Prevalent Hypertension and Stroke in the Sleep Heart Health Study: Association with an ECG-derived Spectrographic Marker of Cardiopulmonary Coupling

Study Objectives:

The electrocardiogram (ECG)-based sleep spectrogram generates a map of cardiopulmonary coupling based on heart rate variability and respiration derived from QRS amplitude variations. A distinct spectrographic phenotype, designated as narrow-band elevated low frequency coupling (e-LFC_NB), has been associated with central apneas and periodic breathing and predicts sleep laboratory failure of continuous positive airway pressure therapy. This study assesses, at a population level, the associations of this spectrographic biomarker with prevalent cardiovascular disease using the Sleep Heart Health Study (SHHS)-I dataset.

Design:

Retrospective analysis of the Sleep Heart Health Study-I dataset.

Setting:

Laboratory for complex physiologic signals analysis.

Measurements and Results:

The fully-automated ECG-derived sleep spectrogram technique was applied to 5247 (of the original 6441) polysomnograms from the SHHS-I. Associations were estimated with use of various drugs and pathologies including prevalent hypertension and cardiovascular and cerebrovascular disease. Increasing with age and more common in males, e-LFC_NB is also associated with greater severity of sleep apnea and fragmented sleep. After adjustment for potential confounders, an independent association with prevalent hypertension and stroke was found.

Conclusions:

An ECG-derived spectrographic marker related to low frequency cardiopulmonary coupling is associated with greater sleep apnea severity. Whether this biomarker is solely a sign of more severe disease or whether it reflects primary alterations in sleep apnea pathophysiology (which may either cause or result from sleep apnea) is unknown. This ECG-based spectral marker is associated with a higher prevalence of hypertension and stroke.

Citation:

Thomas RJ; Weiss MD; Mietus JE; Peng CK; Goldberger AL; Gottlieb DJ. Prevalent hypertension and stroke in the sleep heart health study: association with an ECG-derived spectrographic marker of cardiopulmonary coupling. SLEEP 2009;32(7):897-904.     

No association of genetic variants in BDNF with major depression: A meta‐ and gene‐based analysis

Major depressive disorder (MDD) is a complex psychiatric condition with strong genetic predisposition. The association of MDD with genetic polymorphisms, such as Val66Met (rs6265), in the brain derived neurotrophic factor (BDNF), have been reported in many studies and the results were conflicting. In this study, we performed a systematic literature search and conducted random‐effects meta‐analysis to evaluate genetic variants in BDNF with MDD. A gene‐based analysis was also conducted to investigate the cumulative effects of genetic polymorphisms in BDNF. A total of 28 studies from 26 published articles were included in our analysis. Meta‐analysis yielded an estimated odds ratio (OR) of 0.96 (95% CI: 0.89–1.05; P = 0.402) for Val66Met (rs6265), 0.83 (95% CI: 0.67–1.04; P = 0.103) for 11757C/G, 1.16 (95% CI: 0.74–1.82; P = 0.527) for 270T/C, 1.03 (95% CI: 0.18–5.75; P = 0.974) for 712A/G and 0.98 (95% CI: 0.85–1.14; P = 0.831) for rs988748. The gene‐based analysis indicated that BDNF is not associated with MDD (P > 0.21). Our updated meta‐ and novel gene‐based analyses provide no evidence of the association of BDNF with major depression. © 2012 Wiley Periodicals, Inc.     

Sleep architecture as correlate and predictor of symptoms and impairment in inter‐episode bipolar disorder: taking on the challenge of medication effects

This study was designed to clarify the association between inter‐episode bipolar disorder (BD) and sleep architecture. Participants completed a baseline symptom and sleep assessment and, 3 months later, an assessment of symptoms and impairment. The effects of psychiatric medications on sleep architecture were also considered. Participants included 22 adults with BD I or II (inter‐episode) and 22 non‐psychiatric controls. The sleep assessment was conducted at the Sleep and Psychological Disorders Laboratory at the University of California, Berkeley. Follow‐up assessments 3 months later were conducted over the phone. Results indicate that, at the sleep assessment, BD participants exhibited greater rapid eye movement sleep (REM) density than control participants with no other group differences in sleep architecture. Sleep architecture was not correlated with concurrent mood symptoms in either group. In the BD group, duration of the first REM period and slow‐wave sleep (SWS) amount were positively correlated with manic symptoms and impairment at 3 months, while REM density was positively correlated with depressive symptoms and impairment at 3 months. The amount of Stage 2 sleep was negatively correlated with manic symptoms and impairment at 3 months. In contrast, for the control group, REM density was negatively correlated with impairment at 3 months. SWS and Stage 2 sleep were not correlated with symptoms or impairment. Study findings suggest that inter‐episode REM sleep, SWS and Stage 2 sleep are correlated with future manic and depressive symptoms and impairment in BD. This is consistent with the proposition that sleep architecture may be a mechanism of illness maintenance in BD.     

