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Published ahead of print on June 1, 2004, doi:10.1164/rccm.200403-262OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 553-560, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200403-262OC

Original Article

Genioglossus Activity During Sleep in Normal Control Subjects and Children with Obstructive Sleep Apnea

Eliot S. Katz and David P. White

Division of Respiratory Diseases, Department of Medicine, Children's Hospital; and Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Eliot S. Katz, M.D., Division of Respiratory Diseases, Mailstop 208, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. E-mail: eliot.katz{at}childrens.harvard.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Children with obstructive sleep apnea syndrome (OSAS) have more collapsible airways compared with normal subjects, yet sustain stable breathing during wakefulness and part of sleep. This indicates successful neuromuscular compensation. Using a custom intraoral surface electrode to record pharyngeal dilator muscle activity (the genioglossus [EMGgg] normalized to the wakeful baseline), we performed overnight polysomnograms in three groups of children: (1) patients with OSAS without continuous positive airway pressure (CPAP) (n = 13); (2) patients with OSAS with CPAP (n = 5); and (3) control subjects without CPAP (n = 13). Our objective was to evaluate the EMGgg as a function of sleep state and during disordered breathing, compared with stable sleep and wakefulness. In control subjects, the EMGgg decreased from wakefulness to Stage 2 (mean ± SD, 65 ± 6%), and further during REM (51 ± 9%) (p < 0.05). In patients with OSAS, the EMGgg for apneic breaths during REM (37 ± 9%) was lower than during stable breathing (83 ± 17%) (p < 0.05) and wakefulness (p < 0.05). CPAP lowered the EMGgg in patients with OSAS during all sleep states. These data indicate that (1) EMGgg compensatory mechanisms remain active during sleep in patients with severe OSAS; (2) EMGgg reductions are temporally associated with sleep apnea events; and (3) REM sleep is associated with the lowest and most variable EMGgg.

Key Words: genioglossus EMG • intraoral surface electrode • REM sleep

Children with the obstructive sleep apnea syndrome (OSAS) have narrower (1, 2) and more collapsible (3, 4) airways compared with normal subjects. However, patients with OSAS are able to sustain stable breathing during wakefulness and at least a portion of sleep (5, 6). Thus, despite pharyngeal anatomy and viscoelasticity prone toward collapse, neuromuscular compensation is often successful. In fact, it has been estimated that mechanical load (primarily anatomy) accounts for only 34% of the variability in adult OSAS severity, with the remainder largely related to muscle activity (5). Similarly, in children, the importance of neuromuscular compensatory reflexes is suggested by the poor correlation between adenotonsillar size and apnea severity (7), the lack of obstruction during wakefulness, and the considerable overlap between airway size in children with and without OSAS (1, 2). Reflex activation of the pharyngeal musculature has been measured in awake children both electromyographically (8) and using acoustic pharyngometry (9). Children with OSAS have increased pharyngeal dilator activity during wakefulness compared with control subjects, consistent with neuromuscular compensation (8). Topical anesthesia of the upper airway significantly decreases the waking pharyngeal cross-sectional airway in children with OSAS compared with control subjects, suggesting that mucosal mechanoreceptors mediate the reflex (9).

Upper airway patency is dependent upon pharyngeal mechanics, neuromuscular activity, and luminal pressure (10). Genioglossal activity (EMGgg) protrudes the tongue, increasing the oropharyngeal size (11) and decreasing airway collapsibility (12). During the sleep-onset period, the EMGgg declines in both patients with OSAS and in control subjects, but more so in the former (8, 13). This suggests that reflex mechanisms are diminished during the transition to sleep. However, as Stage 2 sleep progresses, the EMGgg rises above the wakeful baseline in some children with severe OSAS (8) and most adults (14), consistent with activation of chemo- and/or mechanoreceptors. Data regarding pharyngeal dilator activity during REM and Stage 4 sleep have been reported in adult subjects only, and are highly variable. In adults, the EMGgg during Stage 4 relative to Stage 2 sleep has been observed to increase (15) or remain unchanged (16, 17). During REM sleep, the EMGgg is reported to be qualitatively lower in tonic REM (18), higher during tonic REM (19), decreased during phasic REM eye movements (19, 20), or decreased during REM with intermittent bursts of activity (21). The amplitude and variability of EMGgg activity during Stage 4 and REM sleep has not been established in children.

