Edward O. Bixler, PhD: from the Apollo project and chimpanzees to sleep epidemiology.

What an honor to write about Dr. Edward O. Bixler's contributions to the sleep field. In 1967, Dr. Bixler published a case report on a chimpanzee with implanted brain electrodes while working at an Air Force base in New Mexico. A few years later, in 1971, he published on the sleep effects of flurazepam in individuals with insomnia together with Dr. Anthony Kales, data that he had collected when the Sleep Research & Treatment Center (SRTC) was housed at the University of California Los Angeles. Dr. Bixler, a meticulous scientist, learned from Dr. Kales, a devoted clinician, to study "the whole patient, and all aspects of sleep," a legacy that continued when the SRTC moved to Penn State in Hershey. Indeed, Dr. Bixler's tenure at Penn State from 1971 until 2019 kept the science of the SRTC focused on that premise and helped translate scientific evidence into clinical care. He not only contributed early to the pharmacology of sleep and the effects of hypnotics, but he was also a pioneer in "sleep epidemiology." His "Prevalence of sleep disorders in the Los Angeles metropolitan area" study of 1979 was the first rigorous epidemiological study on sleep disturbances. Starting in 1990, he established the Penn State Adult Cohort to estimate the prevalence and natural history of sleep-disordered breathing and other sleep disorders in adults. Inspired by life-course epidemiology, he established in 2001 the Penn State Child Cohort to estimate the same phenomena in children. This Living Legend paper captures and highlights Dr. Bixler's enduring legacy to sleep science.

Short-term stability and night-to-night variability of sleep parameters in nightmares comorbid with chronic insomnia Disorder across multiple nights of polysomnography.

STUDY OBJECTIVES: The purpose of this study was to examine the degree of short-term stability of polysomnographic (PSG) measured sleep parameters and the overall differences between individuals with comorbid nightmares and insomnia compared to those with chronic insomnia disorder alone or good sleeping controls across four nights in the sleep lab. METHODS: A total of 142 good sleeping controls, 126 chronic insomnia alone, and 24 comorbid insomnia/nightmare participants underwent four consecutive nights of 8-hour PSG recordings. Outcomes included sleep continuity, architecture, and REM-related parameters across nights one through four. Intraclass correlation coefficients with mixed-effect variances and repeated-measure analysis of covariance were used, respectively, to determine short-term stability as well as between-participants and time-by-group interaction effects. RESULTS: Wake after sleep onset and stage 1 showed "poor stability" in the comorbid insomnia/nightmare group compared to "moderate stability" in the good sleeping controls and chronic insomnia alone group. Significant between-group effects (all ps < .05) showed that the comorbid insomnia/nightmare group took longer to fall asleep and had a greater first-night-effect in stage 1 compared to good sleeping controls and chronic insomnia alone group; in addition, the comorbid insomnia/nightmare and insomnia alone groups slept shorter, with fewer awakenings and REM periods, compared to the good sleeping controls. CONCLUSIONS: Nightmares are associated with abnormal sleep above and beyond REM disruption, as sleep continuity was the primary aspect in which poor stability and group differences emerged. The greater inability to fall asleep and instability of sleep fragmentation in those with comorbid insomnia/nightmares compared to chronic insomnia alone may be attributed to the impact of presleep anticipatory anxiety and nightmare-related distress itself. CLINICAL TRIAL INFORMATION: The data analyzed in this study does not come from any current or previous clinical trials. Therefore, there is no clinical trial information to report.

Insomnia with objective but not subjective short sleep duration is associated with incident cardiovascular and/or cerebrovascular disease.

STUDY OBJECTIVES: Insomnia with objective short sleep duration (ISSD) has been associated with cardiometabolic outcomes i.e., hypertension or diabetes. We examined whether ISSD, based on objective or subjective sleep measures are associated with more serious health problems such as incident cardiovascular and/or cerebrovascular disease (CBVD). METHODS: 1,258 men and women from the Penn State Adult Cohort (56.9% women, 48.3±12.95 years) without CBVD at baseline were followed up for 9.21±4.08 years. The presence of CBVD was defined as a history of diagnosis or treatment of heart disease and/or stroke. Insomnia was defined as a complaint of insomnia with a duration ≥ 1 year. Poor sleep was defined as a complaint of difficulty falling asleep, staying asleep, nonrestorative sleep or early morning awakening. Objective short sleep duration was defined as <6-hours sleep based on polysomnography. Subjective short sleep duration was based on the median self-reported percentage of sleep time (i.e., <7 hours). RESULTS: Compared to normal sleepers with normal sleep duration, the highest risk of incident CBVD was in the ISSD group (OR=2.46, 95%CI=1.04-5.79), and the second highest in normal sleepers with short sleep duration (OR=1.68, 95%CI=1.11-2.54). The risk for incident CBVD was not significantly increased in poor sleepers or those with insomnia with normal sleep duration (INSD). Finally, insomnia with subjective short sleep duration, was not associated with increased incident CBVD. CONCLUSIONS: These data add to the cumulative evidence that ISSD, based on objective but not subjective measures, is the more severe biological phenotype of the disorder associated with incident CBVD.