Quantitative electroencephalography during rapid eye movement (REM) and non‐REM sleep in combat‐exposed veterans with and without post‐traumatic stress disorder

Sleep disturbances are a hallmark feature of post‐traumatic stress disorder (PTSD), and associated with poor clinical outcomes. Few studies have examined sleep quantitative electroencephalography (qEEG), a technique able to detect subtle differences that polysomnography does not capture. We hypothesized that greater high‐frequency qEEG would reflect ‘hyperarousal’ in combat veterans with PTSD (n = 16) compared to veterans without PTSD (n = 13). EEG power in traditional EEG frequency bands was computed for artifact‐free sleep epochs across an entire night. Correlations were performed between qEEG and ratings of PTSD symptoms and combat exposure. The groups did not differ significantly in whole‐night qEEG measures for either rapid eye movement (REM) or non‐REM (NREM) sleep. Non‐significant medium effect sizes suggest less REM beta (opposite to our hypothesis), less REM and NREM sigma and more NREM gamma in combat veterans with PTSD. Positive correlations were found between combat exposure and NREM beta (PTSD group only), and REM and NREM sigma (non‐PTSD group only). Results did not support global hyperarousal in PTSD as indexed by increased beta qEEG activity. The correlation of sigma activity with combat exposure in those without PTSD and the non‐significant trend towards less sigma activity during both REM and NREM sleep in combat veterans with PTSD suggests that differential information processing during sleep may characterize combat‐exposed military veterans with and without PTSD.     

Enhancing well‐being and alleviating depressive symptoms with positive psychology interventions: a practice‐friendly meta‐analysis

Do positive psychology interventions—that is, treatment methods or intentional activities aimed at cultivating positive feelings, positive behaviors, or positive cognitions—enhance well‐being and ameliorate depressive symptoms? A meta‐analysis of 51 such interventions with 4,266 individuals was conducted to address this question and to provide practical guidance to clinicians. The results revealed that positive psychology interventions do indeed significantly enhance well‐being (mean r=.29) and decrease depressive symptoms (mean r=.31). In addition, several factors were found to impact the effectiveness of positive psychology interventions, including the depression status, self‐selection, and age of participants, as well as the format and duration of the interventions. Accordingly, clinicians should be encouraged to incorporate positive psychology techniques into their clinical work, particularly for treating clients who are depressed, relatively older, or highly motivated to improve. Our findings also suggest that clinicians would do well to deliver positive psychology interventions as individual (versus group) therapy and for relatively longer periods of time. © 2009 Wiley Periodicals, Inc. J Clin Psychol: In Session 65: 1–21, 2009.     

Sleep and resting‐state functional magnetic resonance imaging connectivity in middle‐aged adults and the elderly: A population‐based study

Sleep problems increase with ageing. Increasing evidence suggests that sleep problems are not only a consequence of age‐related processes, but may independently contribute to developing vascular or neurodegenerative brain disease. Yet, it remains unclear what mechanisms underlie the impact sleep problems may have on brain health in the general middle‐aged and elderly population. Here, we studied sleep's relation to brain functioning in 621 participants (median age 62 years, 55% women) from the population‐based Rotterdam Study. We investigated cross‐sectional associations of polysomnographic and subjectively measured aspects of sleep with intrinsic neural activity measured with resting‐state functional magnetic resonance imaging on a different day. We investigated both functional connectivity between regions and brain activity (blood‐oxygen‐level‐dependent signal amplitude) within regions, hierarchically towards smaller topographical levels. We found that longer polysomnographic total sleep time is associated with lower blood‐oxygen‐level‐dependent signal amplitude in (pre)frontal regions. No objective or subjective sleep parameters were associated with functional connectivity between or within resting‐state networks. The findings may indicate a pathway through which sleep, in a ‘real‐life’ population setting, impacts brain activity or regional brain activity determines total sleep time.     