Obstructive apneas and hypopneas are most commonly observed during REM sleep in children (22). The pathophysiology of the REM state vulnerability includes muscle atonia (20), decreased lung volume (23), diminished chemoreceptor/mechanoreceptor responsiveness (24, 25) and/or inhibitory REM processes (24). The literature regarding pharyngeal dilator activity during disordered breathing in pediatrics is disparate. In children, external surface EMGgg recordings have not demonstrated a consistent change at the onset of apnea (26). Similar results were obtained in infants using intraoral surface electrodes (27). However, increased levels of EMGgg at the onset of apnea have also been reported in children with OSAS (6), preterm infants (28), and in micrognathic infants after spontaneous neck flexion (29). By contrast, in adults, the intramuscular EMGgg decreases during obstructive breaths relative to arousal (10) and wakefulness (18). Thus, further work, using more precise methodologies, is needed in children.

The objectives of the present study were to evaluate the EMGgg amplitude and variability as a function of sleep state and during obstructive events in children with and without OSAS. We hypothesized that (1) the stability of breathing during Stage 4 sleep may be accounted for by increased EMGgg amplitude and/or decreased EMGgg variability; (2) REM sleep is associated with decreased EMGgg amplitude and/or increased EMGgg variability; and (3) sleep state specific oscillations in EMGgg account for the temporal occurrence of obstructive events predominantly during REM, and to a lesser extent Stage 2 sleep, in anatomically predisposed children.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Subjects in this study were divided into three groups: (1) patients with OSAS studied without continuous positive airway pressure (CPAP) (OSAS/NoCPAP, n = 16); (2) patients with OSAS studied with CPAP (OSAS/CPAP, n = 5); and (3) control subjects studied without CPAP (Controls, n = 15). Five of the patients with OSAS/NoCPAP also participated as subjects with OSAS/CPAP. Two of the patients with OSAS had previously (before our polysomnogram) had an adenotonsillectomy, but none had an adenotonsillectomy between their baseline polysomnogram and the experimental study. The control group of nonsnoring, asymptomatic subjects was recruited from the community. None of the control subjects had an adenotonsillectomy. The study was approved by the institutional review board at Children's Hospital, Boston. Signed, informed consent was obtained from the parent, and assent from the child.

EMGgg
A custom intraoral mouthpiece electrode was constructed for each subject to measure EMGgg (8, 30). The signals were amplified, rectified, and integrated on a moving-time-average basis, with a time constant of 100 milliseconds. Inspiration was identified using the abdominal effort channel. The tonic EMGgg was defined as the mean EMGgg activity during the first 1 second of expiration. The phasic EMGgg was defined as the area under the curve of EMGgg activity during inspiration, including tonic activity. The mean phasic and tonic EMGgg was normalized as a percentage of wakefulness activity, defined during approximately 10 minutes of relaxed wakeful breathing. During REM sleep, paroxysmal elevations in EMGgg activity greater than 4 times the baseline EMGgg (during the preceding 10 seconds) lasting more than 0.1 seconds were excluded from the analysis of stable breathing (31).

Protocol
All subjects underwent a single overnight polysomnogram in the supine position using an intraoral surface electrode, to determine both apnea severity and the EMGgg. Subjects with OSAS/CPAP were studied on pressure settings sufficient to eliminate flow limitation. Our polysomnographic montage, event definitions, and clinical classification are described in detail in the online supplement.