Racial/ethnic disparities in the trajectories of insomnia symptoms from childhood to young adulthood.

STUDY OBJECTIVES: To examine differences in the longitudinal prevalence of childhood insomnia symptoms across black/African American, Hispanic/Latinx, and non-Hispanic white groups. METHODS: Participants were 519 children from the Penn State Child Cohort (baseline [V1] from 2000-2005) who were followed up 8 years later as adolescents (V2) and 15 years later as young adults (S3). Mean age at S3 was 24.1 ±â€…2.7 years. Approximately, 76.5% identified as non-Hispanic white, 12.9% as black/African American, 7.1% as Hispanic/Latinx, and 3.5% as "other" race/ethnicity. Insomnia symptoms were defined as parent-reported (childhood) or self-reported (adolescence and young adulthood) moderate-to-severe difficulties initiating/maintaining sleep. Longitudinal trajectories of insomnia symptoms were identified across three-time points and the odds of each trajectory were compared between racial/ethnic groups, adjusting for sex, age, overweight, sleep apnea, periodic limb movements, psychiatric/behavioral disorders, and psychotropic medication use. RESULTS: Black/African Americans compared to non-Hispanic whites were at significantly higher odds of having a childhood-onset persistent trajectory through young adulthood (OR = 2.58, 95% CI [1.29, 5.14]), while Hispanics/Latinx were at nonsignificantly higher odds to have the same trajectory (OR = 1.81, 95% CI [0.77, 4.25]). No significant racial/ethnic differences were observed for remitted and waxing-and-waning trajectories since childhood or incident/new-onset trajectories in young adulthood. CONCLUSIONS: The results indicate that disparities in insomnia symptoms among black/African American and, to a lesser extent, Hispanic/Latinx groups start early in childhood and persist into young adulthood. Identifying and intervening upon upstream determinants of racial/ethnic insomnia disparities are warranted to directly address these disparities and to prevent their adverse health sequelae. CLINICAL TRIAL INFORMATION: N/A; Not a clinical trial.

Circadian misalignment impacts the association of visceral adiposity with metabolic syndrome in adolescents.

STUDY OBJECTIVES: Although insufficient sleep is a risk factor for metabolic syndrome (MetS), the circadian timing of sleep (CTS) is also involved in cardiac and metabolic regulation. We examined whether delays and deviations in the sleep midpoint (SM), a measure of CTS, modify the association between visceral adipose tissue (VAT) and MetS in adolescents. METHODS: We evaluated 277 adolescents (median 16 years) who had at least 5 nights of at-home actigraphy (ACT), in-lab polysomnography (PSG), dual-energy X-ray absorptiometry (DXA) scan, and MetS score data. Sleep midpoint (SM), sleep irregularity (SI), and social jetlag (SJL) were examined as effect modifiers of the association between VAT and MetS, including waist circumference, blood pressure, insulin resistance, triglycerides, and cholesterol. Linear regression models adjusted for demographics, ACT-sleep duration, ACT-sleep variability, and PSG-apnea-hypopnea index. RESULTS: The association between VAT and MetS was significantly stronger (p-values for interactions < 0.001) among adolescents with a schooldays SM later than 4:00 (2.66 [0.30] points increase in MetS score), a SI higher than 1 hour (2.49 [0.30]) or a SJL greater than 1.5 hours (2.15 [0.36]), than in those with an earlier SM (<3:00; 1.76 [0.28]), lower SI (<30 minutes; 0.98 [0.70]), or optimal SJL (<30 minutes; 1.08 [0.45]). CONCLUSIONS: A delayed sleep phase, an irregular sleep-wake cycle, and greater social jetlag on schooldays identified adolescents in whom VAT had a stronger association with MetS. Circadian misalignment is a risk factor that enhances the impact of visceral obesity on cardiometabolic morbidity and should be a target of preventative strategies in adolescents.

Age-related differences in the association of mild-to-moderate sleep apnea with incident cardiovascular and cerebrovascular diseases.