Sleep disorders and an increased risk of Parkinson's disease in individuals with non‐apnea sleep disorders: a population‐based cohort study

Sleep disorders are common non‐motor symptoms in patients with Parkinson's disease. Our study aims to explore the relationship between non‐apnea sleep disorders and future Parkinson's disease. This is a cohort study using a nationwide database. The participants were recruited from the Taiwan National Health Insurance Research Database between 2000 and 2003. A total of 91 273 adult patients who had non‐apnea sleep disorders without pre‐existing Parkinson's disease were enrolled. An age‐, gender‐, income‐, urbanization‐ and Charlson comorbidity index score‐matched control cohort consisting of 91 273 participants was selected for comparison. The two cohorts were followed for the occurrence of Parkinson's disease, death or until the end of 2010, whichever came first. The Kaplan–Meier analyses revealed patients with non‐apnea sleep disorders tended to develop Parkinson's disease (log‐rank test, P < 0.001). After a multivariate adjustment in a Cox regression model, non‐apnea sleep disorders was an independent risk factor for the development of Parkinson's disease [crude hazard ratio: 1.63, 95% confidence interval (CI): 1.54–1.73, P < 0.001; adjusted hazard ratio: 1.18, 95% CI: 1.11–1.26, P < 0.001]. In the subgroup analysis, patients with chronic insomnia (lasting more than 3 months) had the greatest risk (crude hazard ratio: 2.91, 95% CI: 2.59–3.26, P < 0.001; adjusted hazard ratio: 1.37, 95% CI: 1.21–1.55, P < 0.001). In conclusion, this study revealed that non‐apnea sleep disorders, especially chronic insomnia, are associated with a higher risk for future Parkinson's disease.     

Objective measures of sleep duration and continuity in major depressive disorder with comorbid hypersomnolence: a primary investigation with contiguous systematic review and meta‐analysis

Hypersomnolence plays an important role in the presentation, treatment and course of mood disorders. However, there has been relatively little research that examines objective measures of sleep duration and continuity in patients with depression and hypersomnolence, despite the use of these factors in sleep medicine nosological systems. This study compared total sleep time and efficiency measured by naturalistic actigraphic recordings followed by ad libitum polysomnography (PSG; without prescribed wake time) in 22 patients with major depressive disorder and co‐occurring hypersomnolence against age‐ and sex‐matched healthy sleeper controls. The major depressive disorder and co‐occurring hypersomnolence group demonstrated significantly longer sleep duration compared with healthy sleeper controls quantified by sleep diaries, actigraphy and ad libitum PSG. No between‐group differences in sleep efficiency (SE), latency to sleep or wake after sleep onset were observed when assessed using objective measures. To further contextualize these findings within the broader scientific literature, a systematic review was performed to identify other comparable investigations. A meta‐analysis of pooled data demonstrated patients with mood disorders and co‐occurring hypersomnolence have significantly greater sleep duration and similar SE compared with healthy controls when assessed using ad libitum PSG. These results suggest current sleep medicine nosology that distinguishes hypersomnia associated with psychiatric disorders primarily as a construct characterized by low SE and increased time in bed may not be accurate. Future studies that establish the biological bases hypersomnolence in mood disorders, as well as clarify the accuracy of nosological thresholds to define excessive sleep duration, are needed to refine the diagnosis and treatment of these disorders.     

Association of IMMP2L deletions with autism spectrum disorder: A trio family study and meta‐analysis

IMMP2L, the gene encoding the inner mitochondrial membrane peptidase subunit 2‐like protein, has been reported as a candidate gene for Tourette syndrome, autism spectrum disorder (ASD) and additional neurodevelopmental disorders. Here we genotyped 100 trio families with an index proband with autism spectrum disorder in Han Chinese population and found three cases with rare exonic IMMP2L deletions. We have conducted a comprehensive meta‐analysis to quantify the association of IMMP2L deletions with ASD using 5,568 cases and 10,279 controls. While the IMMP2L deletions carried non‐recurrent breakpoints, in contrast to previous reports, our meta‐analysis found no evidence of association (P > 0.05) between IMMP2L deletions and ASD. We also observed common exonic deletions impacting IMMP2L in a separate control (5,971 samples) cohort where subjects were screened for psychiatric conditions. This is the first systematic review and meta‐analysis regarding the effect of IMMP2L deletions on ASD, but further investigations in different populations, especially Chinese population may be still needed to confirm our results.     

