Regional cerebral blood flow alterations in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a condition characterized by upper airway muscle atonia with continued diaphragmatic efforts, resulting in repeated airway obstructions, periods of intermittent hypoxia, large thoracic pressure changes, and substantial shifts in arterial pressure with breathing cessation and resumption. The hypoxic exposure and hemodynamic changes likely induce the structural and functional deficits found in multiple brain areas, as shown by magnetic resonance imaging (MRI) procedures. Altered cerebral blood flow (CBF) may contribute to these localized deficits; thus, we examined regional CBF, using arterial spin labeling procedures, in 11 OSA (age, 49.1±12.2 years; 7 male) and 16 control subjects (42.3±10.2 years; 6 male) with a 3.0-Tesla MRI scanner. CBF maps were calculated, normalized to a common space, and regional CBF values across the brain quantified. Lowered CBF values emerged near multiple bilateral brain sites in OSA, including the corticospinal tracts, superior cerebellar peduncles, and pontocerebellar fibers. Lateralized, decreased CBF appeared near the left inferior cerebellar peduncles, left tapetum, left dorsal fornix/stria terminalis, right medial lemniscus, right red nucleus, right midbrain, and midline pons. Regional CBF values in OSA are significantly reduced in major sensory and motor fiber systems and motor regulatory sites, especially in structures mediating motor coordination; those reductions are often lateralized. The asymmetric CBF declines in motor regulatory areas may contribute to loss of coordination between upper airway and diaphragmatic musculature, and lead to further damage in the syndrome.

Neural and physiological responses to a cold pressor challenge in healthy adolescents.

Abnormal autonomic function is common in pediatric diseases. Assessment of central mechanisms underlying autonomic challenges may reveal vulnerabilities antecedent to system failure. Our objective was to characterize central markers and physiological responses to a cold pressor challenge in normal children as a critical step for establishing such screening. We performed functional magnetic resonance imaging (fMRI) and collected physiological measures during cold application to the foot in 24 healthy adolescents (15.5 ± 0.4 years, 13 male). The protocol included a 120-sec baseline, 120-sec right-foot cold water immersion (4°C), and 120-sec recovery. Analyses included heart rate (HR) cross-correlations with fMRI signals. Cold application increased HR 13% 5-7 sec after onset, which remained elevated throughout the challenge. Respiratory rate transiently increased (peak 22%), then declined (nadir 12% below baseline), before normalizing at 75 sec. Cold onset rapidly increased somatosensory cortex and medullary signals, which fell after 25 sec. Right anterior insular cortex signals increased early, followed after 20 sec by the left anterior insula, with HR declining 8 sec later. Amygdalae signals also rose, but signals declined in the posterior cingulate cortex, caudate nucleus, hippocampus, and hypothalamus. Declining signals appeared late in the cerebellar fastigial nuclei (60-120 sec), and in the pons and thalamus. Somatosensory cortex, fastigial nuclei, and hypothalamic responses were principally left-sided, with bilateral responses elsewhere. Late left anterior insula responses likely underlie the HR decline; the late cerebellar pattern may modulate recovery. The laterality, timing, and amplitude of normative responses and rostral response differentiation indicate the complex integration of adolescent autonomic processing and provide indices for pathological comparisons.

Nocturnal dipping is preserved in children with sleep disordered breathing regardless of its severity.