BACKGROUND: Mild-to-moderate obstructive sleep apnea (mmOSA) is highly prevalent in the general population. However, studies on its association with incident cardiovascular and/or cerebrovascular disease (CBVD) are limited. We examined the association between mild-to-moderate OSA and incident cardiovascular and/or cerebrovascular (CBVD) in a general population sample, and whether age modifies this association. METHODS: A total of 1173 adults from the Penn State Adult Cohort (20-88 years) without CBVD or severe OSA at baseline were followed-up after 9.2 (±4.1) years. Incident CBVD was defined based on a self-report of a physician diagnosis or treatment for heart disease and/or stroke. Logistic regression examined the association of mild-to-moderate OSA (AHI 5-29.9) with incident CBVD and the combined effect of mmOSA and MetS on incident CBVD after adjusting for multiple confounders. RESULTS: Age significantly modified the association between mmOSA with incident CBVD (p-interaction = 0.04). Mild-to-moderate OSA was significantly associated with incident CBVD in adults aged <60 years (OR = 1.74, 95%CI = 1.06-2.88, p = 0.029), but not in adults aged ≥60 years (OR = 0.71, 95%CI = 0.39-1.27, p = 0.247). Even mild OSA (AHI 5-14.9) carried a significant risk for incident CBDV in adults aged <60 years (OR = 1.86, 95%CI = 1.05-3.28, p = 0.032). An additive effect was found between mmOSA and MetS with incident CBVD in those aged <65 years (OR = 3.84, 95%CI = 1.95-7.56, p<0.001). CONCLUSIONS: The risk of incident CBVD is increased in young and middle-aged but not older adults with mmOSA, which may affect the way we currently diagnose and treat this highly prevalent sleep-related breathing disorder.

Urban vs. rural differences in psychiatric diagnoses, symptom severity, and functioning in a psychiatric sample.

OBJECTIVE: Identifying whether certain groups of people experience elevated rates or severities of psychiatric symptoms provides information to guide healthcare allocation. People living in urban areas have higher rates of some psychiatric disorders relative to people living in rural settings, however, it is unclear if psychiatric severity is more elevated in urban vs. rural settings. This study investigates the urban vs. rural differences in rates of psychiatric disorders and severity of psychiatric symptoms. METHOD: A cohort of patients (63% women, 85% White) presenting to an outpatient psychiatric treatment center in the U.S. completed patient-reported outcomes at all clinic visits as part of standard care. Rurality was determined by municipality population density. Sociodemographic characteristics, psychiatric diagnoses, trauma exposure, psychiatric symptom severity, functioning, and suicidality were compared by rural vs. urban municipality. RESULTS: There were virtually no differences between patients living in rural vs. urban municipalities on rates of psychiatric disorders, severity of psychiatric symptoms, functional impairment, and suicidality (ps≥.09). The only difference was that patients living in rural municipalities had higher exposure to serious accidents than patients living in urban municipalities (p < .01); exposure to nine other traumatic events did not differ between groups (p≥.07). CONCLUSIONS: People living in urban and rural municipalities have a similar need for mental health treatment. Access to care may be one explanatory factor for the occasional rural-urban differences in rates of psychiatric disorders. In other words, if people living in rural areas can access care, their symptom presentations appear unlikely to differ from those of people living in urban areas.

Objective and subjective measures of sleep initiation are differentially associated with DNA methylation in adolescents.

INTRODUCTION: The onset of puberty is associated with a shift in the circadian timing of sleep, leading to delayed sleep initiation [i.e., later sleep onset time (SOT)] due to later bedtimes and/or longer sleep onset latency (SOL). Several genome-wide association studies (GWAS) have identified genes that may be involved in the etiology of sleep phenotypes. However, circadian rhythms are also epigenetically regulated; therefore, epigenetic biomarkers may provide insight into the physiology of the pubertal sleep onset shift and the pathophysiology of prolonged or delayed sleep initiation. RESULTS: The gene-wide analysis indicated differential methylation within or around 1818 unique genes across the sleep initiation measurements using self-report, actigraphy (ACT), and polysomnography (PSG), while GWAS-informed analysis yielded 67 genes. Gene hits were identified for bedtime (PSG), SOL (subjective, ACT and PSG) and SOT (subjective and PSG). DNA methylation within 12 genes was associated with both subjective and PSG-measured SOL, 31 with both ACT- and PSG-measured SOL, 19 with both subjective and ACT-measured SOL, and one gene (SMG1P2) had methylation sites associated with subjective, ACT- and PSG-measured SOL. CONCLUSIONS: Objective and subjective sleep initiation in adolescents is associated with altered DNA methylation in genes previously identified in adult GWAS of sleep and circadian phenotypes. Additionally, our data provide evidence for a potential epigenetic link between habitual (subjective and ACT) SOL and in-lab SOT and DNA methylation in and around genes involved in circadian regulation (i.e., RASD1, RAI1), cardiometabolic disorders (i.e., FADS1, WNK1, SLC5A6), and neuropsychiatric disorders (i.e., PRR7, SDK1, FAM172A). If validated, these sites may provide valuable targets for early detection and prevention of disorders involving prolonged or delayed SOT, such as insomnia, delayed sleep phase, and their comorbidity.

