Cortical grey matter changes, behavior and cognition in children with sleep disordered breathing.

This paper investigated cortical thickness and volumetric changes in children to better understand the impact of obstructive sleep disordered breathing (SDB) on the neurodevelopment of specific regions of the brain. We also aimed to investigate how these changes were related to the behavioral and cognitive deficits observed in the condition. Neuroimaging, behavioral, and sleep data were obtained from 30 children (15 non-snoring controls, 15 referred for assessment of SDB) aged 7 to 17 years. Gyral-based regions of interest were identified using the Desikan-Killiany atlas. Student's t-tests were used to compare regions of interest between the controls and SDB groups. We found that the cortical thickness was significantly greater in the right caudal anterior cingulate and right cuneus regions and there were volumetric increases in the left caudal middle frontal, bilateral rostral anterior cingulate, left, right, and bilateral caudate brain regions in children with SDB compared with controls. Neither cortical thickness nor volumetric changes were associated with behavioral or cognitive measures. The findings of this study indicate disruptions to neural developmental processes occurring in structural regions of the brain; however, these changes appear unrelated to behavioural or cognitive outcomes.

Sleep disordered breathing in children disrupts the maturation of autonomic control of heart rate and its association with cerebral oxygenation.

KEY POINTS: Sleep disordered breathing (SDB) affects 4-11% of children and is associated with adverse neurocognitive, behavioural and cardiovascular outcomes, including reduced autonomic control. The relationship between heart rate variability (HRV; a measure of autonomic control) and age found in non-snoring control children was absent during sleep in children with SDB. Age significantly predicted increasing cerebral oxygenation during wake in non-snoring control children, whereas during sleep, HRV significantly predicted decreasing cerebral oxygenation. Cerebral oxygenation was not associated with either age or HRV in children with SDB during both wake and sleep. SDB significantly disrupts the normal maturation of autonomic control and the positive association between autonomic control and cerebral oxygenation found in non-snoring children, and we speculate that the dampened autonomic control exhibited by children with SDB may have an attenuating effect on cerebral autoregulation via the moderating influence of HRV on cerebral blood flow. ABSTRACT: The repetitive episodes of hypoxia that are features of sleep disordered breathing (SDB) in children are associated with alterations in autonomic control of heart rate in an age-dependent manner. We aimed to relate heart rate variability (HRV) parameters to age and measures of cerebral oxygenation in children (3-12 years old) with SDB and non-snoring controls. Children (SDB, n = 117; controls, n = 42; 3-12 years) underwent overnight polysomnography. Total (TP), low- (LF) and high-frequency (HF) power, tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) were analysed during wake and sleep. Pearson's correlations determined the association between age and HRV parameters, and multiple linear regressions between HRV, age and cerebral oxygenation parameters. During wake, age had a positive association with LF power, reflecting increased parasympathetic and sympathetic activity with increasing age for both control and SDB groups. This association was also evident during sleep in controls, but was absent in children with SDB. In controls, during wake TOI had a positive, and FTOE a negative association with age. During sleep, TP, LF and HF power were significant, negative determinants of TOI and positive determinants of FTOE. These associations were not seen in children with SDB during wake or sleep. SDB disrupts the normal maturation of the autonomic control of heart rate and the association between HRV and cerebral oxygenation exhibited by non-snoring control children of primary school age. These results highlight the impact SDB has on cardiovascular control and the potential impact on adverse cardiovascular outcomes.

Age Effects on Cerebral Oxygenation and Behavior in Children with Sleep-disordered Breathing.

RATIONALE: Childhood sleep-disordered breathing ranges in severity from primary snoring to obstructive sleep apnea and is associated with behavioral and neurocognitive deficits. It remains unknown why children with primary snoring, who do not experience peripheral oxygen desaturation or sleep fragmentation, experience similar daytime deficits as those with obstructive sleep apnea or why effects are age-dependent. OBJECTIVES: To examine cerebral tissue oxygenation and oxygen extraction as an explanation for daytime deficits in children with primary snoring. METHODS: Children referred for suspected sleep-disordered breathing and nonsnoring control subjects underwent overnight polysomnography with near-infrared spectroscopy. Children were categorized into 3- to 6-year (n = 87) and 7- to 12-year (n = 72) old groups, and according to the obstructive apnea-hypopnea index into primary snoring (≤1 event/h), mild (>1-5 events/h), and moderate/severe obstructive sleep apnea (>5 events/h). Cognitive and behavioral performance were assessed. MEASUREMENTS AND MAIN RESULTS: In the 3- to 6-year group, there were no differences in cerebral oxygenation or oxygen extraction between severity groups. In the 7- to 12-year group, cerebral oxygenation was significantly lower, although these differences were small, in control subjects versus primary snoring during quiet wakefulness before sleep onset, N1, and REM. Oxygen extraction was significantly higher in control subjects versus primary snoring during N1 sleep, with no differences between primary snoring and obstructive sleep apnea groups. Cerebral oxygenation was not associated with cognitive performance in either age group or behavior in the 3- to 6-year group; however, it was associated with behavior in the school-aged children. CONCLUSIONS: Children with sleep-disordered breathing are able to maintain cerebral oxygenation, and the small changes observed are not related to cognitive deficits. However, in older children these differences were related to behavioral measures.