OBJECTIVE: Sleep disordered breathing (SDB) in adults has been associated with a loss of nocturnal dipping in blood pressure (BP) and heart rate, however, there have been limited studies in children. We measured BP non-invasively and continuously overnight in 105 children aged 7-12 with a range of severities of SDB and 36 non-snoring controls to examine nocturnal dipping profiles. STUDY DESIGN: Children with SDB were divided into three severity groups according to their obstructive apnea hypopnea index. Nocturnal dipping profiles across sleep stages were described both as a proportion of children exhibiting a ≥10% fall in systolic arterial pressure (SAP) and heart rate (HR) from wake to sleep and according to SAP sleep/SAP wake ratio as extreme dippers (ratio ≤ 0.8), dippers (ratio < 0.8 and ≤0.9), non-dippers (ratio < 0.9 and ≤1.0), and reverse dippers (ratio > 1.0). RESULTS: The mean fall in BP between wake and NREM 1/2, SWS, and REM sleep was not different between the groups and there were no differences between the dipping profiles of children in each group. CONCLUSIONS: SDB did not alter nocturnal dipping patterns of BP and HR compared to controls, a finding which may suggest that these young children have not been exposed to the effects of SDB long enough or that SDB severity was not great enough to affect nocturnal dipping profiles. However, further studies are required to determine if the elevated BP previously reported in this group of children will have long-term effects on the cardiovascular system.

Arousal from sleep pathways are affected by the prone sleeping position and preterm birth: preterm birth, prone sleeping and arousal from sleep.

OBJECTIVES: Preterm infants exhibit depressed arousability from sleep when compared with term infants. As the final cortical element of the arousal process may be the most critical for survival, we hypothesized that the increased vulnerability of preterm infants to the Sudden Infant Death Syndrome (SIDS) could be explained by depressed cortical arousal (CA) responses. We evaluated the effects of preterm birth on stimulus-induced arousal processes in both the prone and supine sleeping positions. STUDY DESIGN: 10 healthy preterm infants were studied with daytime polysomnography, in both supine and prone sleeping positions, at 36 weeks gestational age, 2-4 weeks, 2-3 months and 5-6 months post-term corrected age. Sub-cortical activations and cortical arousals (CA) were expressed as proportions of total arousal responses. Preterm data were compared with data from 13 healthy term infants studied at the same corrected ages. RESULTS: In preterm infants increased CAs were observed in the prone position at all ages studied. Compared to term infants, preterm infants had significantly fewer CAs in QS when prone at 2-3 months of age and more CAs when prone at 2-4 weeks in AS. There were no differences in either sleep state when infants slept supine. CONCLUSIONS: Prone sleeping promoted CA responses in healthy preterm infants throughout the first six months of post-term age. We have previously suggested that in term infants enhanced CA represents a critical protection against a potentially harmful situation; we speculate that for preterm-born infants the need for this protection is greater than in term infants.

Functional neuroanatomy and sleep-disordered breathing: implications for autonomic regulation.

A major concern with sleep-disordered breathing conditions, which include obstructive sleep apnea (OSA), central apnea, and congenital central hypoventilation syndrome (CCHS), is the high incidence of accompanying autonomic dysfunction and metabolic disorders. Patients with OSA show exaggerated sympathetic tone, leading to hypertension, cardiac arrhythmia, profuse sweating, impaired cerebral perfusion, and stroke. In addition, OSA appears in 86% of obese Type II diabetic patients, suggesting common deleterious processes. Autonomic deficiencies also appear in CCHS patients, who are often hypoglycemic. The impaired autonomic control may stem from injury to central sympathetic and parasympathetic regulatory areas resulting from apnea-related inflammation, hypoxia, or perfusion-related consequences in OSA, and genetic mutation repercussions in CCHS. Disturbed sleep organization from apnea arousals may also disrupt hormonal release. Brain areas affected in both OSA and CCHS include cortical and limbic regions that influence hypothalamic-regulated sympathetic control and hormone release, essential for glycemic regulation, as well as parasympathetic nuclei influencing the pancreas and other viscera, and raphé serotonergic sites, important for thermal and vascular regulation. Brain injury and altered functional responses appear in OSA and CCHS, assessed with magnetic resonance imaging techniques, in areas which show regional gray matter loss, alterations of free water within tissue, loss of axonal integrity, and disruption of functional responses to autonomic and ventilatory challenges. Evaluation of neural injury and distortion in functional signals to autonomic challenges in localized brain areas can provide insights into common pathological mechanisms for dysregulation of hormonal release and autonomic processes in sleep-disordered breathing and metabolic disorders.

Differential responses of the insular cortex gyri to autonomic challenges.

