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J Physiol (2003), 553.2, pp. 533-544
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2003.045708
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ABSTRACT |
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Pharyngeal dilator muscles are clearly important in the pathophysiology of obstructive sleep apnoea syndrome (OSA). We have previously shown that the activity of both the genioglossus (GGEMG) and tensor palatini (TPEMG) are decreased at sleep onset, and that this decrement in muscle activity is greater in the apnoea patient than in healthy controls. We have also previously shown this decrement to be greater in older men when compared with younger ones. In order to explore the mechanisms responsible for this decrement in muscle activity nasal continuous positive airway pressure (CPAP) was applied to reduce negative pressure mediated muscle activation. We then investigated the effect of sleep onset (transition from predominantlyto predominantly
EEG activity) on ventilation, upper airway muscle activation and upper airway resistance (UAR) in middle-aged and younger healthy men. We found that both GGEMG and TPEMG were reduced by the application of nasal CPAP during wakefulness, but that CPAP did not alter the decrement in activity in either muscle seen in the first two breaths following an
(Received 1 May 2003; accepted after revision 4 September 2003; first published online 5 September 2003)
Corresponding author R. B. Fogel: Division of Sleep Medicine, RFB 390, 221 Longwood Avenue, Boston, MA 02115, USA. Email: rfogel{at}partners.org
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INTRODUCTION |
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Obstructive sleep apnoea (OSA) is a common disorder affecting 2-4 % of the middle-aged population (Young et al. 1993). The disorder is characterized by repetitive collapse of the pharyngeal airway during sleep (Remmers et al. 1978) and is associated with important adverse consequences for afflicted individuals (Flemons & Tsai, 1997; Teran-Santos et al. 1999; Peppard et al. 2000) The pathogenesis of OSA is complex but it is likely to be due to a combination of an anatomically small pharyngeal anatomy in conjunction with a sleep-related decline in upper airway dilator muscle activity (Remmers et al. 1978; Haponik et al. 1983; Horner et al. 1989; Schwab et al. 1995). We have previously shown an interaction between these components. Thus, during wakefulness, patients with OSA have augmented activity of the genioglossus (GGEMG) muscle as well as other pharyngeal dilator muscles such as the tensor palatini (TPEMG) when compared with healthy controls (Mezzanotte et al. 1992; Fogel et al. 2001). This activity is thought to represent a neuromuscular compensatory mechanism for an anatomically small and more collapsible pharyngeal airway. This augmented upper airway dilator muscle activity is lost at sleep onset in association with pharyngeal collapse (Mezzanotte et al. 1996). Thus the mechanisms controlling pharyngeal muscle activation are important in understanding disease pathogenesis.
As OSA is a state-related disorder, understanding the factors controlling upper airway muscle activity at sleep onset is important. We have previously shown that in normal men there is an abrupt decline in ventilation (
e) and a rise in upper airway resistance (UAR) at the transition from to EEG (wakefulness to sleep) (Worsnop et al. 1998). These changes are accompanied by a fall in GGEMG and TPEMG at to transitions. After the initial fall in GGEMG, this muscle is recruited and activity increases such that in stable NREM (non rapid eye movement) sleep its activity level is similar to that seen in wakefulness, whereas no such recruitment is seen in the TPEMG whose levels continue to decline as sleep deepens. Furthermore, we have shown that this fall in GGEMG and TPEMG in the first two breaths following the to transition is greater in patients with OSA than in normal patients (Mezzanotte et al. 1996). Finally, we have also recently demonstrated that the changes in upper airway and pump muscle activation are greater in a group of middle-aged compared with younger men (Worsnop et al. 2000).
