Termination of respiratory events with and without cortical arousal in obstructive sleep apnea.

RATIONALE: A total of 20-30% of respiratory events in obstructive sleep apnea are terminated without clear arousal. Arousals are thought to predispose to further events by promoting hyperventilation, hypocapnia, and upper-airway dilator muscle hypotonia. Therefore, events terminated without arousal may promote stable breathing. OBJECTIVES: To compare physiologic changes at respiratory event termination with American Sleep Disorders Association (ASDA) Arousal to No Arousal, and determine whether secondary respiratory events are less common and have higher dilator muscle activity after No Arousal compared with ASDA Arousal. METHODS: Patients with obstructive sleep apnea wore sleep staging, genioglossus (EMG(GG)), and tensor palatini (EMG(TP)) electrodes plus a nasal mask and pneumotachograph. During stable sleep, continuous positive airway pressure (CPAP) was lowered for 3-minute periods to induce respiratory events. Physiologic variables were compared between events terminated with (1) ASDA Arousal, (2) No Arousal, or (3) sudden CPAP increase (CPAPinc, control). MEASUREMENTS AND MAIN RESULTS: Sixteen subjects had adequate data. EMG(GG), EMG(TP), and heart rate increased after ASDA Arousal (340 ± 57%, 215 ± 28%, and 110.7 ± 2.3%) and No Arousal (185 ± 32%, 167 ± 15%, and 108.5 ± 1.6%) but not CPAPinc (90 ± 10%, 94 ± 11%, and 102.1 ± 1%). Ventilation increased more after ASDA Arousal than No Arousal and CPAPinc, but not after accounting for the severity of respiratory event. Fewer No Arousals were followed by secondary events than ASDA Arousals. However, low dilator muscle activity did not occur after ASDA Arousal or No Arousal (EMG(GG) rose from 75 ± 5 to 125 ± 7%) and secondary events were less severe than initial events (ventilation rose 4 ± 0.4 to 5.5 ± 0.51 L/min). CONCLUSIONS: Respiratory events that were terminated with ASDA Arousal were more severely flow-limited, had enhanced hyperventilation after event termination, and were more often followed by secondary events than No arousal. However, secondary events were not associated with low dilator muscle activity and airflow was improved after both No Arousal and ASDA Arousal.

Determining sleep quality in children with sleep disordered breathing: EEG spectral analysis compared with conventional polysomnography.

STUDY OBJECTIVES: To identify the extent of sleep disruption in children with various severities of sleep disordered breathing (SDB) using both conventional visually scored assessment of sleep stages and arousal indices together with EEG power spectral analysis. DESIGN: Sleep stages and power spectral analysis of the sleep EEG in children with varying severities of SDB with matched control subjects with no history of snoring were compared across the whole night, across sequential hours from sleep onset, and across sleep stages. MEASUREMENTS: Overnight polysomnography was performed on 90 children (49M/41F) aged 7-12 y with SDB and 30 age-matched healthy controls (13M/17F). Sleep stages were visually scored and the EEG spectra were analyzed in 5-s epochs. RESULTS: Conventional visual scoring indicated that, although sleep duration was reduced in severely affected children, sleep quality during the essential stages of SWS and REM was preserved, as evidenced by the lack of any significant decrease in their duration in SDB severity groups. This finding was supported by the lack of substantial differences in EEG spectral power between the groups over the whole night, within specific hours, and in individual sleep stages. CONCLUSIONS: Both conventional scoring and EEG spectral analysis indicated only minor disruptions to sleep quality in children with SDB when assessed across the night, in any specific hour of the night, or in any specific sleep stage. These results suggest that reduced daytime functioning previously reported in children with SDB may not be due to sleep disruption. We speculate that in children, in contrast to adults, a stronger sleep drive may preserve sleep quality even in severe SDB.

Genioglossus motor unit activity in supine and upright postures in obstructive sleep apnea.