Normal Subjects, Subjects with OSAS/CPAP, and Subjects with OSAS/NoCPAP
Breaths occurring during stable breathing (nonapneic/hypopneic and nonarousal) were identified using standard criteria (32, 33). The mean phasic and tonic EMGgg was determined (1) for stable breaths, during 10 minutes of baseline breathing during eyes-closed wakefulness; (2) for stable breaths, during the first Stage 2 sleep episode lasting at least 10 minutes; (3) for stable breaths, during the first Stage 4 sleep episode lasting at least 10 minutes; and (4) for stable breaths, during the first REM sleep episode lasting at least 10 minutes. The mean SaO2 and end-tidal (partial) carbon dioxide pressure (PETCO2) were determined during aforementioned intervals. REM sleep breaths were subdivided based on the presence of contemporaneous eye movements during inspiration or the preceding 1 second (20, 34) (see online supplement for details).

Subjects with OSAS/NoCPAP Only
In addition to the above, breaths were identified during apnea/hypopnea and obstructive arousals (the first two breaths after each obstructive event) using standard criteria (32, 33). The mean phasic and tonic EMGgg was determined for the first 50 apnea/hypopnea and obstructive arousal breaths during both Stage 2 and REM sleep for each subject.

Data Analysis
The inter- (control subjects, OSA/NoCPAP, OSA/CPAP) and intragroup EMGgg differences (Stage 2, Stage 4, and REM stable breathing; and apnea) in the logarithmically-transformed EMGgg were evaluated with a repeated-measures analysis of variance followed by a Tukey HSD post-hoc test. The intra- and intergroup variability of the EMGgg of stable breaths measurements during sleep states was evaluated by comparing the EMGgg standard deviations using Bartlett's test and the F statistic (35). The correlation coefficient between the overall apnea–hypopnea index (AHI) and the tonic/phasic EMGgg in each sleep state was determined.

Intergroup differences in the change in SaO2 and PETCO2 between behavioral states were assessed using an unpaired t test (two tails). Statistical analysis was performed with commercial software (SPSS 9.0; SPSS Inc., Chicago, IL). Statistical significance was accepted when p < 0.05. All values are reported as a mean ± SD. For additional details, see online supplement.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographic and Polysomnographic Data
All children recruited as control subjects (n = 15) had no polysomnographic evidence of OSAS. Three children in the OSAS/NoCPAP group and two control subjects could not fall asleep with the intraoral surface electrode in place, or had excessively high impedance in their recordings, and have, therefore, been eliminated from further analysis. Demographic and polysomnographic data from the 13 subjects with OSAS/NoCPAP, 5 subjects with OSAS/CPAP, and 13 control subjects for whom usable EMGgg data were obtained are summarized in Table 1. The five patients with OSAS studied with and without CPAP had a higher AHI (12.2 ± 8.8/hour) compared with the eight patients with OSAS studied only without CPAP (4.6 ± 3.6/hour) (p < 0.05), indicating more severe disease in the former subgroup. SaO2 data were available from all subjects. PETCO2 data were available for 9 control subjects, 10 subjects with OSAS/CPAP, and 4 subjects with OSAS/NoCPAP. An example of raw data from a subject with OSAS/CPAP during each behavioral state is shown in Figure 1.


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  		TABLE 1. Demographic and polysomnographic data of study subjects

 


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  		Figure 1. Ten-year-old with severe sleep apnea studied on continuous positive airway pressure (CPAP) (90-second epoch). There is an overall decrease in the tonic and phasic genioglossal electromyogram (EMGgg) during Stage 2 and Stage 4 sleep compared with wakefulness. The EMGgg is most variable in REM with periods of very low activity. There is very little EMGgg variability during Stage 4 sleep. GG = genioglossus; MTA = moving time average; O1-A2 = occipital electroencephalogram.

 
Tonic EMGgg Activity during Stable Breathing
The mean tonic EMGgg activity for each subject during stable breathing in each behavioral state (normalized to wakefulness) is shown in Figures 2 and 3.



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  		Figure 2. The state-specific mean tonic EMGgg normalized as a percentage of awake activity during stable breathing for individual subjects and group means is shown.

 


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  		Figure 3. The state-specific phasic and tonic EMGgg normalized as a percentage of awake activity for the five patients with OSAS studied with and without CPAP.