Detection of human papillomavirus in esophageal papillomas: systematic review and meta‐analysis

Since first suggested (in 1982), etiological role for human papillomavirus (HPV) in esophageal papillomas has aroused increasing interest. The objective of this study was to perform systematic review and formal meta‐analysis of the literature reporting on HPV detection in esophageal squamous cell papillomas (ESCP). Literature was searched through May 2012. The effect size was calculated as event rates (95% CI), with homogeneity testing using Cochran's Q and I² statistics. Meta‐regression was used to test the impact of study‐level covariates (HPV detection method, geographic origin) on effect size, and potential publication bias was estimated using funnel plot symmetry. Thirty nine studies were eligible, covering 427 ESCPs from different geographic regions. Altogether, 132 (30.9%) cases tested HPV positive; effect size 0.375 (95% CI 0.319–0.434) using the fixed‐effects (FE) model and 0.412 (95% CI 0.295–0.540) using the random‐effects model. In meta‐analysis stratified by (i) HPV detection technique and (ii) geographic study origin, the between‐study heterogeneity was not significant (p = 0.071 and p = 0.105, respectively). In meta‐regression, HPV detection method (p = 0.260) and geographic origin (p = 0.436) were not significant study‐level covariates accounting for the heterogeneity in HPV prevalence. Some evidence for publication bias was found only for PCR‐based studies, with a marginal impact on summary effect size estimates. In sensitivity analysis, all meta‐analytic results were robust to all one‐by‐one study removals. In stratified meta‐analysis and formal meta‐regression, the variability in HPV detection rates in ESCPs is not explained by the HPV detection method or geographic origin of the study.     

Psychological interventions for posttraumatic stress disorder and depression in refugees: A meta‐analysis of randomized controlled trials

Millions of refugees around the globe suffer from posttraumatic stress disorder (PTSD) and/or depression. We conducted a meta‐analysis of randomized controlled trials (RCTs) to determine the efficacy of psychological interventions for PTSD and/or depression in refugees. The meta‐analysis was registered on the PROSPERO database (CRD42017071384). A search using the Medline, PsycINFO, and PILOTS databases was conducted in January 2019, resulting in 17 RCTs, of which 14 were conducted with adult refugees (1,108 participants) and 3 with young refugees (<18 years; 151 participants). Further inclusion criteria were at least 10 participants completing an active psychological intervention for PTSD, depression, or both and less than 50% of participants receiving concurrent psychotropic drugs. Random effects models showed that active interventions for adult PTSD yielded a medium to large aggregated effect size (g = 0.77; 95% confidence interval [CI] [0.26, 1.28]) at posttreatment when compared with passive and active control conditions. Active interventions for adult depression also produced large controlled effect sizes at posttreatment (g = 0.82; 95% CI [0.24, 1.40]). The effects appeared to persist over the average follow‐up period of 6 months. The findings suggest that psychological interventions can effectively reduce symptoms of both PTSD and depression in adult refugees. However, the considerable heterogeneity between studies indicates that the efficacy may vary significantly. Future studies should aim to explore the substantial heterogeneity in effect sizes between studies with adult refugees. Additionally, more trials with young refugees suffering from PTSD or depression are needed to determine treatment efficacy for this population.     

Body temperature,activity and melatonin profiles in adults with attention‐deficit/hyperactivity disorder and delayed sleep: a case–control study