Mild-to-moderate obstructive sleep apnea and mortality risk in a general population sample: The modifying effect of age and cardiovascular/cerebrovascular comorbidity.

About 5.4%-45.7% of the general population has mild-to-moderate obstructive sleep apnea (mmOSA), which is highly comorbid with cardiovascular and/or cerebrovascular diseases (CBVD). We examined the association between mmOSA and all-cause mortality and the modifying effect of age and CBVD. A total of 1681 adults 20-88 years old from the Penn State Adult Cohort (PSAC) (41.9% male) were followed up for 20.1 ± 6.2 years for all-cause mortality. Mild and moderate OSA were defined as an apnea/hypopnea index (AHI) 5-14.9 and 15-29.9 events/hour, respectively. CBVD was defined as a report of a physician diagnosis or treatment for heart disease and/or stroke. Cox proportional hazards regression models were used to estimate all-cause mortality adjusted for confounders. All-cause mortality risk was significantly increased in the mmOSA group in young and middle-aged adults (<60 years) (HR = 1.59, 95%CI 1.08-2.04) but not in older adults (≥60 years) (HR = 1.05, 95%CI 0.80-1.39). A synergistic effect between mmOSA and CBVD was stronger in those <60 years (HR = 3.82, 95%CI 2.25-6.48 in <60 years vs 1.86 95%CI 1.14-3.04 in ≥60 years). There was an additive effect between moderate OSA and hypertension in <60 but not in those ≥60 years. Mild OSA was associated with all-cause mortality only in the presence of CBVD. Mortality risk is increased in young and middle-aged adults with moderate OSA, whereas the mortality risk associated with mild OSA is elevated only, regardless of age, in the presence of comorbid CBVD. AHI cut-offs warranting treatment of mmOSA may need to be adjusted based on age and comorbidities.

Circadian Misalignment Impacts the Association of Visceral Adiposity With Elevated Blood Pressure in Adolescents.

BACKGROUND: Although insufficient sleep has been shown to contribute to obesity-related elevated blood pressure, the circadian timing of sleep has emerged as a novel risk factor. We hypothesized that deviations in sleep midpoint, a measure of circadian timing of sleep, modify the association between visceral adiposity and elevated blood pressure in adolescents. METHODS: We studied 303 subjects from the Penn State Child Cohort (16.2±2.2 years; 47.5% female; 21.5% racial/ethnic minority). Actigraphy-measured sleep duration, midpoint, variability, and regularity were calculated across a 7-night period. Visceral adipose tissue (VAT) was measured with dual-energy X-ray absorptiometry. Systolic blood pressure (SBP) and diastolic blood pressure levels were measured in the seated position. Multivariable linear regression models tested sleep midpoint and its regularity as effect modifiers of VAT on SBP/diastolic blood pressure levels, while adjusting for demographic and sleep covariables. These associations were also examined as a function of being in-school or on-break. RESULTS: Significant interactions were found between VAT and sleep irregularity, but not sleep midpoint, on SBP (P interaction=0.007) and diastolic blood pressure (P interaction=0.022). Additionally, significant interactions were found between VAT and schooldays sleep midpoint on SBP (P interaction=0.026) and diastolic blood pressure (P interaction=0.043), whereas significant interactions were found between VAT and on-break weekdays sleep irregularity on SBP (P interaction=0.034). CONCLUSIONS: A delayed and an irregular sleep midpoint during school and during free-days, respectively, increase the impact of VAT on elevated blood pressure in adolescents. These data suggest that deviations in the circadian timing of sleep contribute to the increased cardiovascular sequelae associated with obesity and that its distinct metrics require measurement under different entrainment conditions in adolescents.

Short-term and intermediate-term fine particulate air pollution are synergistically associated with habitual sleep variability in adolescents - A cross-sectional study.