 
Intragroup comparisons.
In normal subjects, the mean tonic EMGgg was significantly lower in Stage 2, Stage 4, and REM sleep compared with wakefulness (p < 0.05). REM sleep EMGgg activity was lower than in both Stage 2 and Stage 4 (p < 0.05). In subjects with OSAS/NoCPAP, the mean tonic EMGgg was not significantly different in Stage 2 or Stage 4 sleep compared with wakefulness, but was significantly decreased in REM compared with wakefulness (p < 0.05). There were no significant differences between the sleep states. In subjects with OSAS/CPAP, the mean tonic EMGgg was significantly lower in Stage 2, Stage 4, and REM sleep compared with wakefulness (p < 0.05). REM sleep EMGgg activity was also lower than in Stage 2 (p < 0.05).

Intergroup comparisons.
Control subjects had a lower mean tonic EMGgg (normalized to wakefulness) than either the OSAS/NoCPAP or OSAS/CPAP groups in all sleep states (p < 0.05). In the group of five patients with OSAS that were studied with and without CPAP, the mean tonic EMGgg was significantly lower with CPAP in all sleep states (p < 0.05).

Correlation to AHI.
In patients with OSAS/NoCPAP, the relationship between overall AHI and the tonic EMGgg in Stage 2, Stage 4, and REM was 0.63, 0.59, and 0.51, respectively (p < 0.05). That is, the higher the AHI, the higher the tonic EMGgg.

Variability.
Using Bartlett's test and the F statistic, the intrasubject variability of the tonic EMGgg was greater during REM compared with wakefulness, Stage 2 or Stage 4 for all groups (p < 0.05). The variability of the tonic EMGgg was also greater during wakefulness and Stage 2 compared with Stage 4 for all groups (p < 0.05). An example of the distribution of the tonic EMGgg for individual breaths across states in a patient with OSAS/NoCPAP is shown in Figure 4. Variability data for the OSAS/NoCPAP group as a whole is presented in Figure E1 of the online supplement.



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  		Figure 4. Eleven-year-old with severe sleep apnea without CPAP. Histograms of the tonic EMGgg normalized as a percentage of the awake activity for 120 stable breaths are shown in each state: (A) wakefulness; (B) Stage 2; (C) Stage 4; and (D) REM. The distribution of the first 50 apneic breaths in Stage 2 and REM sleep are also shown. Although the mean tonic EMGgg is not significantly different between states, there is a marked increase in variability in REM sleep. There is little overlap between apneic and nonapneic breaths, particularly during REM sleep.

 
Phasic EMGgg Activity during Stable Breathing
Intragroup comparisons.
In the control group during inspiration, no EMGgg activity above the tonic activity was observed, and therefore phasic activity is not reported for this group. In subjects with OSAS/NoCPAP, the mean phasic EMGgg amplitude during stable breathing was not significantly different in Stage 2 (95% ± 21) or Stage 4 (94% ± 18) compared with wakefulness, but was decreased in REM (83% ± 17) (p < 0.05). There were no significant differences between sleep states. There were five patients with OSAS/NoCPAP in whom the level of EMGgg during Stage 2 sleep was greater than baseline. The AHI of this subgroup of patients with OSAS (13 ± 7.8/hour) was greater than that of the remainder of the patients with OSAS (4.1 ± 3.6/hour) (p < 0.05), indicating more severe disease. In subjects with OSAS/CPAP, the mean phasic EMGgg amplitude was significantly lower in Stage 2, Stage 4, and REM compared with wakefulness (p < 0.05) (see Figure 3). REM activity was lower than Stage 2 sleep (p < 0.05).

Intergroup comparisons.
In the group of five OSAS subjects who were studied with and without CPAP, the mean phasic EMGgg activity was significantly lower with CPAP in all sleep states (p < 0.05) (see Figure 3).

Correlation to AHI.
In patients with OSAS/NoCPAP, the relationship between AHI and the phasic EMGgg in Stage 2, Stage 4, and REM was 0.66, 0.62, and 0.56, respectively (p < 0.05). Thus, the higher the AHI, the higher the phasic EMGgg.

