epoch-by-epoch agreement with the PSG (PABAK coefficients ranging from 0.56 to 0.63). CONCLUSIONS: When measuring sleep with the Actiwatch2 in young adults with T1DM, the low threshold setting provides the most accurate estimates of sleep parameters in comparison with PSG.

Sleep and airway assessment: A review for dentists.

INTRODUCTION: Dentists can be the first professionals to recognize a patient's potential sleep problem since they typically have more frequent contact with their patients than do physicians. It is important that dentists have a reasonable understanding of sleep disorders and how to assess their patients if they suspect such a problem so that a timely referral can be made or treatment can be provided as appropriate. OBJECTIVE: To review the key literature relevant to sleep-disordered breathing (SDB) characteristics and diagnosis, including history, examination, and investigation with an emphasis on radiographic airway analyses. CONCLUSION: The authors present a concise explanation of SDB conditions and an outline for thorough patient examination and evaluation, including radiographic airway analyses. Limited two-dimensional and three-dimensional norms exist for adult patients with no SDB and even less so for children. Much more research is needed, particularly in the pediatric population.

EEG power and glucose fluctuations are coupled during sleep in young adults with type 1 diabetes.

OBJECTIVE: To determine the coupling between brain activity and glucose variations during sleep in young adults with type 1 diabetes mellitus (T1DM). METHODS: 27 participants, age 18-30, wore a continuous glucose monitoring system (CGMS) and underwent in-laboratory overnight polysomnography (PSG). Quantitative electroencephalogram (qEEG) metrics were determined from the PSG and included Delta, Theta, Alpha, Sigma, Beta and Gamma Band power at 5-min intervals. Wavelet Coherence Analysis was employed to determine the time varying and frequency specific coupling between glucose and EEG Band power. ANOVA was used to compare differences across fluctuation speeds and EEG bands. RESULTS: There was a high degree of time varying and frequency specific coupling between glucose variations and EEG power in all EEG Bands during sleep. The average number of intervals of statistically significant coherence was highest for fluctuations periods between 10 and 30min in all Bands (p<0.0001 for each). Mean significant coherence was negatively correlated with hemoglobin A1c, a marker of glycemic control. CONCLUSIONS: The relationship between glucose and EEG power during sleep is time varying and frequency dependent in young adults with T1DM. SIGNIFICANCE: Understanding the time varying mutual relationship between glucose changes and brain activity during sleep may have implications for disease management in T1DM.

Intracerebroventricular injections of dronabinol, a cannabinoid receptor agonist, does not attenuate serotonin-induced apnea in Sprague-Dawley rats.

BACKGROUND: Evidence suggests that vagal nerve activity may play a role in sleep apnea induction. In anesthetized rats, dronabinol, a cannabinoid (CB) receptor agonist, injected into the nodose ganglia attenuates reflex apnea and increases genioglossus activity, and reflex apnea attenuation is blocked by systemic pre-treatment with cannabinoid type 1 and/or type 2 receptor antagonists. However, it is unclear whether dronabinol has similar effects in the central nervous system; CB receptors are widely distributed in the brain, especially on neuronal circuitry important for respiration and upper airway activation. Here, we examine the effects of intracerebroventricular (ICV) injection of dronabinol on serotonin (5-HT)-induced apnea. METHODS: Adult male Sprague-Dawley rats were anesthetized and instrumented with bilateral electrodes to monitor genioglossi EMG and with a piezoelectric strain gauge to monitor respiratory pattern. Serotonin was intravenously infused into a femoral vein to induce reflex apnea. After baseline recordings, rats were placed in a stereotaxic apparatus. A unilateral osteotomy was made to allow access for injection to the right lateral ventricle, and the dura were carefully removed. Dronabinol (100, 10, 1, or 0.1 µg/3 µl DMSO) or control (3 µl DMSO) was injected into the right lateral ventricle and 5-HT infusion was repeated. Data (mean ± SEM) were analyzed using a mixed model analysis with a repeated/fixed measure. RESULTS: There was no main effect in 5-HT-induced apnea or breath duration, or in breath instability, between ICV dronabinol injected and ICV vehicle control injected groups. Moreover, there was no main effect in phasic or tonic genioglossus activity between ICV dronabinol injected and ICV vehicle control injected groups. CONCLUSION: Our data show that ICV injection of dronabinol did not decrease 5-HT-induced apneas, and did not increase genioglossus activity. This in contrast to published results of dronabinol's effect on apnea via the vagus nerve. Our results suggest that the effects of dronabinol on reflex apneas are peripherally mediated via suppression of vagal nerve activity.

Efficacy and mechanisms of behavioral therapy components for insomnia coexisting with chronic obstructive pulmonary disease: study protocol for a randomized controlled trial.

BACKGROUND: Difficulty falling asleep, staying asleep or poor-quality sleep (insomnia) is common in people with chronic obstructive pulmonary disease (COPD). Insomnia is related to greater mortality and morbidity, with four times the risk of mortality for sleep times below 300 min. However, insomnia medications are used with caution in COPD due to their potential adverse effects. While cognitive behavioral therapy for insomnia (CBT-I) is effective for people with primary insomnia and people with other chronic illnesses, the efficacy and mechanisms of action of such a therapy are yet unclear in people with both insomnia and COPD. The purpose of this study is to rigorously test the efficacy of two components of insomnia therapy - CBT-I and COPD education (COPD-ED) - in people with coexisting insomnia and COPD, and to identify mechanisms responsible for therapy outcomes. The rationale for the proposed study is that once the efficacy and mechanisms of CBT-I and COPD-ED are known, new and innovative approaches for insomnia coexisting with COPD can be developed to non-pharmacologically minimize insomnia and fatigue, thereby leading to longer, higher-quality and more productive lives for people with COPD, and reduced societal cost due to the effects of insomnia. METHODS: We are conducting a randomized, controlled, parallel-group (N = 35 each group) comparison of CBT-I, COPD-ED and non-COPD, non-sleep health education Attention Control (AC) using a highly efficient four-group design. Arm 1 comprises 6 weekly sessions of CBT-I + AC; Arm 2 = 6 weekly sessions of COPD-ED + AC; Arm 3 = 6 weekly sessions of CBT-I + COPD-ED; and Arm 4 = 6 weekly sessions of AC. This design will allow completion of the following specific aims: (1) to determine the efficacy of individual treatment components, CBT-I and COPD-ED, on insomnia and fatigue, (2) to define the mechanistic contributors to the outcomes after CBT-I and COPD-ED. DISCUSSION: The research is innovative because it represents a new and substantive departure from the usual insomnia therapy, namely by testing traditional CBT-I with education to enhance outcomes. The work proposed in aims 1 and 2 will provide systematic evidence of the efficacy and mechanisms of components of a novel approach to insomnia comorbid with COPD. Such results are highly likely to provide new approaches for preventive and therapeutic interventions for insomnia and fatigue in COPD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01973647 . Registered on 22 October 2013.

Physiology of Sleep.

IN BRIEF Far from a simple absence of wakefulness, sleep is an active, regulated, and metabolically distinct state, essential for health and well-being. In this article, the authors review the fundamental anatomy and physiology of sleep and its regulation, with an eye toward interactions between sleep and metabolism.