BACKGROUND: Both air pollution and poor sleep have been associated with increased risk of cardiovascular diseases. However, the association between air pollution and sleep health, especially among adolescents, is rarely investigated. METHODS: To investigate the association between fine particulate (PM2.5) air pollution and habitual sleep patterns, we analyzed data obtained from 246 adolescents who participated in the Penn State Child Cohort follow-up examination. We collected their individual-level 24-h (short-term) PM2.5 concentration by using a portable monitor. We estimated their residential-level PM2.5 concentration during the 60-day period prior to the examination (intermediate-term) using a kriging approach. Actigraphy was used to measure participants' sleep durations for seven consecutive nights. Habitual sleep duration (HSD) and sleep variability (HSV) were calculated as the mean and SD of the seven-night sleep duration. Multivariable-adjusted linear regression models were used to assess the association between PM2.5 exposures and HSD/HSV. An interaction between short-term and intermediate-term PM2.5 was created to explore their synergistic associations with HSD/HSV. RESULTS: Elevated short-term and intermediate-term PM2.5 exposure were significantly (p < 0.05) associated with higher HSV, but not HSD. Specifically, the mean (95% CI) increase in HSV associated with 1 SD higher 24-h (26.3 µg/m3) and 60-day average (2.2 µg/m3) PM2.5 were 14.6 (9.4, 14.8) and 4.9 (0.5, 9.2) minutes, respectively. In addition, there was a synergistic interaction (p = 0.08) between short-term and intermediate-term PM2.5 exposure on HSV, indicative that the association between intermediate-term PM2.5 and HSV became stronger as short-term PM2.5 increases, and vice versa. CONCLUSION: Short-term individual-level and intermediate-term residential-level PM2.5 exposures are adversely and synergistically associated with increased sleep variability, an indicator of instability of sleep quantity, in adolescents. Through such an association with sleep pattern, PM2.5 air pollution may increase long-term cardiometabolic risks.

Acute Impact of Fine Particulate Air Pollution on Cardiac Arrhythmias in a Population-Based Sample of Adolescents: The Penn State Child Cohort.

Background Fine particulate (fine particles with aerodynamic diameters ≤2.5 µm [PM2.5]) exposure has been associated with a risk of cardiac arrhythmias in adults. However, the association between PM2.5 exposure and cardiac arrhythmias in adolescents remains unclear. Methods and Results To investigate the association and time course between PM2.5 exposure with cardiac arrhythmias in adolescents, we analyzed the data collected from 322 adolescents who participated in the PSCC (Penn State Child Cohort) follow-up examination. We obtained individual-level 24-hour PM2.5 concentrations with a nephelometer. Concurrent with the PM2.5 measure, we obtained 24-hour ECG data using a Holter monitor, from which cardiac arrhythmias, including premature atrial contractions and premature ventricular contractions (PVCs), were identified. PM2.5 concentration and numbers of premature atrial contractions/PVCs were summarized into 30-minute-based segments. Polynomial distributed lag models within a framework of a negative binomial model were used to assess the effect of PM2.5 concentration on numbers of premature atrial contractions and PVCs. PM2.5 exposure was associated with an acute increase in number of PVCs. Specifically, a 10 µg/m3 increase in PM2.5 concentration was associated with a 2% (95% CI, 0.4%-3.3%) increase in PVC counts 0.5 to 1.0, 1.0 to 1.5, and 1.5 to 2.0 hours after the exposure. Cumulatively, a 10 µg/m3 increment in PM2.5 was associated with a 5% (95% CI, 1%-10%) increase in PVC counts within 2 hours after exposure. PM2.5 concentration was not associated with premature atrial contraction. Conclusions PM2.5 exposure was associated with an acute increased number of ventricular arrhythmias in a population-based sample of adolescents. The time course of the effect of PM2.5 on ventricular arrhythmia is within 2 hours after exposure.

Association of insomnia phenotypes based on polysomnography-measured sleep duration with suicidal ideation and attempts.

OBJECTIVE: To assess the association of insomnia phenotypes, being insomnia with short sleep duration (ISSD) and insomnia with normal sleep duration (INSD), with suicidality in a randomly selected population-based sample. METHODS: Data were analyzed from the Penn State Adult Cohort. Participants (N = 1741, 52.5 years, 57.4% female) were randomly recruited from the general population between January 1990 through March 1999 and mortality data were available through December 2018. Insomnia symptoms were defined as self-reports of moderate-to-severe difficulties initiating or maintaining sleep, early morning awakening and non-restorative sleep, or having chronic insomnia (n = 719). Short sleep duration was defined as <6 hours of in-lab polysomnography-measured sleep duration (n = 879). Suicidality (SAI; n = 102) was ascertained by a lifetime history of suicidal ideation (SI; n = 84), suicide attempts (SA; n = 48) or death by suicide (DBS; n = 10). RESULTS: Compared to normal sleepers who slept ≥6 hours, participants with ISSD and INSD were associated with 1.72-fold and 2.22-fold increased odds of SAI, respectively; these associations were significant for SI, with 2.09-fold and 2.24-fold increased odds, respectively, but not for SA, after adjusting for physical and mental health comorbidities. ISSD and INSD differed in SAI age of onset and hospitalizations after SA. CONCLUSIONS: The results of this cohort study suggest that both INSD and ISSD phenotypes are associated with increased suicidal ideation, while the INSD phenotype has an earlier age of onset and is more likely to experience hospitalizations after attempting suicide. These results highlight the importance of targeting insomnia symptoms to help prevent suicide.