Variability.
Using Bartlett's test and the F statistic, the intrapatient variability of the phasic EMGgg was greater during REM compared with wakefulness, Stage 2, or Stage 4 for both the OSAS/CPAP and OSAS/NoCPAP groups (p < 0.05). The variability of the phasic EMGgg was also greater during wakefulness and Stage 2 compared with Stage 4 for both groups (p < 0.05).

EMGgg Activity during REM (Stable Breathing) in Relation to Eye Movements
The individual subject and group mean tonic EMGgg data during REM breaths with and without eye movements are shown in Figure 5. In control subjects, the EMGgg trended lower during REM breaths with eye movements (p = 0.15). In the OSAS/NoCPAP group, there was no significant difference in tonic EMGgg in relation to eye movements. In the OSAS/CPAP group, there was a significant decrease in EMGgg during breaths with eye movements (p < 0.05). An example of the temporal association between eye movements and EMGgg decrements is shown in Figure 2E in the online supplement.



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  		Figure 5. The mean tonic EMGgg normalized as a percentage of the awake activity for individual subjects during REM breaths with and without associated eye movements (EM). The mean tonic EMGgg (vertical lines) was significantly lower during EM only in the OSAS/CPAP group. NS = not significant.

 
EMGgg Activity during Apneic/Hypopneic Breaths Compared with Stable Breathing
An example of raw data from an OSAS/NoCPAP subject during a series of obstructive apneas is shown in Figure 6. The mean phasic EMGgg during apneic/hypopneic breaths in Stage 2 and REM was lower than in stable breathing in the same sleep states, as well as wakefulness (p < 0.05) (Figure 7). The mean tonic EMGgg activities during apneic/hypopneic breaths in Stage 2 (60 ± 8) and REM (41 ± 6) were also lower than in stable breathing in the same sleep states, as well as wakefulness (p < 0.05). There was, however, some overlap between the EMGgg activity (both tonic and phasic) of apneic/hypopneic and stable breaths in individual patients, especially during REM (see Figure 4). Both the mean tonic and phasic EMGgg during apneic/hypopneic breaths were lower during events in REM compared Stage 2 sleep. The mean tonic and phasic EMGgg during obstructive arousals (normalized to wakefulness) was 2,171 ± 562% and 720 ± 339%, respectively.



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  		Figure 6. A series of obstructive hypopneas characterized by flow limitation on the nasal pressure tracing. The EMGgg is minimal during the obstructive breaths and increases markedly at apnea termination.

 


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  		Figure 7. The state-specific phasic EMGgg normalized as a percentage of awake activity for stable and apneic/hypopneic breaths is shown for individual patients with OSAS. The mean phasic EMGgg (vertical lines) was significantly lower for apneic/hypopneic breaths compared with stable breaths in both Stage 2 and REM sleep, as well as wakefulness (p < 0.05).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The primary findings of this study are as follows. (1) In control subjects and in subjects with OSAS/CPAP, EMGgg activity decreases from wakefulness to stable Stage 2, and decreases further during REM sleep. (2) In patients with OSAS/NoCPAP, EMGgg increased during stable Stage 2 sleep in some patients with severe OSAS, but subsequently decreased during REM sleep in all patients. (3) EMGgg variability during stable breathing is highest during REM, intermediate during Stage 2, and lowest during Stage 4 sleep. (4) The application of CPAP to patients with OSAS decreases the relative tonic and phasic EMGgg during all sleep states. (5) In both Stage 2 and REM sleep, the EMGgg during individual apneic/hypopneic breaths is decreased below wakefulness and sleep-state specific stable breathing. (6) There is little overlap in the EMGgg between apneic/hypopneic and stable breaths within sleep states. (7) During REM, there was a significant mean decrease in the EMGgg during eye movements only in the OSAS/CPAP group.