Pollen levels on the day of polysomnography influence sleep disordered breathing severity in children with allergic rhinitis.

PURPOSE: Allergic rhinitis (AR) is a common risk factor for sleep disordered breathing (SDB) in children. Allergy to pollen is a trigger for allergic rhinitis, causing nasal inflammation, upper airway congestion and obstruction. We aimed to determine if the pollen count on the day of diagnostic polysomnography for SDB affected the result. METHODS: Children (3-18 years; n = 90) who participated in research studies between 1 October and 31 December, when daily regional pollen counts were available, in the years 2005-2016 were eligible for inclusion. All children underwent overnight polysomnography for assessment of SDB severity. Pollen was categorised as grass or other pollen. Multiple stepwise linear regression was performed to determine whether the pollen count for that day, a diagnosis of asthma, age, and BMI-z-score were determinants of respiratory parameters measured on polysomnography, including the obstructive apnoea hypopnoea index (OAHI), SpO2 nadir, average SpO2 drop, SpO2 < 90%, oxygen desaturation index > 4% (ODI4), and average transcutaneous CO2 (TCM). RESULTS: Sixteen/90 children had AR. In children with AR, an increase in grass pollen of 1 grain/m3 predicted an increase in OAHI of 0.2 events/h, ODI4 of 0.18 times/h, SpO2 < 90% of 0.03 times/h, and TCM of 0.07 mmHg. None of the factors were determinants of SDB severity in children without AR. CONCLUSION: Our findings highlight that daily pollen counts may be an important factor influencing the severity of SDB on a single night of polysomnography in children with clinical allergic rhinitis and should be taken into account when determining treatment options.

Obesity and anthropometric determinants of autonomic control in children with sleep-disordered breathing-which measurements matter?

BACKGROUND: Obesity and anthropometric measurements predict more severe sleep-disordered breathing (SDB) in children, and are associated with cardiovascular risk factors in children without SDB. We aimed to investigate whether anthropometric measurements predicted autonomic control in children with SDB. We hypothesised that anthropometric measures would be significant predictors of decreased heart rate variability. METHODS: Children (3-17 years) with SDB (n = 298) and non-snoring controls (n = 126) underwent polysomnography. BMI z-score, neck, waist and hip circumference were recorded. Heart rate variability, indicating autonomic control, was analysed during wake, non-rapid eye movement stages N1, N2 and N3, and rapid eye movement (REM) sleep. The determinants of heart rate variability (low-frequency power [LF], high-frequency power [HF] and LF/HF ratio) were analysed using multiple stepwise linear regression. Independent variables were age, neck, waist and hip circumference, neck-to-waist ratio, waist-to-hip ratio and waist-to-height ratio, obstructive apnoea hypopnoea index, arousal index and SpO2 nadir. RESULTS: Waist and hip circumference, and waist-to-height ratio were significant negative determinants of both HF and LF power during wake, reflecting dampened autonomic control (LF: waist/height ratio, B = -1917 (95% CI: -3640, -194), p = 0.03; HF: hip circumference, B = -27, (-48, -7), p = 0.01), N1&2 (LF/HF: hip circumference, B = 0.01 (0.004, 0.024), p = 0.005) and N3 (LF: waist/height ratio, B = -2495, (-4005, -986), p = 0.001; HF, hip circumference, B = -54, (-102, -6), p = 0.03; LF/HF, waist circumference, B = 0.01, (0.004, 0.015), p = 0.002). Age was the strongest determinant of heart rate variability during wake and sleep. CONCLUSION: This study suggests that while age is a determinant of autonomic control in children with SDB, the strongest modifiable factor determining dampened autonomic control is increased central adiposity, as reflected in the waist and hip circumference and the waist-to-height ratio.