Trajectories of Insomnia Symptoms From Childhood Through Young Adulthood.

OBJECTIVES: Insomnia symptoms are transdiagnostic to physical and mental health disorders. Given the lack of population-based cohorts with objective sleep measures and long-term follow-ups, little is known about the chronicity of childhood insomnia symptoms. We determined the developmental trajectories of insomnia symptoms, their evolution into adult insomnia, and the role of objective sleep duration in the transition to adulthood. METHODS: A total of 502 children (median 9 years old, 71.7% response rate) were studied 7.4 years later as adolescents (median 16 years old) and 15 years later as adults (median 24 years old). Insomnia symptoms were ascertained as moderate-to-severe difficulties initiating and/or maintaining sleep via parent- or self reports at all 3 time points, adult insomnia via self-report in young adulthood, and objective short-sleep duration via polysomnography in childhood and adolescence. RESULTS: Among children with insomnia symptoms, the most frequent trajectory was persistence (43.3%), followed by remission (26.9% since childhood, 11.2% since adolescence) and a waxing-and-waning pattern (18.6%). Among children with normal sleep, the most frequent trajectory was persistence (48.1%), followed by developing insomnia symptoms (15.2% since adolescence, 20.7% in adulthood) and a waxing-and-waning pattern (16.0%). The odds of insomnia symptoms worsening into adult insomnia (22.0% of children, 20.8% of adolescents) were 2.6-fold and 5.5-fold among short-sleeping children and adolescents, respectively. CONCLUSIONS: Early sleep interventions are a health priority because pediatricians should not expect insomnia symptoms to developmentally remit in a high proportion of children. Objective sleep measures may be clinically useful in adolescence, a critical period for the adverse prognosis of the insomnia with short-sleep duration phenotype.

Evidence of a maturational disruption in non-rapid eye movement sleep slow wave activity in youth with attention-deficit/hyperactivity, learning and internalizing disorders.

BACKGROUND: Sleep slow wave activity (SWA) peaks during childhood and declines in the transition to adolescence during typical development (TD). It remains unknown whether this trajectory differs in youth with neuropsychiatric disorders. METHODS: We analyzed sleep EEGs of 664 subjects 6 to 21 y (449 TD, 123 unmedicated, 92 medicated) and 114 subjects 7-12 y (median 10.5 y) followed-up at 18-22 y (median 19 y). SWA (0.4-4 Hz) power was calculated during non-rapid eye movement sleep. RESULTS: TD and unmedicated youth showed cubic central and frontal SWA trajectories from 6 to 21 y (p-cubic<0.05), with TD youth showing peaks in central SWA at 6.8 y and frontal at 8.2 y. Unmedicated attention-deficit/hyperactivity (ADHD) and/or learning disorders (LD) showed peak central SWA 2 y later (at 9.6 y, coinciding with peak frontal SWA) than TD, followed by a 67% steeper slope by 19 y. Frontal SWA peak and slope in unmedicated ADHD/LD, and that of central and frontal in internalizing disorders (ID), were similar to TD. Unmedicated ADHD/LD did not differ in the longitudinal SWA percent change by 18-22 y; unmedicated ID showed a lower longitudinal change in frontal SWA than TD. Medicated youth showed a linear decline in central and frontal SWA from 6 to 21 y (p-linear<0.05). CONCLUSIONS: ADHD/LD youth show a maturational delay and potential topographical disruption in SWA during childhood and steeper decline throughout adolescence, suggesting faster synaptic pruning. Youth with ID experience less changes in frontal SWA by late adolescence. Psychotropic medications may impact the maturational trajectory of SWA, but not the magnitude of developmental decline by late adolescence.

Behavioral, neurocognitive, polysomnographic and cardiometabolic profiles associated with obstructive sleep apnea in adolescents with ADHD.