EMGgg: Stage 2 and Stage 4 Sleep
Children with OSAS have an increased EMGgg during wakefulness (8), likely mediated by mucosal mechanoreceptors (9). At the wake–sleep transition, there is a reduction in EMGgg both in children with and without OSAS, but more so in the former (8). This diminution in muscle activation is associated with increased airway resistance and collapsibility. In normal children, we observed that EMGgg remains below the wakeful baseline during stable Stage 2 sleep, suggesting that additional neuromuscular activity is unnecessary in the setting of a mechanically stable airway. In some children with severe OSAS, after a marked EMGgg decline at sleep onset, it rebounds above the waking activity, consistent with a reflex driven by mechano- and/or chemoreceptors (8). Interestingly, normal adults also tend to increase their EMGgg above the wakeful baseline after the sleep-onset decline (14). This is consistent with the concept that adults have an inherently more collapsible pharyngeal airway than children (4, 36). We observed that patients with OSAS with an elevated EMGgg during Stage 2 sleep (above the wakeful baseline) had more severe apnea than the remainder of patients with OSAS. In addition, a significant correlation between OSAS severity (i.e., AHI) and the EMGgg was present during all sleep stages, consistent with muscular compensation for a collapsible airway. Thus, we conclude that there is a state-dependence of the EMGgg resulting in a decrease during Stage 2 sleep, but that mechano- and/or chemoreceptors mechanisms appear to augment pharyngeal dilator activity during sleep if the airway is sufficiently compromised. In normal adults, the EMGgg in Stage 4 compared with Stage 2 has been reported to either increase (15) or remain unchanged (16, 17). In the former study, neither hypercapnea, hypoxemia, nor respiratory effort could account for the increase observed. Our data demonstrate a trend toward decreasing EMGgg between Stage 2 and Stage 4 sleep in normal children and patients with OSAS/CPAP. In addition, the EMGgg was lower during both Stage 2 and Stage 4 sleep in OSAS on CPAP compared with the same patients without CPAP, suggesting mechanoreceptor input is an important determinant of pharyngeal dilator activity during non-REM sleep. However, gas exchange was also improved on CPAP. With respect to the Stage 2-to-Stage 4 transition, we speculate that the state-effect per se is a reduction in EMGgg, but that afferent activity (mechano- and chemoreceptors) modulates the resultant EMGgg depending on the collapsibility properties of the upper airway.

EMGgg: REM Sleep
There are few reports of EMGgg activity during REM sleep in humans and none in children. In normal adult subjects, the EMGgg in REM compared with non-REM has been observed to be qualitatively reduced but punctuated by "vigorous inspiratory bursts" (21) or unchanged overall with a decrement during eye movements (20). In adult OSAS subjects on CPAP, the EMGgg was markedly decreased in REM compared with non-REM sleep (37). Our data clearly indicate a reduction in both tonic and phasic EMGgg during REM sleep in children with and without OSAS. This reduction was evident during periods of stable breathing, and further reductions were seen during obstructive events (see below). Thus, we conclude that decrements in EMGgg (and probably other pharyngeal dilator muscles) is a major contributor to the severity of sleep-disordered breathing during REM sleep. Other potential factors contributing to the vulnerability of REM sleep include: (1) a reduction in lung volume, which could increase upper-airway collapsibility or exacerbate ventilation-perfusion matching; (2) the atonia of chest wall muscles, which increases thoraco-abdominal asynchrony, thereby decreasing the efficiency of respiration; and (3) marked variations in respiratory rate and tidal volume.

REM sleep is a heterogeneous state that is conceptualized as having baseline tonic features, interrupted by apparently random, paroxysmal phasic processes of central origin. In children, we observed both sudden increases and decreases in EMGgg during REM. We did not, however, observe a relationship between eye movements and EMGgg in normal control subjects and patients with OSAS/NoCPAP. On the other hand, many of the latter subjects had marked disruption of REM sleep with apnea/hypopneas and gas exchange abnormalities. The lack of specificity between eye movements and obstructive events was also reported in English bulldogs with spontaneous OSAS (38). Thus, phasic eye movements may be associated with both paroxysmal increases and decreases in EMGgg. Nevertheless, our data support the view that REM sleep, as a whole, is associated with tonic and phasic reductions in EMGgg, and that obstructive events occur during additional paroxysmal reductions in activity, independent of eye movements (see below).