This study investigated whether a change in posture affected the activity of the upper-airway dilator muscle genioglossus in participants with and without obstructive sleep apnea (OSA). During wakefulness, a monopolar needle electrode was used to record single motor unit activity in genioglossus in supine and upright positions to alter the gravitational load that causes narrowing of the upper airway. Activity from 472 motor units was recorded during quiet breathing in 17 males, nine of whom had OSA. The mean number of motor units for each participant was 11.8 (SD 3.4) in the upright and 16.0 (SD 4.2) in the supine posture. For respiratory-modulated motor units, there were no significant differences in discharge frequencies between healthy controls and participants with OSA. Within each breath, genioglossus activity increased through the recruitment of phasic motor units and an increase in firing rate, with an overall increase of ~6 Hz (50%) across both postures and participant groups. However, the supine posture did not lead to compensatory increases in the peak discharge frequencies of inspiratory and expiratory motor units, despite the increase in gravitational load on the upper airway. Posture also had no significant effect on the discharge frequency of motor units that showed no respiratory modulation during quiet breathing. We postulate that, in wakefulness, any increase in genioglossus activity to compensate for the gravitational effects on the upper airway is achieved primarily through the recruitment of additional motor units in both healthy controls and participants with OSA.

Mechanisms underlying the association between insomnia, anxiety, and depression in adolescence: Implications for behavioral sleep interventions.

There is robust evidence of an association between insomnia, anxiety, and depression in adolescence. The aim of this review is to describe and synthesize potential mechanisms underlying this association and explore implications for the design of adolescent behavioral sleep interventions. Specifically, we examine whether insomnia symptoms are a mechanism for the development of internalizing symptoms in adolescence and whether sleep interventions are an effective treatment for both insomnia and internalizing symptoms in adolescence because they target the shared mechanisms underlying these disorders. Research using different methodologies points to the role of sequential, parallel, and interacting mechanisms. In this paper, we review a wide range of relevant biological (i.e., polymorphisms and dysregulation in serotonin, dopamine, and circadian clock genes; alterations in corticolimbic and mesolimbic brain circuits; cortisol reactivity to stress; inflammatory cytokine dysregulation; biased memory consolidation; changes in sleep architecture), psychological (i.e., cognitive inflexibility, interpretational biases, judgment biases, negative attribution styles, worry, rumination, biased attention to threat, dysfunctional beliefs and attitudes about sleep, misperception of sleep deficit), and social mechanisms (i.e., reduced and impaired social interactions, unhelpful parenting behaviors, family stress) and propose an integrative multilevel model of how these phenomena may interact to increase vulnerability to both insomnia and internalizing disorders. Several 'biopsychosocial' mechanisms hold promise as viable treatment targets for adolescent behavioral sleep interventions, which may reduce both insomnia and internalizing symptoms.

Mechanisms of the deep, slow-wave, sleep-related increase of upper airway muscle tone in healthy humans.

Upper airway muscle activity is reportedly elevated during slow-wave sleep (SWS) when compared with lighter sleep stages. To uncover the possible mechanisms underlying this elevation, we explored the correlation between different indices of central and reflex inspiratory drive, such as the changes in airway pressure and end-expiratory CO2 and the changes in the genioglossus (GG) and tensor palatini (TP) muscle activity accompanying transitions from the lighter N2 to the deeper N3 stage of non-rapid eye movement (NREM) sleep in healthy young adult men. Forty-six GG and 38 TP continuous electromyographic recordings were obtained from 16 men [age: 20 ± 2.5 (SD) yr; body mass index: 22.5 ± 1.8 kg/m2] during 32 transitions from NREM stages N2 to N3. GG but not TP activity increased following transition into N3 sleep, and the increase was positively correlated with more negative airway pressure, increased end-tidal CO2, increased peak inspiratory flow, and increased minute ventilation. None of these correlations was statistically significant for TP. Complementary GG and TP single motor unit analysis revealed a mild recruitment of GG units and derecruitment of TP units during the N2 to N3 transitions. These findings suggest that, in healthy individuals, the increased GG activity during SWS is driven primarily by reflex stimulation of airway mechanoreceptors and central chemoreceptors.NEW & NOTEWORTHY The characteristic increase in the activity of the upper airway dilator muscle genioglossus during slow-wave sleep (SWS) in young healthy individuals was found to be related to increased stimulation of airway mechanoreceptors and central chemoreceptors. No evidence was found for the presence of a central SWS-specific drive stimulating genioglossus activity in young healthy individuals. However, it remains to be determined whether a central drive exists in obstructive sleep apnea patients.

Sensory detection of threshold intensity resistive loads in severe obstructive sleep apnoea.