BACKGROUND: A high comorbidity between attention-deficit/hyperactivity disorder (ADHD) and obstructive sleep apnea (OSA) as well as similar impairments across neurobehavioral outcomes has been described in children. However, there is a paucity of research examining the comorbidity of these two disorders in adolescents. This study examined the association of OSA with sleep, neurobehavioral, and cardiometabolic outcomes in adolescents with ADHD from the general population. METHODS: 421 adolescents (16.9 ± 2.3 years, 53.9% male) underwent 9-hr polysomnography, neurobehavioral, and physical evaluation. ADHD was ascertained by a parent-or-self-report of a lifetime diagnosis/treatment of ADHD. OSA was defined as an apnea hypopnea index of ≥2 events/hour. Groups of controls (n = 208), OSA-alone (n = 115), ADHD-alone (n = 54), and ADHD+OSA (n = 44) were studied. Multivariable-adjusted general linear models tested group differences in PSG parameters, neurobehavioral, and cardiometabolic outcomes after controlling for sex, race/ethnicity, age, and/or body mass index percentile. RESULTS: The ADHD+OSA group had significantly longer sleep onset latency, shorter total sleep time, lower sleep efficiency, and higher percent of stage 1 sleep, as compared with all other groups, however, these differences were diminished by excluding adolescents on psychoactive medication. The ADHD-alone group showed significantly higher periodic limb movements than controls. The ADHD+OSA and ADHD-alone groups did not significantly differ on any measure of neurocognitive or behavioral functioning. The ADHD+OSA and OSA-alone groups showed significantly worse cardiometabolic and inflammatory biomarkers when compared to controls or the ADHD-alone, but did not significantly differ between each other. CONCLUSIONS: Adolescents with a diagnosis ADHD+OSA showed phenotypic risk factors for OSA (i.e., overweight/obesity, visceral adiposity, metabolic syndrome, and inflammation) but not worse neurobehavioral outcomes when compared with ADHD-alone. While comorbidity is possible, these data support that adolescents with a suspicion of ADHD should be screened for OSA, before a diagnosis is reached and psychoactive medication initiated.

Association of a novel EEG metric of sleep depth/intensity with attention-deficit/hyperactivity, learning, and internalizing disorders and their pharmacotherapy in adolescence.

STUDY OBJECTIVES: Psychiatric/learning disorders are associated with sleep disturbances, including those arising from abnormal cortical activity. The odds ratio product (ORP) is a standardized electroencephalogram metric of sleep depth/intensity validated in adults, while ORP data in youth are lacking. We tested ORP as a measure of sleep depth/intensity in adolescents with and without psychiatric/learning disorders. METHODS: Four hundred eighteen adolescents (median 16 years) underwent a 9-hour, in-lab polysomnography. Of them, 263 were typically developing (TD), 89 were unmedicated, and 66 were medicated for disorders including attention-deficit/hyperactivity (ADHD), learning (LD), and internalizing (ID). Central ORP during non-rapid eye movement (NREM) sleep was the primary outcome. Secondary/exploratory outcomes included central and frontal ORP during NREM stages, in the 9-seconds following arousals (ORP-9), in the first and second halves of the night, during REM sleep and wakefulness. RESULTS: Unmedicated youth with ADHD/LD had greater central ORP than TD during stage 3 and in central and frontal regions during stage 2 and the second half of the sleep period, while ORP in youth with ADHD/LD on stimulants did not significantly differ from TD. Unmedicated youth with ID did not significantly differ from TD in ORP, while youth with ID on antidepressants had greater central and frontal ORP than TD during NREM and REM sleep, and higher ORP-9. CONCLUSIONS: The greater ORP in unmedicated youth with ADHD/LD, and normalized levels in those on stimulants, suggests ORP is a useful metric of decreased NREM sleep depth/intensity in ADHD/LD. Antidepressants are associated with greater ORP/ORP-9, suggesting these medications induce cortical arousability.

Hypothalamic-pituitary-adrenal (HPA) axis response to exogenous corticotropin-releasing hormone (CRH) is attenuated in men with chronic insomnia.

Although insomnia is by far the most common sleep disorder, our understanding of its neurobiology is limited. Insomnia, particularly when associated with objective sleep disturbance, has been associated with activation of the hypothalamic-pituitary-adrenal axis. The objective of this experimental study was to compare the response of the hypothalamic-pituitary-adrenal axis to ovine corticotropin-releasing hormone, a stress test, in men with insomnia versus controls. Circulating adrenocorticotropic hormone and cortisol levels were assayed before (-30 min, -15 min), at (0 min) and after (+5 min, +15 min, +30 min, +60 min, +90 min, +120 min) exogenous ovine corticotropin-releasing hormone administration in 23 men (11 insomnia, 12 controls), who underwent four consecutive nights of in-lab polysomnography. Men with insomnia compared with controls demonstrated markedly and significantly shorter total sleep time (368.4 ± 8.99 min versus 411.61 ± 8.61 min; p < 0.01) and lower sleep efficiency (76.77 ± 1.80% versus 86.04 ± 1.72%; p < 0.01) on polysomnography, and showed decreased adrenocorticotropic hormone and cortisol levels after ovine corticotropin-releasing hormone administration. Adrenocorticotropic hormone levels at 15 min and 30 min were significantly lower in men with insomnia than in controls (p < 0.05). Similarly, the peak levels of cortisol at +60 min, and the total and net area under the curve levels of this hormone were significantly lower in men with insomnia than controls (all p < 0.01). Adrenocorticotropic hormone and cortisol response to ovine corticotropin-releasing hormone administration was attenuated in men with insomnia associated with objective sleep disturbance, suggesting that objectively defined insomnia subtypes have a disrupted hypothalamic-pituitary-adrenal axis function and highlight the need to develop treatments targeting the underlying hypothalamic-pituitary-adrenal axis dysregulation.