In the present study, both Stage 2 and REM sleep were associated with increased EMGgg variability compared with Stage 4 sleep, even during stable breathing. This suggests that the compensatory effectiveness of neuromuscular control mechanisms is also highly variable, possibly contributing to the propensity of obstructive events to occur during Stage 2 and REM sleep. The origin of this variability is likely to be quite different, however. Stage 2 sleep is characterized by active chemoreceptor and mechanoreceptor reflexes, interacting with apneic and arousal thresholds (39). On the other hand, in REM sleep, the respiratory variability persists even after deafferentation, suggesting that central REM processes underlie the variability. Phasic REM processes are associated with marked drops in EMGgg, tachypnea, irregular breathing, and differential activation of individual motor units and fractionations (40). We observed an overall reduction in EMGgg during REM sleep even during periods of stable breathing, and a further reduction during disordered breathing. Thus, we speculate that the preponderance of apnea in REM sleep in children relates to the combination of a state-specific reduction in pharyngeal dilator activity and paroxysmal central phasic REM processes.

EMGgg: Relation to Apnea/Hypopnea
In adults, periodic reductions in central respiratory drive to both the respiratory pump and pharyngeal musculature may contribute to the pathophysiology of OSAS (10, 18). The onset of apnea and hypopnea coincides with the nadir of EMGgg activity. As EMGgg decreases, hypopneas and then apneas develop, although these studies have not demonstrated a threshold level of EMGgg below which obstruction occurs (18). By contrast, in children, no consistent decrement in EMGgg at apnea onset has been observed using external surface electrodes (26) or sublingual surface electrodes in infants (27). Some pediatric studies have even reported increased EMGgg activity at the start of an apnea in children (6) and infants (28). On the contrary, our data indicate a clear decrease in EMGgg during obstructive events in older children. In fact, there was little overlap between the EMGgg of stable breaths and apneic/hyponeic breaths (see Figure 4). Our study design differed from the previous pediatric work cited above in three important respects. (1) We recorded the EMGgg using intraoral rather than external surface electrodes. Insofar as external surface electrodes also record from the geniohyoid, mylohyoid, and platysma, we believe that the intraoral surface electrode is a more sensitive and specific measure of genioglossal activity. (2) We compared the EMGgg between apneic/hypopneic breaths and stable breathing, rather than apnea-only breaths compared with preapneic breaths. As preapneic breaths are often hypopneic or influenced by arousals from previous apneas, these breaths may not represent an appropriate baseline for comparison to apneic breaths (26). In addition, Praud and coworkers also reported a decrease in EMGgg at the onset of apnea in five of seven patients, with no change in the other two (26). Although this was not statistically significant, it trended in the same direction as our results. Thus, we do not believe that our findings are actually contradictory. (3) The patients with OSAS in our study were considerably older (10.5 ± 1.9 years) than those studied by Praud and coworkers (3.8 years) or Gauda and coworkers (0.3 years). Thus, particularly in the case of infants, it is possible that developmental differences do exist. Preterm infants frequently have postsigh or postmovement mixed apneas during which the EMGgg may appear to increase at apnea onset and decrease thereafter (28). In general, our results are consistent with the adult literature in which EMGgg decreases at the onset of apnea and increases at apnea termination (10, 18, 28).