Risk factors for obstructive sleep apnoea in Australian children.

AIM: This study aims to determine whether demographic or clinical factors predict obstructive sleep apnoea (OSA) severity in Australian children. METHODS: Demographic details and medical histories of 301 Australian children (3-17 years old) referred for assessment of OSA were examined retrospectively. Children underwent overnight polysomnography and were classified as having primary snoring (PS) (obstructive apnoea hypopnoea index (OAHI) ≤ 1 event per hour; n = 150), mild OSA (>1 OAHI ≤ 5 events per hour; n = 76) or moderate/severe (MS) OSA (OAHI > 5 events per hour; n = 75). Information obtained from parent-report questionnaire determined the predictive value of the following factors for determining OSA severity: gender, ethnicity, body mass index, asthma and/or allergic rhinitis, socio-economic status and parental smoking status (mother/father/both). Chi-squared analyses were used to compare the distribution of the demographic and clinical factors across the three groups. Statistically significant risk factors were subsequently entered into logistic regression analysis. RESULTS: Ethnicity and parental smoking were significant risk factors for MS OSA. Children with non-Caucasian ethnicity were 36% more likely than Caucasian children to be diagnosed with MS OSA than PS (P = 0.002). Children with fathers who smoked were 53% more likely to have MS OSA than PS compared with those with fathers who did not smoke (P = 0.008). Obesity was associated with OSA severity in primary school-aged children only. Gender, socio-economic status and history of asthma and/or allergic rhinitis were not risk factors. CONCLUSIONS: Non-Caucasian ethnicity, paternal smoking and obesity in older children were associated with an increased risk of polysomnography-confirmed MS OSA in Australian children.

The surge in heart rate and blood pressure at respiratory event termination is dampened in children with down syndrome.

BACKGROUND: Children with Down syndrome (DS) have a high prevalence of sleep disordered breathing (SDB) and altered cardiovascular autonomic control. We aimed to analyze the effect of DS on the surge in heart rate (HR) and pulse transit time (PTT, an inverse surrogate measure of blood pressure change) at respiratory event termination. METHODS: 44 children (3-19 y) with DS and 44 typically developing (TD) children matched for SDB severity, age and sex underwent overnight polysomnography. Multilevel modelling determined the effect of DS on HR and PTT changes between a 10s pre-event to the latter half of each respiratory event (late-event) and 15s post-event during NREM and REM, accounting for SDB severity and event length. RESULTS: The children with DS had a significantly smaller % change in HR late-event to post-event (NREM: DS 26.4 % ± 17.5 % (mean ± SD), TD 30.7 % ± 21.0 %; REM DS 16.9 % ± 15.3 %, TD 21.0 % ± 14.0 %; p < 0.05 for both) compared with TD children for obstructive events, and central events (13.2 % ± 17.0 %, TD 18.8 % ± 17.0 %; p < 0.01) during REM. %change in PTT was significantly smaller in the DS group during NREM and REM from pre-event and late-event to post-event compared with TD children for obstructive and central events. CONCLUSION: These results suggest children with DS have dampened HR and BP responses to respiratory events compared with TD children. Whether this is symptomatic of autonomic dysfunction or a protective factor for the cardiovascular system in children with DS remains to be elucidated.

The impact of central and obstructive respiratory events on cerebral oxygenation in children with sleep disordered breathing.

STUDY OBJECTIVES: Both central and obstructive respiratory events are features of sleep disordered breathing. The repetitive hypoxia associated with obstructive events is believed to underpin the adverse neurocognitive and cardiovascular sequelae of this disorder, however whether central events contribute to this has not been investigated. To compare changes in cerebral and peripheral oxygenation, blood pressure and heart rate, associated with central and obstructive events in children aged 3-6 and 7-12 years. METHODS: Sixty children referred for suspected sleep disordered breathing underwent overnight polysomnography. Beat-by-beat analysis determined changes from baseline in cerebral oxygenation, peripheral oxygen saturation, fractional tissue oxygen extraction, pulse transit time (a surrogate measure of blood pressure change), and heart rate, associated with central and obstructive respiratory events, during NREM and REM sleep. RESULTS: Eight hundred ninty-two events were analyzed: 493 central and 399 obstructive. Central events had a greater % change from baseline in cerebral oxygenation and heart rate nadir compared with obstructive events and these were greater in NREM compared with REM sleep. The 3- to 6-year-old children experienced a greater % change in TOI compared with the 7-12 year olds, while % change in heart rate was greater in 7-12 year olds. CONCLUSION: Central respiratory events had similar falls in cerebral oxygenation and heart rate to obstructive events and should be considered when examining the sequelae of sleep disordered breathing, particularly as central events are common in children with sleep disordered breathing.