Control of upper airway muscle activity is complex, and the changes that occur at sleep onset are not completely understood. Factors that may affect GGEMG and TPEMG include direct input from the brainstem respiratory central pattern generator (CPG) (Bianchi et al. 1995), chemoreceptive inputs (Onal et al. 1981a,b), vagal input due to changes in lung volume (Bartlett & St John, 1988) and a tonic 'wakefulness' drive that is present in the respiratory system (Orem, 1990). Finally, substantial evidence supports the presence of a intrapharyngeal negative pressure reflex (NPR) that contributes to upper airway muscle activity in animals (Mathew et al. 1982a,b) and humans (Horner et al. 1991a,b). It is well known that the application of negative pressure to the pharyngeal airway in animals and in humans leads to a substantial increase in the activity of the genioglossus as well as other upper airway muscles (Horner et al. 1991b; Akahoshi, 2001; Fogel et al. 2001; Malhotra et al. 2002). These data suggest that during wakefulness genioglossal muscle activation is directly proportional to intrapharyngeal pressure, and this relationship is not affected by alterations in partial pressure of carbon dioxide (PCO2) (Akahoshi, 2001) or inspiratory airflow (Malhotra et al. 2002).
The application of nasal continuous positive airway pressure (CPAP) markedly attenuates the pressure change across the upper airway during inspiration, and as such leads to a substantial decrease in upper airway muscle activation during wakefulness both in normal humans and in patients with OSA. The reduction in muscle activation is greater in the apnoea patient, consistent with the fact that they have a more narrowed upper airway, and thus a greater reliance on this NPR to augment muscle activity (Mezzanotte et al. 1992).
In this study, we used the application of nasal CPAP to accomplish two goals. First, by examining the changes in upper airway and pump muscle activation during sleep onset, on and off nasal CPAP, we manipulated the effects of negative pressure related muscle activation, and could therefore examine the isolated effect of loss of wakefulness on these muscles. We hypothesized that sleep onset would still be associated with a significant reduction in upper airway muscle activity, even in the presence of CPAP, consistent with loss of a tonic wakefulness drive. We also hypothesized that by minimizing the rise in upper airway resistance at sleep onset, CPAP would attenuate the recruitment in GGEMG previously described during NREM sleep.
Second, by studying both younger and older men, on and off CPAP, we could examine several things. We could first determine if there is greater basal muscle activation awake in older versus younger men, indicating an upper airway muscle response to a smaller or more collapsible airway in the older individuals. If this were the case, a greater fall in muscle activity would be expected with CPAP during wakefulness. Second, we could determine if the greater change in upper airway muscle activation at the to transition previously reported in older men was due to this higher waking muscle activation with loss of reflex drive at sleep onset. Alternatively, if the augmented decrement in muscle activity was due to a greater intrinsic effect of sleep onset on muscle activation in the older individuals, this could be demonstrated as well. Thus, considerable information regarding ageing effects on pharyngeal muscle activation should emerge.
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METHODS |
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Subjects
Twelve young men between the ages of 18 and 25 years (mean (± S.E.M.) age 22.75 ± 0.39 years and mean body mass index 22.87 ± 0.57 kg m-2) and 13 older men between the ages of 45 and 65 years (mean age 51.00 ± 1.8 years and mean body mass index 23.66 ± 0.30 kg m-2) participated in the study. All were healthy and without sleep complaints. Informed consent was obtained from each subject, with the protocol conforming to the principles outlined in the Declaration of Helsinki and having the prior approval of the Human Subjects Committee of the Brigham and Women's Hospital. Each subject was studied for 2 nights separated by at least 1 week. One older subject was unable to sleep during the protocol, and another was found to have prominent central apnoea at sleep onset. Thus data from 12 young and 11 older subjects were analysed.
Equipment and techniques
The laboratory procedures, EMG recordings, and measurement of ventilation and resistance were conducted as previously described (Wheatley et al. 1993). In order to assess sleep-wake state, subjects were instrumented with two channels of electroencephalography (EEG), two channels of electro-oculography (EOG) and chin EMG.
Airway mechanics. Subjects wore a nasal mask (Respironics, Inc., Murraysville, PA, USA) connected to a non-rebreathing valve. Inspiratory and expiratory airflow were determined with a pneumotachometer (model 3700A, Hans Rudolph Inc., Kansas City, MO, USA) and differential pressure transducer (Validyne Corp., Northridge, CA, USA), calibrated with a rotameter. Subjects were instructed to breathe exclusively through the nose and were carefully monitored by video camera to ensure that the mouth was completely closed. Mask leak was detected from a perforated catheter surrounding the mask-face interface, which continuously sampled for CO2. In addition, end tidal pressure of carbon dioxide (PET,CO2) was monitored from the mask using an infrared analyser (Capnograph Monitor, BCI, Waukesha, WI, USA). During sleep, the mouth was taped shut in order to minimize mouth breathing.