Reregulation of cortisol levels and sleep in patients with prescription opioid use disorder during long-term residential treatment.

OBJECTIVE: Research has demonstrated that hypothalamic-pituitary-adrenal (HPA) axis function and sleep patterns are dysregulated in patients diagnosed with opioid use disorder (OUD). It is unclear whether and/or when cortisol and sleep might re-regulate over time, and, whether re-regulation is associated with abstinence following discharge from residential treatment. The current study evaluated changes in sleep and basal cortisol levels in prescription OUD patients in residential treatment, and the association between these measures and treatment outcome following discharge. METHOD: As part of a larger study, 55 participants with prescription OUD provided two days of salivary cortisol samples and 12 consecutive nights of sleep actigraphy between days 19-30 of residential treatment (Time Point 1; TP1). Thirteen of the original 55 participants remained in residence and repeated the measures between days 60-72 (Time Point 2; TP2). Thirty-seven healthy controls (HC) provided baseline measures (TP1) of salivary cortisol and sleep. Treatment outcome data, abstinence vs relapse, were established at 120 days following discharge. RESULTS: Prescription OUD patients had higher cortisol levels and lower total sleep time (TST) than HC at TP1. At TP2, TST and cortisol levels no longer differed from HCs in the subgroup of patients who remained abstinent following discharge after TP2. Individuals whose cortisol and TST did not change from TP1 to TP2 were more likely to relapse following discharge from residential treatment. CONCLUSION: Re-regulation of TST and cortisol levels while in residential treatment was associated with better treatment outcome following discharge for prescription OUD patients.

Association of Pediatric Obstructive Sleep Apnea With Elevated Blood Pressure and Orthostatic Hypertension in Adolescence.

Importance: Although pediatric guidelines have delineated updated thresholds for elevated blood pressure (eBP) in youth and adult guidelines have recognized obstructive sleep apnea (OSA) as an established risk factor for eBP, the relative association of pediatric OSA with adolescent eBP remains unexplored. Objective: To assess the association of pediatric OSA with eBP and its orthostatic reactivity in adolescence. Design, Setting, and Participants: At baseline of this population-based cohort study (Penn State Child Cohort) in 2000-2005, a random sample of 700 children aged 5 to 12 years from the general population was studied. A total of 421 participants (60.1%) were followed up in 2010-2013 after 7.4 years as adolescents (ages, 12-23 years). Data analyses were conducted from July 6 to October 29, 2020. Main Outcomes and Measures: Outcomes were the apnea-hypopnea index (AHI) score, ascertained via polysomnography conducted in a laboratory; eBP measured in the seated position identified using guideline-recommended pediatric criteria; orthostatic hyperreactivity identified with BP assessed in the supine and standing positions; and visceral adipose tissue assessed via dual-energy x-ray absorptiometry. Results: Among the 421 participants (mean [SD] age at follow-up, 16.5 [2.3] years), 227 (53.9%) were male and 92 (21.9%) were racial/ethnic minorities. A persistent AHI of 2 or more since childhood was longitudinally associated with adolescent eBP (odds ratio [OR], 2.9; 95% CI 1.1-7.5), while a remitted AHI of 2 or more was not (OR, 0.9; 95% CI 0.3-2.6). Adolescent OSA was associated with eBP in a dose-response manner; however, the association of an AHI of 2 to less than 5 among adolescents was nonsignificant (OR, 1.5; 95% CI, 0.9-2.6) and that of an AHI of 5 or more was approximately 2-fold (OR, 2.3; 95% CI, 1.1-4.9) after adjusting for visceral adipose tissue. An AHI of 5 or more (OR, 3.1; 95% CI, 1.2-8.5), but not between 2 and less than 5 (OR, 1.3; 95% CI, 0.6-3.0), was associated with orthostatic hyperreactivity among adolescents even after adjusting for visceral adipose tissue. Childhood OSA was not associated with adolescent eBP in female participants, while the risk of OSA and eBP was greater in male participants. Conclusions and Relevance: The results of this cohort study suggest that childhood OSA is associated with adolescent hypertension only if it persists during this developmental period. Visceral adiposity explains a large extent of, but not all, the risk of hypertension associated with adolescent OSA, which is greater in male individuals.