Respiratory related evoked potentials (RREPs) were used to investigate whether sensory detection of small mid-inspiratory resistive loads (≈1.2-6.2 cmH2OL-1s), delivered during wakefulness, was impaired in obstructive sleep apnoea (OSA). It was reasoned that impaired detection of minor airway patency challenge may lead to difficult-to-remedy further collapse. There was a significant reduction in OSA (n=16) vs. control (n=17) participants in the slope of the relationship between the P1 RREP component amplitude, which reflects arrival of somatosensory information at the cortex, and stimulus intensity, expressed as change in epiglottic pressure (mean [95% confidence intervals]: -0.50 [-0.97, -0.03] vs. -1.78 [-2.54, -1.02]; P=0.004), suggesting a reduction in sensitivity to small respiratory loads. However there was no significant difference in sensitivity after background Pepi was taken into account (P=0.268). Additionally, there were no significant group differences in the threshold of the P1 amplitude/stimulus intensity relationship, or in the P1 latency. These results indicate a reduced sensitivity to detection of small upper airway negative pressure stimuli in OSA related to a reduction in mechanoreceptor activation (likely related to increased airway resistance in OSA vs. controls; P=0.002) rather than defective mechanosensory function.

Autonomic regulation across phases of the menstrual cycle and sleep stages in women with premenstrual syndrome and healthy controls.

To investigate the influence of menstrual cycle phase and the presence of severe premenstrual symptoms on cardiac autonomic control during sleep, we performed heart rate variability (HRV) analysis during stable non-rapid eye movement (NREM) and REM sleep in 12 women with severe premenstrual syndrome and 14 controls in the mid-follicular, mid-luteal, and late-luteal phases of the menstrual cycle. Heart rate was higher, along with lower high frequency (HF) power, reflecting reduced vagal activity, and a higher ratio of low frequency (LF) to high frequency power, reflecting a shift to sympathetic dominance, in REM sleep compared with NREM sleep in both groups of women. Both groups of women had higher heart rate during NREM and REM sleep in the luteal phase recordings compared with the mid-follicular phase. HF power in REM sleep was lowest in the mid-luteal phase, when progesterone was highest, in both groups of women. The mid-luteal phase reduction in HF power was also evident in NREM sleep in control women but not in women with PMS, suggesting some impact of premenstrual syndrome on autonomic responses to the hormone environment of the mid-luteal phase. In addition, mid-luteal phase progesterone levels correlated positively with HF power and negatively with LF/HF ratio in control women in NREM sleep and with the LF/HF ratio during REM sleep in both groups of women. Our findings suggest the involvement of female reproductive steroids in cardiac autonomic control during sleep in women with and without premenstrual syndrome.

Acetazolamide attenuates the ventilatory response to arousal in patients with obstructive sleep apnea.

STUDY OBJECTIVES: The magnitude of the post-apnea/hypopnea ventilatory overshoot following arousal may perpetuate subsequent respiratory events in obstructive sleep apnea (OSA) patients, potentially contributing to the disorder's severity. As acetazolamide can reduce apnea severity in some patients, we examined the effect of acetazolamide on the ventilatory response to spontaneous arousals in CPAP-treated OSA patients. DESIGN: We assessed the ventilatory response to arousal in OSA patients on therapeutic CPAP before and after administration of acetazolamide for 7 days. SETTING: Sleep research laboratory. PARTICIPANTS: 12 (7M/5F) CPAP-treated OSA patients. INTERVENTIONS: Sustained-release acetazolamide 500 mg by mouth twice daily for one week. MEASUREMENTS AND RESULTS: A blinded investigator identified spontaneous arousals (3-15 s) during NREM sleep. Breath-by-breath measurements of minute ventilation, end-tidal CO(2), tidal volume, expiratory/inspiratory-time, and total breath duration were determined (4-s intervals) 32 s prior and 60 s following each arousal. Acetazolamide significantly increased resting ventilation (7.3 ± 0.2 L/min versus 8.2 ± 0.4 L/min; P < 0.05) and attenuated the percent increase in ventilation following arousal by ~2.5 fold (122.0% ± 4.4% versus 108.7% ± 3.5% pre-arousal level; P < 0.05). There was a positive correlation between the mean increase in ventilatory response to arousal and mean AHI (r(2) = 0.44, P = 0.01). However, absolute peak levels of ventilation following arousal remained unchanged between conditions (8.8 ± 0.4 L/min versus 8.9 ± 0.1 L/min). CONCLUSIONS: Acetazolamide substantially attenuates the increase in ventilation following spontaneous arousal from sleep in OSA patients. This study suggests an additional mechanism by which acetazolamide may contribute to the improvement in ventilatory instability and OSA severity. The data also provide support for reinforcing the importance of ventilatory control in OSA pathogenesis.

Preschool children with obstructive sleep apnea: the beginnings of elevated blood pressure?