Pressures were monitored in the mask with an open catheter attached to a pressure transducer (Validyne Corporation) and in the airway at the level of the epiglottis using a pressure-tipped catheter (MPC-500, Millar, Houston, TX, USA). One nostril was decongested (oxymetazalone HCl) and anaesthetized (lidocaine (lignocaine) HCl), and the Millar catheter was inserted through this nostril and localized at the epiglottis. Prior to insertion, both pressure signals were calibrated simultaneously in a rigid cylinder using a standard water manometer. These two pressure signals plus flow were demonstrated to be without amplitude or phase lags at up to 2 Hz. Any drift in the pressure catheters was corrected on a breath-by-breath basis by an automated computer program that defined end-inspiration and end-expiration by identifying the point of zero flow and correcting any offset in the pressure catheter. Minute ventilation and resistance (peak resistance and average inspiratory resistance) were calculated on a breath-by-breath basis.
Muscle activation. The GGEMG was measured with a pair of unipolar intramuscular electrodes referenced to a single ground, producing a bipolar recording. Two stainless steel Teflon-coated 30 gauge wire electrodes were inserted 15-20 mm into the body of the genioglossal muscle 3 mm lateral to the frenulum on each side using a 25 gauge needle, which was quickly removed, leaving the wires in place. This technique has been used previously in our laboratory (Malhotra et al. 2000, 2002; Fogel et al. 2001). TPEMG was measured in a similar manner to that of the GG muscle, using a pair of referenced unipolar intramuscular electrodes producing a bipolar recording. The tip of the pterygoid hamulus was located at the junction of the hard and soft palate, on each side of the palate. A 25 gauge needle with a 30 gauge stainless steel Teflon-coated wire was then inserted at a 45 deg angle along the lateral surface of the medial pterygoid plate, to a depth of approximately 10-15 mm into the palate. The needle was then removed, leaving the electrode in place. To confirm TP electrode placement, the following respiratory manoeuvres, which have been shown previously to activate the TP muscle, were performed: sucking, blowing and swallowing (Malhotra et al. 2000). Diaphragm EMG (DIAEMG) was obtained from electrodes placed at the right sixth to eighth intercostals spaces adjacent to the costal margin.
The raw EMG was amplified to provide an easily visible phasic inspiratory signal during quiet breathing (Grass Instruments, Quincy, MA, USA), band pass filtered (between 30 and 1000 Hz), and stored for subsequent data analysis by computer software. Sections of the recording containing movement and other artifacts were removed before analysis. In addition, sections of the DIAEMG containing QRS complexes (100-160 ms duration) were removed and replaced with the immediately preceding and succeeding sections. An EKG was recorded to implement this component of the analysis. The raw EMG signals for all muscles were then integrated by using a 100 ms moving time average (MTA). Several values were calculated on a breath-by-breath basis for each muscle. The first was the tonic level. Activity in the prior expiratory phase was divided into 10 equal segments and the level of tonic activity of the muscle was defined as the activity of the lowest segment. The second was phasic activity, which was defined as the area under the inspiratory MTA curve, above the tonic level. The third was total inspiratory activity, which was defined as the area under the MTA curve. It should be noted that because tonic activity was defined as the lowest level of activity during expiration, all muscles would necessarily be identified as having at least some phasic activity. As the diaphragm and genioglossus typically show prominent levels of inspiratory phasic activity, all three values are reported for these muscles. For the tensor palatini, (which does not typically show such a pattern) total inspiratory activity is reported. In order to allow comparison between subjects and between the CPAP and control nights, the GGEMG and TPEMG were quantified as percentages of the total inspiratory activity observed during swallowing. This was carried out as this manoeuvre was readily reproducible, produced a consistent level of activation in each individual on the two different nights and was almost always equivalent to the maximal activation for both upper airway muscles. To define the level of EMG activity during a swallow, the total inspiratory activity for all swallows from a night for each individual were averaged, yielding a single value for each muscle, for each condition and for each individual. The average number of available swallows was 56 (range 15-174) and 35 (range 8-139), for the younger subjects for normal and CPAP nights respectively, and 58 (range 8-196) and 36 (range 9-80) for the older subjects, for the normal and CPAP nights, respectively. The tonic level and phasic and total EMG activity for each breath were then expressed as percentages of this value. No easily reproducible manoeuvre could be identified for the diaphragm, and thus the diaphragm was recorded in arbitrary units, which were then normalized to the baseline level on each night.