Irregular sleep–wake patterns and delayed sleep times are common in adults with attention‐deficit/hyperactivity disorder, but mechanisms underlying these problems are unknown. The present case–control study examined whether circadian abnormalities underlie these sleep problems in a naturalistic home setting. We included 12 medication‐naïve patients with attention‐deficit/hyperactivity disorder and delayed sleep phase syndrome, and 12 matched healthy controls. We examined associations between sleep/wake rhythm in attention‐deficit/hyperactivity disorder and circadian parameters (i.e. salivary melatonin concentrations, core and skin temperatures, and activity patterns) of the patients and controls during five consecutive days and nights. Daily bedtimes were more variable within patients compared with controls (F = 8.19, P < 0.001), but melatonin profiles were equally stable within individuals. Dim‐light melatonin onset was about 1.5 h later in the patient group (U = 771, Z = ?4.63, P < 0.001). Patients slept about 1 h less on nights before work days compared with controls (F = 11.21, P = 0.002). The interval between dim‐light melatonin onset and sleep onset was on average 1 h longer in patients compared with controls (U = 1117, Z = ?2.62, P = 0.009). This interval was even longer in patients with extremely late chronotype. Melatonin, activity and body temperatures were delayed to comparable degrees in patients. Overall temperatures were lower in patients than controls. Sleep‐onset difficulties correlated with greater distal–proximal temperature gradient (DPG; i.e. colder hands, r² = ?0.32, P = 0.028) in patients. Observed day‐to‐day bedtime variability of individuals with attention‐deficit/hyperactivity disorder and delayed sleep phase syndrome were not reflected in their melatonin profiles. Irregular sleep–wake patterns and delayed sleep in individuals with attention‐deficit/hyperactivity disorder and delayed sleep phase syndrome are associated with delays and dysregulations of the core and skin temperatures.     

Expression of interleukin‐17 in primary Sjögren's syndrome and the correlation with disease severity: A systematic review and meta‐analysis

The aberrant expression of interleukin‐17 (IL‐17) has been reported in primary Sjögren's syndrome (pSS). Abnormalities in IL‐17 can promote the production of pro‐inflammatory cytokines and aggravate autoimmune disorders. The aim of this study was to investigate alterations of IL‐17 in patients with pSS and explore the correlation between IL‐17 and disease severity. Eight databases were searched for original studies reporting the expression of IL‐17 in patients with pSS and controls. Eligible reports were included in the pooled analysis, and subgroup evaluations were performed according to different types of controls and IL‐17 measurement methods. Newcastle‐Ottawa Scale criteria were used to assess the risk of bias of the included studies. In total, 45 articles are included in the meta‐analysis. The expression of IL‐17 is significantly increased in patients with pSS compared to controls. Furthermore, patients with pSS without immunosuppressive treatment show markedly higher IL‐17 levels. In addition, patients with pSS with positive rheumatoid factors tend to express a higher level of IL‐17 than patients with negative rheumatoid factors. Negative correlations between IL‐17 levels and ocular parameters are also found in patients with pSS. The results are similar after adjustment by “trim and fill” methods. In conclusion, the expression of IL‐17 is obviously increased in patients with pSS, especially among those without immunosuppressive treatment. In addition, IL‐17 level correlates with the disease severity of pSS. These findings demonstrate the significance of IL‐17 overexpression in patients with pSS and may provide insights for the development of therapeutic interventions targeting IL‐17 for pSS.     

Ratiometric analysis in hyperpolarized NMR (I): test of the two‐site exchange model and the quantification of reaction rate constants

Conventional methods for the analysis of in vivo hyperpolarized ¹³C NMR data from the lactate dehydrogenase (LDH) reaction usually make assumptions on the stability of rate constants and/or the validity of the two‐site exchange model. In this study, we developed a framework to test the validity of the assumption of stable reaction rate constants and the two‐site exchange model in vivo via ratiometric fitting of the time courses of the signal ratio L(t)/P(t). Our analysis provided evidence that the LDH enzymatic kinetics observed by hyperpolarized NMR are in near‐equilibrium and satisfy the two‐site exchange model for only a specific time window. In addition, we quantified both the forward and reverse exchange rate constants of the LDH reaction for the transgenic and mouse xenograft models of breast cancer using the ratio fitting method developed, which includes only two modeling parameters and is less sensitive to the influence of instrument settings/protocols, such as flip angles, degree of polarization and tracer dosage. We further compared the ratio fitting method with a conventional two‐site exchange modeling method, i.e. the differential equation fitting method, using both the experimental and simulated hyperpolarized NMR data. The ratio fitting method appeared to fit better than the differential equation fitting method for the reverse rate constant on the mouse tumor data, with less relative errors on average, whereas the differential equation fitting method also resulted in a negative reverse rate constant for one tumor. The simulation results indicated that the accuracy of both methods depends on the width of the transport function, noise level and rate constant ratio; one method may be more accurate than the other based on the experimental/biological conditions aforementioned. We were able to categorize our tumor models into specific conditions of the computer simulation and to estimate the errors of rate quantification. We also discussed possible approaches to the development of more accurate rate quantification methods for hyperpolarized NMR. Copyright © 2013 John Wiley & Sons, Ltd.