Determining insular functional topography is essential for assessing autonomic consequences of neural injury. We examined that topography in the five major insular cortex gyri to three autonomic challenges, the Valsalva, hand grip, and foot cold pressor, using functional magnetic resonance imaging (fMRI) procedures. Fifty-seven healthy subjects (age ± std: 47 ± 9 years) performed four 18 s Valsalva maneuvers (30 mm Hg load pressure), four hand grip challenges (16 s at 80% effort), and a foot cold pressor (60 s, 4°C), with fMRI scans recorded every 2 s. Signal trends were compared across gyri using repeated measures ANOVA. Significantly (P<0.05) higher signals in left anterior versus posterior gyri appeared during Valsalva strain, and in the first 4 s of recovery. The right anterior gyri showed sustained higher signals up to 2 s post-challenge, relative to posterior gyri, with sub-gyral differentiation. Left anterior gyri signals were higher than posterior areas during the hand grip challenge. All right anterior gyri showed increased signals over posterior up to 12 s post-challenge, with decline in the most-anterior gyrus from 10 to 24 s during recovery. The left three anterior gyri showed relatively lower signals only during the 90 s recovery of the cold pressor, while the two most-anterior right gyri signals increased only during the stimulus. More-differentiated representation of autonomic signals appear in the anterior right insula for the Valsalva maneuver, a bilateral, more-posterior signal representation for hand grip, and preferentially right-sided, anterior-posterior representation for the cold pressor. The functional organization of the insular cortex is gyri-specific to unique autonomic challenges.

No evidence of elevated germline mutation accumulation under oxidative stress in Caenorhabditis elegans.

Variation in rates of molecular evolution has been attributed to numerous, interrelated causes, including metabolic rate, body size, and generation time. Speculation concerning the influence of metabolic rate on rates of evolution often invokes the putative mutagenic effects of oxidative stress. To isolate the effects of oxidative stress on the germline from the effects of metabolic rate, generation time, and other factors, we allowed mutations to accumulate under relaxed selection for 125 generations in two strains of the nematode Caenorhabditis elegans, the canonical wild-type strain (N2) and a mutant strain with elevated steady-state oxidative stress (mev-1). Contrary to our expectation, the mutational decline in fitness did not differ between N2 and mev-1. This result suggests that the mutagenic effects of oxidative stress in C. elegans are minor relative to the effects of other types of mutations, such as errors during DNA replication. However, mev-1 MA lines did go extinct more frequently than wild-type lines; some possible explanations for the difference in extinction rate are discussed.

Elevated blood pressure during sleep and wake in children with sleep-disordered breathing.

OBJECTIVE: Sleep-disordered breathing (SDB) in adults has been associated with elevated blood pressure (BP); however, the effects of severity of SDB on BP in children are uncertain. We addressed this issue by measuring BP noninvasively and continuously during sleep in children with a range of severities of SDB and in a group of nonsnoring control children. METHODS: A total of 105 children referred for assessment of SDB and 36 nonsnoring controls were studied. Routine polysomnography (PSG) was performed with continuous BP monitoring. Children were assigned to groups according to obstructive apnea/hypopnea index (OAHI). BP data were categorized as quiet awake (recorded before sleep onset), non-rapid eye movement sleep 1 and 2 combined, slow-wave sleep, and rapid eye movement sleep. RESULTS: BP during awake before sleep onset and during overnight sleep was elevated by 10 to 15 mm Hg in the 3 SDB groups compared with the control group; this finding was independent of SDB severity. BP during stable sleep (with respiratory events and movements excluded) was also elevated in the children with OSA compared with the control group. BP was elevated in rapid eye movement sleep compared with the non-rapid eye movement sleep, and heart rate was higher during wake state than in all sleep states. CONCLUSIONS: We recorded BP continuously overnight and found that SDB, regardless of the severity, was associated with increased BP during sleep and wake compared with nonsnoring control children. These findings highlight the importance of considering the cardiovascular effects of SDB of any severity in children, and the need to review current clinical management that focuses primarily on more severe SDB.