Nasal CPAP application. On one of the two nights (order randomized) subjects were studied on nasal CPAP. Initially, 5-10 min of data were recorded during quiet breathing in order to estimate the level of GGEMG and TPEMG. Nasal CPAP was then applied (BIPAP S/T-D, Respironics, Inc., Murraysville, PA, USA) at 5 cmH2O and increased to a maximum of 10 cmH2O, or until the minimal level of GGEMG was obtained. If no obvious reduction in GGEMG was initially discernible, the subjects were studied on 5 cmH2O. The level of CPAP producing this minimal GGEMG was then used throughout the protocol (see below).
Protocol. Each subject reported to the laboratory at approximately 9 p.m., having fasted for at least 4 h. After obtaining informed consent, the sleep staging electrodes, pressure catheters and intramuscular EMG wires were placed. Subjects then assumed the supine posture in bed, and the nasal mask was attached. Subjects subsequently lay with eyes open in this posture, and were allowed to acclimatise to the equipment. The order of the study nights (CPAP or control) was randomized. After recording data during wakefulness, subjects were allowed to fall asleep (remaining in the supine posture). In order to obtain multiple sleep onsets (primarily transitions from quiet wakefulness to stage 1 sleep, as defined by the loss of EEG activity), they were woken if they had obtained 5 consecutive minutes of sleep without spontaneous awakenings, and were then allowed to fall asleep again. This procedure was repeated until approximately 4 h of data had been collected on each night.
Data recording and analyses
All signals (GGEMG, TPEMG and DIAEMG (raw and an electronically derived moving time average), airway pressure (mask, and epiglottic), PET,CO2, EKG, sleep staging and inspiratory flow were recorded on a 16-channel Grass model 78 polygraph (Grass Instruments, Astro-Med, Inc., West Warwick, RI, USA). Certain signals (GGEMG, TPEMG and DIAEMG, airway pressures, EEG, inspiratory flow, EKG) were also recorded onto computer using data acquisition software (Spike 2, Cambridge Electronic Design Ltd, Cambridge, UK).
For each individual, the occipital EEG during each breath was assessed as being predominantly or , as previously described (Worsnop et al. 1998, 2000). Briefly, for each subject, 10 min of and 10 min of were visually identified. For each breath in these two periods, the frequency characteristics of the corresponding EEG were determined using a peak-to-peak procedure. Intervals in the 0.3-50 Hz range were determined and these intervals were divided into those >8 Hz (longer than 0.125 s) and those <8 Hz. For each breath, a ratio of the number of EEG intervals >8 Hz to the total number of intervals was calculated. The distributions of EEG ratios for the breaths in the selected 10 min of and were plotted. The point of intersection between these two distributions was identified, and the ratio corresponding to this point of intersection became the criterion ratio for that subject as previously described. Thus any breath with a ratio less than the criterion ratio was classified as an breath and any breath with a ratio greater than the criterion ratio was classified as . This procedure was used to classify every breath for each subject as occurring either during or EEG activity (see Worsnop et al. 1998, 2000, for further description of this procedure). This procedure is illustrated in Fig. 1.