Age and autonomic control, but not cerebral oxygenation, are significant determinants of EEG spectral power in children.

STUDY OBJECTIVES: Sleep disordered breathing (SDB) in children has significant effects on daytime functioning and cardiovascular control; attributed to sleep fragmentation and repetitive hypoxia. Associations between electroencephalograph (EEG) spectral power, autonomic cardiovascular control and cerebral oxygenation have been identified in adults with SDB. To date, there have been no studies in children. We aimed to assess associations between EEG spectral power and heart rate variability as a measure of autonomic control, with cerebral oxygenation in children with SDB. METHODS: One hundred sixteen children (3-12 years) with SDB and 42 controls underwent overnight polysomnography including measurement of cerebral oxygenation. Power spectral analysis of the EEG derived from C4-M1 and F4-M1, quantified delta, theta, alpha, and beta waveforms during sleep. Multiple regression tested whether age, SDB severity, heart rate (HR), HR variability (HRV), and cerebral oxygenation were determinants of EEG spectral power. RESULTS: There were no differences in EEG spectral power derived from either central or frontal regions for any frequency between children with different severities of SDB so these were combined. Age, HR, and HRV low frequency power were significant determinants of EEG spectral power depending on brain region and sleep stage. CONCLUSION: The significant findings of this study were that age and autonomic control, rather than cerebral oxygenation and SDB severity, were predictive of EEG spectral power in children. Further research is needed to elucidate how the physiology that underlies the relationship between autonomic control and EEG impacts on the cardiovascular sequelae in children with SDB.

Overweight and obese children with sleep disordered breathing have elevated arterial stiffness.

BACKGROUND: The prevalence of obese children with sleep disordered breathing (SDB) is increasing. Obesity and SDB are independent cardiovascular risk factors, of which arterial stiffness is an early sign. Pulse wave velocity (PWV), is a marker of arterial stiffness and central systolic blood pressure (cSBP) is a better predictor of cardiovascular outcome than peripheral blood pressure. Therefore, we aimed to determine PWV and cSBP in overweight/obese or normal weight children with sleep disordered breathing (SDB), and non-snoring normal weight controls. METHODS: Children (3-18 y) with SDB (overweight/obese [BMI z-scores ≥ 1.04], n = 48; normal weight n = 44) referred for clinical assessment of SDB and normal weight non-snoring controls recruited from the community (n = 38) underwent overnight polysomnography. PWV was calculated using photoplethysmography. cSBP was calculated using applanation tonometry in a subset of children older than 8 y (n = 55) who had usable waveforms. RESULTS: Overweight/obese SDB group had higher PWV (mean cm/s (95% CI); wake: 366 (355-380); sleep: 340 (324-357)), than the normal-weight SDB group (wake: 257 (247-267), p = 0.002; sleep: 255 (242-269), p = 0.005), and non-snoring controls (wake: 238 (226-249), p = 0.002; sleep: 235 (220-250), p < 0.001). The normal-weight SDB group had higher PWV than controls (p = 0.03). Overweight/obese children with SDB had higher cSBP (105 (100-110) mmHg) compared with the normal weight children with SDB (96 (90-102)) and the non-snoring controls (97 (91-104); p < 0.05 for both). CONCLUSION: This study suggests that overweight/obesity substantially worsens the cardiovascular sequelae of SDB, highlighting the imperative to treat obesity and SDB in children early in order to reduce future cardiovascular disease risk.

The impact of sleep disordered breathing on cardiovascular health in overweight children.