Limitations of the Present Study
There are a number of limitations of the present study. First, many of the subjects with OSAS/CPAP continued to demonstrate phasic EMGgg activity despite CPAP, suggesting ongoing neuromuscular compensation. The CPAP was set to eliminate any obvious apneas, hypopneas, respiratory effort related arousals, and flow limitation, but these patients may have had some residual increase in upper airway resistance. We do not believe that this otherwise affected our results, as the EMGgg amplitude and variability of these subjects qualitatively tracked that of normal subjects. Second, we recognize that the association between EMGgg activity and the dilating force generated by the upper airway muscle is nonlinear. However, EMGgg activity is considered to be a reliable measure of neural drive, and, thus, our interpretation that neuromuscular variability accounts for the temporal occurrence of obstructive events remains plausible. Third, there are several ways to measure the phasic EMGgg activity. Relying on the peak phasic activity may overrepresent brief spikes of activity, thus, obscuring the actual trends. The mean phasic activity corrects for spike activity but ignores important changes in inspiratory time. We chose to report the area under the curve phasic EMGgg, which is minimally affected by brief spike activity and is sensitive to changes in inspiratory time. Thus, the shortened inspiratory times characteristic of REM sleep may have contributed to the reduction in EMGgg that was observed. We acknowledge this possibility, but believe that this reduction in EMGgg still represents periods with either decreased respiratory drive or ineffective ventilation (10, 41). Fourth, as our primary aim was to accurately evaluate the EMGgg during tonic REM and obstructive events, we chose to limit our focus to breaths in which the activity remained within 400% of the baseline (i.e., eliminating breaths with large, brief phasic activation) (31). Nevertheless, significant increases in EMGgg (those less than 400%) were still evident, and may have affected our analysis of EMGgg associated with eye movements. Fifth, our subject population was older (mean 11 years old) than the most common age of presentation for pediatric OSAS (2–8 years old). We don't believe that this affected our results insofar as previous developmental studies have indicated minimal changes within this age range (42). The original data in 2000 from Marcus and colleagues demonstrate that the correlation coefficient between airway collapsibility and age for children between 6 and 16 years old was only 0.2 (not significant). Sixth, the subjects in our study were not specifically matched for BMI. Nevertheless, the mean BMI percentile was comparable between the control and OSAS groups, and only one subject was obese. Thus, we do not believe that this affected our results. Seventh, it is possible that there was a time-of-night effect on the EMGgg contributing to the decline in the EMGgg during Stage 2, Sage 4 and REM sleep. Alhough this pattern was not apparent from data collected toward the end of the study, we had insufficient instances in which two suitable Stage 4 or REM sleep cycles (same body position and electrode impedance) were available to address this, but this is the subject of a future study. The possibility of a circadian effect on the EMGgg deserves future study. Finally, we did not measure the activity of other muscles that may participate in the maintenance of airway patency, including the geniohyoid and palatal muscles. In addition, factors such as lung volume changes, blood flow, and mucosal surface forces may also play a role in promoting airway collapse.

Conclusions
Normal children have a consistent decrease in EMGgg from wakefulness to stable Stage 2 sleep. There is a trend toward a further decline in EMGgg during Stage 4 sleep, with the lowest activity occurring during REM sleep. Thus, the inherently stable upper airway in normal children necessitates little neuromuscular compensation during sleep. Children with OSAS have an increased EMGgg compared with control subjects in all sleep states, indicating active neuromuscular compensation. The application of CPAP resulted in a marked decrease in the EMGgg activity during sleep in children with OSAS, demonstrating that normalization of airway-resistance and gas-exchange parameters obviated the need for EMGgg reflex activation. We observed that obstructive events in both Stage 2 and REM sleep were associated with lower EMGgg than either stable breathing during sleep or wakefulness. Further, that EMGgg variability was greatest during REM, intermediate during Stage 2, and lowest in Stage 4 sleep in children with and without OSAS. We surmise that state-dependent variations in EMGgg likely account for the predisposition to apnea during Stage 2 and REM sleep. The pathophysiology of the increased variability during Stage 2 sleep is postulated to arise from alterations in mechanoreceptor/chemoreceptor control. By contrast, central neural processes seem to drive the EMGgg variability during REM sleep. Further studies will be required to elucidate the determinants of the state-dependent EMGgg variability.


   FOOTNOTES
 
Supported by National Institutes of Health (NHLBI) grants HL073238-01 (E.S.K.) and 1 P50 HL60292 (D.P.W.), and National Center for Research Resources grant #MO1 RR02172 to Children's Hospital, Boston, General Clinical Research Center.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: E.S.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.P.W. has participated as a speaker in scientific meetings or courses organized and financed by various sleep technology companies (Itimar, Respironics), and has received research grants from Respironics Inc., Itamar Medical LLC, Alfred E. Mann Foundation, and Widemed.

Received in original form March 1, 2004; accepted in final form May 31, 2004


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