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Figure 1. An illustration of how criterion ratio is determined A, a single breath from a period of | ||
Analysis of sleep-onset effects. Once each breath had been classified as or , computer software was used to identify sets of consecutive breaths occurring on either side of an to transition. An adequate - transition was defined by having at least three consecutive breaths followed by at least two consecutive breaths. Each breath in the transition was then assigned a position relative to the transition from -5 to +5 as previously described by Worsnop et al. (2000). Thus, every transition had breaths -3 to +2, with fewer transitions having breaths in positions -5 and -4, and +3, +4 and +5. Each breath could then be given an identifiable position within a transition from -5 to +5. For each subject, the following parameters were averaged at each breath position: e, UAR, GGEMG and TPEMG (as percentages of swallow activity) and DIAEMG (arbitrary units). In addition, for each variable the mean level (-5 to -1) and the mean level (+1 to +2) was also calculated. These procedures were performed separately on the data for the control and CPAP nights.
Statistical analyses. All statistical analyses were performed with commercially available software (SigmaStat + Sigmaplot, SPSS, Chicago, USA). A 2 
2 2 ANOVA for repeated measures (with the factors breathing type, age and sleep-wake state) was performed to determine the effects of CPAP, sleep-wake state and age on muscle activation, airflow and upper airway resistance. When a significant effect was found, Tukey's test was used to determine which groups were significantly different. To determine whether CPAP had an effect on the pattern of muscle recruitment following the transition, a 2 10 ANOVA for repeated measures was performed (with the factors breathing type and breath no.) to see whether there was a significant interaction effect. For all analyses, was set at 0.05. Results are presented as means ± S.E.M. An age by CPAP by breath no. analysis was performed to assess the effect of CPAP on the pattern of muscle recruitment in both groups. Spearman's correlation was used to assess the relationship between genioglossal and tensor palatini muscle activation and UAR during wakefulness and sleep.
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RESULTS |
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CPAP and state effects in all subjects
Complete data sets during control and CPAP were obtained in all 23 individuals for e, UAR, GGEMG and DIAEMG. In one young individual amplifier problems made it impossible to obtain an adequate TPEMG while there were insufficient transitions for TPEMG for one young subject in the control and one in the CPAP conditions. Thus for TPEMG the data presented are from 22 individuals in each condition. Figure 2 shows an example of raw data in one individual during control and CPAP showing the reduction in muscle activation during sleep onset. The breath-by-breath changes across the transition for e, UAR and epiglottic pressure are shown in Fig. 3. Minute ventilation, expressed as a percentage of baseline fell at the to transition (Fig. 3, F = 28.01, P < 0.001), the magnitude of the sleep effect being unaffected by the application of nasal CPAP. UAR was reduced by CPAP application (Fig. 3, F = 9.74, P < 0.01) and there was a significant interaction between breathing condition and sleep-wake state, as CPAP prevented the increase in UAR seen at the to transition under control conditions (F = 8.17, P = 0.01).
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Figure 2. An example of raw data from one older individual during control (A) and continuous positive airway pressure (CPAP; B) Shown are EEG, inspiratory airflow (FLOW), moving time averaged diaphragm (Dia), tensor palatini (TP) and genioglossus (GG) EMGs, and mask (Pmask) and epiglottic (Pepi) pressure signals. The | ||
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Figure 3. Breath-by-breath changes in inspiratory minute ventilation ( Data are shown from breath -5 to +5 with the transition marked by the vertical dashed line. There was no difference in the pattern of change in minute ventilation while on CPAP, but CPAP reduced waking pharyngeal resistance and prevented the rise in UAR at the | ||
Table 1 and Fig. 4 show the mean ± S.E.M. values for GGEMG, TPEMG and UAR for control and CPAP, during (breaths -5 to -2) and (breaths +1 and +2). As seen in Fig. 4 and Table 1, CPAP caused a significant reduction in GGEMG (tonic level, phasic and total) during wakefulness (F = 15.93, P < 0.001) and in TPEMG (F = 11.05, P = 0.01). A significant reduction in both GGEMG and TPEMG was seen at the to transition (total inspiratory GGEMG, F = 13.78, P = 0.001; TPEMG: F = 13.42, P < 0.001). However, again, the magnitude of the sleep effect on muscle activation for breaths +1 to +2 did not differ between the CPAP and control conditions (no significant interaction effect). Figure 5 shows the breath-by-breath changes in muscle activation for all three muscles, plotted as the percentage change from the mean baseline. As can be seen, although the pattern of fall in muscle activity was similar during control and CPAP for the tensor palatini, there was a significant change in the pattern of muscle activation for the genioglossus while on nasal CPAP. As shown in Fig. 5, on the control night, after an initial fall in GGEMG at the to transition, there was a subsequent recruitment of GGEMG as also occurred with DIAEMG. However, on the CPAP night, GGEMG fell at the to transition, and continued to slowly decline up to breath +5 (a significant breath by CPAP interaction). There was a tendency for the decrease in DIAEMG at sleep onset to be greater on the CPAP night than the control night, possibly in relation to the lower UAR or the hyperinflation on CPAP, although this difference did not reach statistical significance. As we calculated muscle activity as the area under the MTA curve, these values could be influenced by the duration of inspiration. However, as can be seen in Tables 1 and 2, CPAP, state and age did not have any effect on inspiratory duration.