BACKGROUND: Up to 50% of overweight/obese children have obstructive sleep apnea (OSA) compared to up to 6% of normal weight children. We compared cardiovascular variables between normal weight and overweight/obese children with and without OSA, and controls. METHODS: Seventy-four referred children and 24 normal weight non-snoring controls (8-18 years) were recruited. Referred children were grouped according to their obstructive apnea hypopnea index (OAHI): OSA (>1 event/h) or primary snoring (PS ≤ 1 event/h) and whether they were normal weight (BMI z-score <1.04) or overweight/obese (BMI z-score ≥ 1.04). Wake blood pressure (BP), heart rate (HR), and pulse transit time (PTT, an inverse continuous surrogate measure of blood pressure) during sleep were recorded. RESULTS: Wake BP was higher in the overweight/obese OSA group than in the control, normal weight PS, and overweight/obese PS groups (p < 0.05 for all). During sleep, BP, and HR were elevated in the overweight/obese OSA group compared to those in non-snoring controls (p < 0.05). More children who were overweight/obese had reduced BP and HR dipping from wake to sleep than normal weight children. The BMI z-score predicted HR and PTT when asleep and both age and BMI z-score predicted BP when awake. CONCLUSION: This study showed that BMI has both combined and independent effects on BP and HR in children with OSA. We have previously shown that treatment of OSA reduces BP and suggest that treatment of OSA in the growing number of overweight/obese children may improve cardiovascular outcomes.

Regional brain tissue changes and associations with disease severity in children with sleep-disordered breathing.

STUDY OBJECTIVES: Children with sleep-disordered breathing (SDB) exhibit behavioral, cognitive, and autonomic deficits, suggestive of neural injury. We assessed whether the tissue alterations resulted from acute or chronic processes, and whether alterations correlated with disease severity. METHODS: Brain tissue integrity was examined with mean diffusivity (MD) (3.0 T scanner) in 20 nonsnoring controls (mean age ± SEM, 12.2 ± 0.6 years; 10 males) and 18 children with SDB (12.3 ± 0.7 years; 11 males). Sleep, cognitive, and behavioral measures were compared between groups following overnight polysomnography using Student's t tests. Whole-brain MD maps were realigned and averaged, normalized, smoothed, and compared between groups using ANCOVA (covariates: age, gender, and socioeconomic status). Partial correlations were calculated between whole-brain smoothed MD maps and obstructive apnea-hypopnea indices (OAHIs). RESULTS: Age, gender, and sleep variables did not differ between groups. The SDB group showed higher OAHIs, body mass indices, and systolic blood pressure. Significantly reduced MD values (acute changes) appeared in the hippocampus, insula, thalamus, temporal and occipital cortices, and cerebellum, but were increased (chronic damage) in the frontal and prefrontal cortices in the SDB group over controls. Both positive and negative correlations appeared with extent of tissue changes and disease severity. Externalizing and Total Problem Behaviors were significantly higher in children with SDB. Verbal, performance, and total IQ scores trended lower, and behavioral scores trended higher. CONCLUSIONS: Pediatric SDB is accompanied by predominantly acute brain changes in areas that regulate autonomic, cognitive, and mood functions, and chronic changes in frontal cortices essential for behavioral control. Interventions need to be keyed to address acute vs chronic injury.

Overweight and obesity add to behavioral problems in children with sleep-disordered breathing.

OBJECTIVE: This study aimed to determine whether overweight and obesity increased the detrimental effects of pediatric sleep-disordered breathing (SDB) on cognition, behavior, mood, and quality of life. METHODS: Children and adolescents (8-16 years) with clinically diagnosed SDB were categorized into two groups: healthy weight (Body Mass Index (BMI) z-score <1.04, N = 11) and overweight/obese (BMI z-score ≥ 1.04, N = 10). Age-matched healthy weight, non-snoring controls (N = 25) were recruited from the community. All participants underwent overnight laboratory polysomnography (PSG). Cognitive, behavioral, and quality of life assessments were conducted in the home following the PSG. Analysis of Covariance (ANCOVA) was used to assess group differences in cognitive outcomes, controlling for socio-economic status. Kruskal-Wallis ANOVA was used to determine group differences in behavior and quality of life. Where group differences were found, hierarchical linear regressions determined the effect of weight on outcomes. RESULTS: Children with SDB had significantly poorer behavior and quality of life than controls, with overweight/obese children with SDB having the greatest dysfunction. No group differences were found in cognitive outcomes. The obstructive apnea hypopnea index (OAHI) was a significant predictor of withdrawn behavior (R2 = 0.42), inattention (R2 = 0.43), and aggressive behavior (R2 = 0.30). BMI z-score added significantly to aggressive behavior (R2 = 0.22) and was an independent predictor of externalizing behaviors (R2 = 0.26). The OAHI predicted school functioning (R2 = 0.30). BMI z-score predicted social functioning (R2 = 0.38) and significantly added to physical functioning over the OAHI (OAHI R2 = 30; BMI z-score R2 = 0.37). CONCLUSIONS: Overweight and obesity comorbid with SDB increase the risk of externalizing behaviors such as aggression but do not affect other behavioral associates of SDB such as inattention and school functioning.