STUDY OBJECTIVES: In adults and older children, snoring and obstructive sleep apnea (OSA) are associated with elevated blood pressure (BP). However, BP has not been assessed in preschool children, the age of highest OSA prevalence. We aimed to assess overnight BP in preschool children with snoring and OSA using pulse transit time (PTT), an inverse continuous indicator of BP changes. DESIGN: Overnight polysomnography including PTT. Children were grouped according to their obstructive apnea-hypopnea index (OAHI); control (no snoring, with OAHI of one event or less per hour), primary snoring (OAHI one event or less per hour), mild OSA (OAHI greater than one event to five events per hour) and moderate-severe OSA (OAHI more than five events per hour). SETTING: Pediatric sleep laboratory. PATIENTS: There were 128 clinically referred children (aged 3-5 years) and 35 nonsnoring community control children. MEASUREMENT AND RESULTS: PTT was averaged for each 30-sec epoch of rapid eye movement (REM) or nonrapid eye movement (NREM) sleep and normalized to each child's mean wake PTT. PTT during NREM was significantly higher than during REM sleep in all groups (P < 0.001 for all). During REM sleep, the moderate-severe OSA group had significantly lower PTT than the mild and primary snoring groups (P < 0.05 for both). This difference persisted after removal of event-related PTT changes. CONCLUSIONS: Moderate-severe OSA in preschool children has a significant effect on pulse transit time during REM sleep, indicating that these young children have a higher baseline BP during this state. We propose that the REM-related elevation in BP may be the first step toward development of daytime BP abnormalities. Given that increased BP during childhood predicts hypertension in adulthood, longitudinal studies are needed to determine the effect of resolution of snoring and/or OSA at this age.

Inspiratory-resistive loading increases the ventilatory response to arousal but does not reduce genioglossus muscle activity on the return to sleep.

Arousals from sleep are thought to predispose to obstructive sleep apnea by causing hyperventilation and hypocapnia, which reduce airway dilator muscle activity on the return to sleep. However, prior studies of auditory arousals have not resulted in reduced genioglossus muscle activity [GG-electromyogram (EMG)], potentially because airway resistance prior to arousal was low, leading to a small ventilatory response to arousal and minimal hypocapnia. Thus we aimed to increase the ventilatory response to arousal by resistive loading prior to auditory arousal and determine whether reduced GG-EMG occurred on the return to sleep. Eighteen healthy young men and women were recruited. Subjects were instrumented with a nasal mask with a pneumotachograph, an epiglottic pressure catheter, and intramuscular GG-EMG electrodes. Mask CO(2) levels were monitored. Three- to 15-s arousals from sleep were induced with auditory tones after resting breathing (No-Load) or inspiratory-resistive loading (Load; average 8.4 cmH(2)O·l(-1)·s(-1)). Peak minute ventilation following arousal was greater after Load than No-Load (mean ± SE; 8.0 ± 0.6 vs. 7.4 ± 0.6 l/min, respectively). However, the nadir end tidal partial pressure of CO(2) did not differ between Load conditions (43.1 ± 0.6 and 42.8 ± 0.5 mmHg, respectively), and no period of reduced GG activity occurred following the return to sleep (GG-EMG baseline, minimum after Load and No-Load = 2.9 ± 1.2%, 3.1 ± 1.3%, and 3.0 ± 1.3% max, respectively). These findings indicate that the hyperventilation, which occurs following tone-induced arousal, is appropriate for the prevailing level of respiratory drive, because loading did not induce marked hypocapnia or lower GG muscle activity on the return to sleep. Whether similar findings occur following obstructive events in patients remains to be determined.

Recruitment and rate-coding strategies of the human genioglossus muscle.