Sleeping like a baby--does gender influence infant arousability?

INTRODUCTION: Victims of the sudden infant death syndrome (SIDS) may have preexisting abnormalities in their arousal pathways, inhibiting the progression of subcortical activation (SCA) to full cortical arousal (CA). Approximately 60% of SIDS victims are male, and it has been suggested that male infants have delayed cortical maturation compared to females. We hypothesized that CA frequency would be lower and CA threshold would be higher in male infants during both active (AS) and quiet (QS) sleep. METHODS: 50 healthy term infants (21 male, 29 female) were studied with daytime polysomnography at 2-4 weeks and 2-3 months after birth. Arousal from sleep was induced using a pulsatile air-jet to the nostrils at increasing pressures. RESULTS: At 2-4 weeks, arousability from AS was similar in males and females, however during QS, male infants required a lower stimulus to induce SCA and CA. This gender difference in arousal threshold was not observed at 2-3 months. CA frequencies were similar between genders during both sleep states at both ages, though overall, CA was more frequent in AS than in QS. CONCLUSIONS: This study demonstrated that at 2-4 weeks, male infants were easier to arouse than female infants during QS. There were no significant effects of gender on total arousability or SCA and CA frequencies at 2-3 months, the age of peak SIDS incidence. Thus, although male infants are at greater risk of SIDS than female infants, this difference is unlikely to be associated with gender differences in CA threshold or frequency.

Arousal from sleep mechanisms in infants.

Arousals from sleep allow sleep to continue in the face of stimuli that normally elicit responses during wakefulness and also permit awakening. Such an adaptive mechanism implies that any malfunction may have clinical importance. Inadequate control of arousal in infants and children is associated with a variety of sleep-related problems. An excessive propensity to arouse from sleep favors the development of repeated sleep disruptions and insomnia, with impairment of daytime alertness and performance. A lack of an adequate arousal response to a noxious nocturnal stimulus reduces an infant's chances of autoresuscitation, and thus survival, increasing the risk for Sudden Infant Death Syndrome (SIDS). The study of arousability is complicated by many factors including the definition of an arousal; the scoring methodology; the techniques used (spontaneous arousability versus arousal responses to endogenous or exogenous stimuli); and the confounding factors that complicate the determination of arousal thresholds by changing the sleeper's responses to a given stimulus such as prenatal drug, alcohol, or cigarette use. Infant age and previous sleep deprivation also modify thresholds. Other confounding factors include time of night, sleep stages, the sleeper's body position, and sleeping conditions. In this paper, we will review these different aspects for the study of arousals in infants and also report the importance of these studies for the understanding of the pathophysiology of some clinical conditions, particularly SIDS.

Influence of swaddling experience on spontaneous arousal patterns and autonomic control in sleeping infants.

OBJECTIVE: To investigate the effects of swaddling experience on infant sleep, spontaneous arousal patterns and autonomic control. STUDY DESIGN: Twenty-seven healthy term infants, who were routinely swaddled at home (n=15) or "naïve" to swaddling (n=12), were monitored with daytime polysomnography in swaddled and unswaddled conditions at 3 to 4 weeks and at 3 months after birth. RESULTS: Swaddling did not alter sleep time, spontaneous arousability, or heart rate variability in routinely swaddled infants at either age. During active sleep at 3 months, cortical arousal frequency was decreased, and total sleep time was increased by swaddling in infants who were naïve to swaddling. Heart rate variability when swaddled was also highest in the naïve group. CONCLUSIONS: The effects of infant swaddling on sleep time, arousability, and autonomic control are influenced by previous swaddling experience. Infants in the naïve to swaddling group exhibited decreased spontaneous cortical arousal, similar to responses observed in future victims of sudden infant death syndrome. Infants in unfamiliar sleeping conditions may therefore be more susceptible to cardiorespiratory challenges that fail to stimulate arousal and may lead to sudden infant death syndrome.

Stimulus type does not affect infant arousal response patterns.

