Age-associated sleep spindle characteristics in Duchenne muscular dystrophy.

Brain oscillations of non-rapid eye movement sleep, including slow oscillations (SO, 0.5-1.5 Hz) and spindles (10-16 Hz), mirror underlying brain maturation across development and are associated with cognition. Hence, age-associated emergence and changes in the electrophysiological properties of these rhythms can lend insight into cortical development, specifically in comparisons between pediatric populations and typically developing peers. We previously evaluated age-associated changes in SOs in male patients with Duchenne muscular dystrophy (DMD), finding a significant age-related decline between 4 and 18 years. While primarily a muscle disorder, male patients with DMD can also have sleep, cognitive, and cortical abnormalities, thought to be driven by altered dystrophin expression in the brain. In this follow-up study, we characterized the age-associated changes in sleep spindles. We found that age-dependent spindle characteristics in patients with DMD, including density, frequency, amplitude, and duration, were consistent with age-associated trends reported in the literature for typically developing controls. Combined with our prior finding of age-associated decline in SOs, our results suggest that SOs, but not spindles, are a candidate intervention target to enhance sleep in patients with DMD.

Normal Neonatal Sleep Defined: Refining Patient Selection and Interpreting Sleep Outcomes for Mandibular Distraction.

BACKGROUND: Although polysomnography is paramount when evaluating neonatal airway obstruction, "normal" published references do not exist. We present normative polysomnography data for newborns age 0-1 month. We compare this reference to pre and postoperative sleep data from infants undergoing mandibular distraction osteogenesis (MDO) at this same age. METHODS: Following IRB approval, normative subjects were recruited from our neonatal intensive care unit to undergo nap polysomnography. One blinded sleep physician read all studies. From 2016 to 2019, we prospectively collected sleep data for newborns undergoing MDO. RESULTS: In total, 22 neonates without airway obstruction provided normative sleep data. Median total apnea-hypopnea index (AHI), obstructive apnea-hypopnea index (OAHI), and central apnea index (CAI) were 7.3, 4.9, and 0.7 events/hour. Median O2 nadir was 91%. Polysomnography for 13 neonates before MDO and during consolidation showed median preoperative AHI was 38.3, OAHI was 37.0, CAI was 1.9, and median O2 nadir was 83%. Following MDO, median AHI was 6.1, OAHI was 4.0, CAI was 1.3, and median O2 nadir was 92.5%. Paired t-tests confirmed significant improvements in all indices; when comparing the postoperative group with the normative group, there was no difference in oxygenation nor any respiratory index. CONCLUSIONS: "Normal" neonates have more obstructive events and lower oxygenation nadirs than previously appreciated. We provide normative nap polysomnography values for this age group and encourage centers with multidisciplinary MDO teams to utilize this data to calibrate patient selection algorithms, inform treatment discussions, and better understand surgical outcomes. Limitations include a small sample size and single institution study.

Slow oscillation density and amplitude decrease across development in pediatric Duchenne and Becker muscular dystrophy.

STUDY OBJECTIVES: From childhood through adolescence, brain rhythms during non-rapid eye movement (NREM) sleep show dramatic development that mirror underlying brain maturation. For example, the function and characteristics of slow oscillations (SOs, <1 Hz) in healthy children are linked to brain development, motor skill, and cognition. However, little is known of possible changes in pediatric populations with neurologic abnormalities. METHODS: We measured slow oscillations in 28 Duchenne and Becker muscular dystrophy male patients from age 4 to 20 years old during overnight in-lab clinical sleep studies. We compared our pediatric patients by age to evaluate the developmental changes of SOs from childhood to early and late adolescence. RESULTS: Consistent with the current neuro- and physically typical literature, we found greater slow oscillation density (count of SOs per minute of each sleep stage) in NREM N3 than N2, and significantly greater slow oscillation density in frontal compared to central and occipital regions. However, separating patients into age-defined groups (child, early adolescent, and late adolescent) revealed a significant age effect, with a specific decline in the rate and amplitude of SOs. CONCLUSIONS: We found that with age, pediatric patients with Duchenne muscular dystrophy show a significant decline in slow oscillation density. Given the role that slow oscillations play in memory formation and retention, it is critical to developmentally characterize these brain rhythms in medically complex populations. Our work converges with previous pediatric sleep literature that promotes the use of sleep electroencephalographic markers as prognostic tools and identifies potential targets to promote our patients' quality of life.

Protective Effects of Inducible HO-1 on Oxygen Toxicity in Rat Brain Endothelial Microvessel Cells.

BACKGROUND: Reperfusion in ischemia is believed to generate cytotoxic oxidative stress, which mediates reperfusion injury. These stress conditions can initiate lipid peroxidation and damage to proteins, as well as promote DNA strand breaks. As biliverdin and bilirubin produced by heme oxygenase isoform 1 (HO-1) have antioxidant properties, the production of both antioxidants by HO-1 may help increase the resistance of the ischemic brain to oxidative stress. In the present study, the survival effect of HO-1 was confirmed using hemin. METHODS: To confirm the roles of HO-1, carbon monoxide, and cyclic guanosine monophosphate further in the antioxidant effect of HO-1 and bilirubin, cells were treated with cycloheximide, desferoxamine, and zinc deuteroporphyrin IX 2,4 bis glycol, respectively. RESULTS: HO-1 itself acted as an antioxidant. Furthermore, iron, rather than carbon monoxide, was involved in the HO-1-mediated survival effect. HO-1 activity was also important in providing bilirubin as an antioxidant. CONCLUSION: Our results suggested that HO-1 helped to increase the resistance of the ischemic brain to oxidative stress.

Sleep-disordered breathing in children with metabolic syndrome: the role of leptin and sympathetic nervous system activity and the effect of continuous positive airway pressure.

OBJECTIVE: The purpose of this work was to determine whether, in children with metabolic syndrome and sleep-disordered breathing, metabolic markers separate them from children with metabolic syndrome without sleep-disordered breathing and whether treatment of sleep-disordered breathing with continuous positive airway pressure is associated with an improvement in metabolic derangement. PATIENTS AND METHODS: Subjects aged 7 to 19 years old with metabolic syndrome and a positive validated sleep questionnaire were recruited. Subjects underwent overnight polysomnography, during which sympathetic nervous system activity was assessed via 8-hourly measurements of norepinephrine and epinephrine, together with leptin. The next morning, a fasting 3-hour oral glucose-tolerance test was performed to calculate whole-body insulin sensitivity. A fasting lipid panel interleukin 6, adiponectin, and C-reactive protein levels were also measured. Children with sleep-disordered breathing were placed on continuous positive airway pressure for 3 months and studied again. Sleep-disordered breathing and no sleep-disordered breathing groups were compared by using Fisher's exact test and t test for independent samples with analysis of covariance to adjust for age and BMI. RESULTS: Of 34 children studied, 25 had sleep-disordered breathing (apnea-hypopnea index: >1.5). Mean hourly norepinephrine and leptin levels were higher in the group with sleep-disordered breathing compared with the group without sleep-disordered breathing (P < .005), with no difference in whole-body insulin sensitivity. Eleven subjects with sleep-disordered breathing completed 3 months of nightly continuous positive airway pressure treatment. In the follow-up study, mean hourly leptin levels were significantly lower than in the initial study, with no change in BMI z score or other measurements. CONCLUSION: Our findings support the hypothesis that sleep-disordered breathing in children with metabolic syndrome is associated with increased sympathetic nervous system activity and leptin levels but not worsening of insulin resistance. Treatment of sleep-disordered breathing with continuous positive airway pressure led to a significant decrease in leptin levels.