Single motor unit (SMU) analysis provides a means to examine the motor control of a muscle. SMUs in the genioglossus show considerable complexity, with several different firing patterns. Two of the primary stimuli that contribute to genioglossal activation are carbon dioxide (CO(2)) and negative pressure, which act through chemoreceptor and mechanoreceptor activation, respectively. We sought to determine how these stimuli affect the behavior of genioglossus SMUs. We quantified genioglossus SMU discharge activity during periods of quiet breathing, elevated CO(2) (facilitation), and continuous positive airway pressure (CPAP) administration (inhibition). CPAP was applied in 2-cmH(2)O increments until 10 cmH(2)O during hypercapnia. Five hundred ninety-one periods (each ∼ 3 breaths) of genioglossus SMU data were recorded using wire electrodes(n = 96 units) from 15 awake, supine subjects. Overall hypercapnic stimulation increased the discharge rate of genioglossus units (20.9 ± 1.0 vs. 22.7 ± 0.9 Hz). Inspiratory units were activated ∼ 13% earlier in the inspiratory cycle, and the units fired for a longer duration (80.6 ± 5.1 vs. 105.3 ± 4.2% inspiratory time; P < 0.05). Compared with baseline, an additional 32% of distinguishable SMUs within the selective electrode recording area were recruited with hypercapnia. CPAP led to progressive SMU inhibition; at ∼ 6 cmH(2)O, there were similar numbers of SMUs active compared with baseline, with peak frequencies of inspiratory units close to baseline, despite elevated CO(2) levels. At 10 cmH(2)O, the number of units was 36% less than baseline. Genioglossus inspiratory phasic SMUs respond to hypercapnic stimulation with changes in recruitment and rate coding. The SMUs respond to CPAP with derecruitment as a homogeneous population, and inspiratory phasic units show slower discharge rates. Understanding upper airway muscle recruitment/derecruitment may yield therapeutic targets for maintenance of pharyngeal patency.

Neural drive to human genioglossus in obstructive sleep apnoea.

One postulated mechanism for obstructive sleep apnoea (OSA) is insufficient drive to the upper-airway musculature during sleep, with increased (compensatory) drive during wakefulness. This generates more electromyographic activity in upper airway muscles including genioglossus. To understand drives to upper airway muscles, we recorded single motor unit activity from genioglossus in male groups of control (n = 7, 7 +/- 2 events h(-1)) and severe OSA (n = 9, 54 +/- 4 events h(-1)) subjects. One hundred and seventy-eight genioglossus units were recorded using monopolar electrodes. Subjects were awake, supine and breathing through a nasal mask. The distribution of the six types of motor unit activity in genioglossus (Inspiratory Phasic, Inspiratory Tonic, Expiratory Phasic, Expiratory Tonic, Tonic and Tonic Other) was identical in both groups. Single unit action potentials in OSA were larger in area (by 34%, P < 0.05) and longer in duration (by 23%, P < 0.05). Inspiratory units were recruited earlier in OSA than control subjects. In control subjects, Inspiratory Tonic units peaked earlier than Inspiratory Phasic units, while in OSA subjects, Inspiratory Tonic and Phasic units peaked simultaneously. Onset frequencies did not differ between groups, but the peak discharge frequency for Inspiratory Phasic units was higher in OSA (22 +/- 1 Hz) than control subjects (19 +/- 1 Hz, P = 0.003), but conversely, the peak discharge frequency of Inspiratory Tonic units was higher in control subjects (28 +/- 1 Hz versus 25 +/- 1 Hz, P < 0.05). Increased motor unit action potential area indicates that neurogenic changes have occurred in OSA. In addition, the differences in the timing and firing frequency of the inspiratory classes of genioglossus motor units indicate that the output of the hypoglossal nucleus may have changed.

Tonic and phasic respiratory drives to human genioglossus motoneurons during breathing.

A tongue muscle, the genioglossus (GG), is important in maintaining pharyngeal airway patency. Previous recordings of multiunit electromyogram (EMG) suggest it is activated during inspiration in humans with some tonic activity in expiration. We recorded from populations of single motor units in GG in seven subjects during quiet breathing when awake. Ultrasonography assisted electrode placement. The activity of single units was separated into six classes based on a step-wise analysis of the discharge pattern. Phasic and tonic activities were analyzed statistically with the coefficient of determination (r2) between discharge frequency and lung volume. Of the 110 motor units, 29% discharged tonically without phasic respiratory modulation (firing rate approximately 19 Hz). Further, 16% of units increased their discharge during expiration (expiratory phasic and expiratory tonic units). Only half the units increased their discharge during inspiration (inspiratory phasic and inspiratory tonic units). Units firing tonically with an inspiratory increase had significantly higher discharge rates than those units that only fired phasically (peak rates 25 vs. 16 Hz, respectively). Simultaneous recordings of two or three motor units showed neighboring units with differing respiratory and tonic drives. Our results provide a classification and the first quantitative measures of human GG motor-unit behavior and suggest this activity results from a complex interaction of inspiratory, expiratory, and tonic drives at the hypoglossal motor nucleus. The presence of different drives to GG implies that complex premotor networks can differentially engage human hypoglossal motoneurons during respiration. This is unlike the ordered recruitment of motor units in limb and axial muscles.