Previous studies have examined infant arousal responses to various arousal stimuli; however it is unclear whether the patterns of responses to different stimuli are comparable within subjects across early development. The aim of the study was to compare the effects of both respiratory and somatosensory stimulation on arousal processes in the same infants throughout the first 6 months of life. Ten healthy term infants were studied with daytime polysomnography at 2-4 weeks, 2-3 and 5-6 months. Infants were challenged with both hypoxia (15% O(2), balanced N(2)) and a pulsatile air-jet to the nostrils. Stimulus-induced sub-cortical activations (SCA) and cortical arousals (CA) were expressed as percentages of total arousals. Heart rate (HR) changes and electroencephalogram (EEG) desynchronization were also contrasted for the two stimuli. During active sleep (AS), there was no significant effect of stimulus type on proportions of CA at any of the ages studied. During quiet sleep (QS), hypoxia elicited higher CA proportions than the air-jet at 2-3 and 5-6 months (P < 0.01). Overall, HR responses associated with SCA and CA and the duration of EEG desynchronization during CA were similar for both stimuli. Mild hypoxia and nasal air-jet stimulation produce qualitatively similar patterns of arousal responses during the first 6 months of life, supporting the concept of a final common neural pathway of cortical activation. Quantitatively, full CA from QS is more likely with hypoxia, in keeping with it being a life-threatening stimulus. This study supports the nasal air-jet as an appropriate stimulus for assessing developmental patterns of infant arousal process.

Minimizing the risks of sudden infant death syndrome: to swaddle or not to swaddle?

OBJECTIVE: To evaluate the effects of swaddling on infant arousability, particularly the progression of subcortical activation (SCA) to full cortical arousal (CA), because impaired arousal may contribute to sudden infant death syndrome. STUDY DESIGN: Healthy term infants, who were routinely swaddled (n = 15) or unswaddled (n = 12) at home, were studied with daytime polysomnography at 3 to 4 weeks and 3 months after birth. When both swaddled and unswaddled, arousability was assessed with a pulsatile jet of air at the nostrils. RESULTS: Larger increases in overall arousal thresholds (SCA plus CA) with swaddling were observed in infants who were easiest to arouse when unswaddled. Swaddling did not alter SCA or CA frequencies of routinely swaddled infants at either age. In infants who were naïve to swaddling, arousal thresholds were increased and CA frequency decreased during swaddled quiet sleep at 3 months. CONCLUSIONS: This study provides a scientific basis for assessing the safety of swaddling in infant care practice. The decreased cortical arousals observed in infants unfamiliar with swaddling may correspond to the increased risk of sudden infant death syndrome for inexperienced prone sleepers.

Maternal smoking impairs arousal patterns in sleeping infants.

OBJECTIVE: Impairment of the arousal process from sleep is thought to be involved in the pathogenesis of sudden infant death syndrome (SIDS). We hypothesized that a greater propensity for cortical arousal in the prone position may, in a normal infant, be a protective mechanism to promote complete arousal in a vulnerable sleeping position, a protection that is absent in SIDS victims. We aimed to examine the arousal process in a group of infants exposed to maternal smoking, who are thus at higher risk for SIDS. DESIGN: Twelve healthy, full-term infants born to smoking mothers were studied using daytime polysomnography at 2 to 4 weeks, 2 to 3 months and 5 to 6 months postnatal age. Data were compared with 13 healthy infants born to nonsmoking mothers. Arousal was induced by pulsatile air-jet stimulation to the nostrils during active and quiet sleep, in both supine and prone positions. For each stimulus, physiologic and electroencephalogram changes were visually assessed and arousal responses were classified as sub-cortical activation or cortical arousal. RESULTS: In smoke-exposed infants, the progression from sub-cortical activation to cortical arousal was depressed at 2 to 4 weeks and 5 to 6 months. There was no effect of maternal smoking observed at 2 to 3 months; however, a significant dose-dependent relationship between cortical activation proportions and urinary cotinine levels was present in both supine and prone positions. CONCLUSION: We have shown that maternal smoking is associated with impaired arousal processes to trigeminal stimulation that may increase the risk for SIDS. This further highlights the importance of public education of the risks of maternal smoking.

Arousal and ventilatory responses to mild hypoxia in sleeping preterm infants.

A failure to adequately respond to hypoxia has been implicated in the Sudden Infant Death Syndrome (SIDS). Preterm infants are at increased risk for SIDS, thus we compared ventilatory and arousal responses to mild hypoxia [15% oxygen (O2)] in preterm and term infants. Eight preterm and 15 term infants were serially studied with daytime polysomnography during which nasal airflow was monitored by pneumotachograph at 2-5 weeks, 2-3 and 5-6 months. At each age, in both groups, hypoxia induced a significant decrease in oxygen saturation (SpO2) during both active sleep (AS) and quiet sleep (QS). Infants invariably aroused in AS; and in QS either aroused or failed to arouse. In preterm infants arousal latency in AS was longer than in term infants (P < 0.05) at 2-5 weeks. Compared with term infants, preterm infants reached significantly lower SpO2 levels at 2-5 weeks in both AS and QS non-arousing tests and at 2-3 months in QS. A biphasic hypoxic ventilatory response was observed in QS non-arousing tests in both groups of infants at all three ages. We conclude that the greater desaturation during a hypoxic challenge combined with the longer arousal latency in preterm infants could contribute to greater risk for SIDS.

Maturation of the initial ventilatory response to hypoxia in sleeping infants.

In infants most previous studies of the hypoxic ventilatory response (HVR) have been conducted only during quiet sleep (QS) and arousal responses have not been considered. Our aim was to quantify the maturation of the HVR in term infants during both active sleep (AS) and QS over the first 6 months of life. Daytime polysomnography was performed on 15 healthy term infants at 2-5 weeks, 2-3 and 5-6 months after birth and infants were challenged with hypoxia (15% O2, balance N2). Tests in AS always resulted in arousal; in QS tests infants either aroused or did not arouse. A biphasic HVR was observed in non arousing tests at all three ages studied. The fall in SpO2 was more rapid in arousal tests at all three ages. At 2-5 weeks, in non-arousing QS tests, there was a greater fall in respiratory frequency (f) despite a smaller fall in SpO2 compared with 2-3 and 5-6 months. When infants aroused there was no difference in the HVR between sleep states or with postnatal age. However, when infants failed to arouse from QS, arterial desaturation was less in the younger infants despite a poorer HVR. We suggest that arousal in response to hypoxia, particularly in AS, is a vital survival mechanism throughout the first 6 months of life.

Variability of the initial phase of the ventilatory response to hypoxia in sleeping infants.

Most of the available data on the hypoxic ventilatory response (HVR) in infants has been obtained in quiet sleep (QS), and only one study has made repeated tests in the same infant. We aimed to gain a more complete knowledge of the maturation and consistency of the initial phase of the HVR by performing multiple tests in both QS and active sleep (AS) over the first 6 mo of life in term infants. Fifteen healthy term infants were studied with daytime polysomnography longitudinally at 2-5 wk, 2-3 mo, and 5-6 mo after birth. Each infant received multiple hypoxic (15% O2, balance N2) challenges (three or more) in both AS and QS. In AS, infants consistently aroused to hypoxia; however, in QS, infants both aroused and failed to arouse. The initial phase of the HVR varied considerably between infants with the changes in ventilation/kg [SD of inspired minute ventilation per kilogram of body weight (V(I)/kg)] being more variable during AS than QS at all three ages and overall decreasing with postnatal age in both sleep states. The variability between replicate V(I)/kg measurements was also significantly greater in AS compared with QS at 2-5 wk postnatal age. There was no evidence of habituation to repeated hypoxic tests in either sleep state. Our study has demonstrated that the initial phase of the HVR is variable both between and within term infants in both AS and QS, with responses being markedly more variable during AS, and becoming more consistent with increasing postnatal age. By performing only one test or by failing to account for arousal responses, previous studies may not have detected the natural variation of the infant HVR.