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Figure 4. Mean (± S.E.M.) GGEMG and TPEMG for all individuals during basal breathing and CPAP The | ||
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Figure 5. Breath-by-breath mean (± S.E.M.) values of GGEMG, TPEMG and DIAEMG (percentage change from No significant difference in the pattern of muscle changes over the transition was seen for TPEMG or DIAEMG during nasal CPAP. However, during basal breathing, there was an initial fall in GGEMG after the | ||
In order to examine whether a significant relationship existed between epiglottic negative pressure and muscle activation (i.e. was negative pressure 'driving' muscle activation) we performed correlational analysis between epiglottic pressure (Pepi) and EMG during wakefulness and sleep. We found a significant relationship between baseline GGEMG, (total inspiratory and phasic activity, percentage swallow) and epiglottic pressure during wakefulness (Fig. 6, r = 0.57, P < 0.02). This relationship remained significant during the first two breaths after the to transition (r = 0.54, P = 0.03), then fell, but remained present, during later pre-arousal NREM sleep (r = 0.46, P = .02). However, no significant relationship was seen between TPEMG and epiglottic pressure either during wakefulness (Fig. 6B) or sleep.
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Figure 6. The correlation between muscle activation and epiglottic negative pressure for both the GGEMG and TPEMG during wakefulness There was a moderate, but significant correlation between epiglottic pressure and phasic GGEMG. No such relationship existed for the TPEMG and epiglottic pressure. | ||
We also examined the relationships between the sleep effects on our various muscles. Here we found strong relationships between the changes in GGEMG, DIAEMG and TPEMG at the to transition (GGEMG vs. TPEMG percentage fall at transition, r = 0.80, P < 0.001). Similar relationships were seen for GGEMG and DIAEMG (r = 0.56, P = 0.01) and DIAEMG and TPEMG (r = 0.76, P < 0.001). These relationships also remained strong on the CPAP night. Although not definitive, these data would be consistent with withdrawal of a common stimulus of similar magnitude to all three muscles at the to transition.
Ageing effects
Table 2 shows the effects of breathing condition (control vs. CPAP) and age (younger vs. older) on UAR and muscle activation during wakefulness. UAR and GGEMG (total inspiratory and phasic activity) were significantly greater during wakefulness in the older men when compared with the younger ones (Table 2, P < 0.01) although there was no significant difference between the two age groups in TPEMG. CPAP caused a significant reduction in UAR and GGEMG in the older men only, without any significant change in these variables seen in the young men.
Figure 7 shows the breath-by-breath changes in GGEMG (Fig. 7A) and UAR (Fig. 7B) in the older and younger men at the to transition during both control and CPAP. While there were significant reductions in GGEMG (tonic, phasic and total) and TPEMG at the to transition (breaths +1 and +2) in both groups (all P < 0.01), there was not a significant difference between the younger and older men in the magnitude of the reductions (F < 0.05, P = NS). However, the pattern of GGEMG activity across the transition was different between the two groups. In the older men on the control night, there was recruitment of GGEMG seen after the initial sleep-related fall, which did not occur in the younger men. This recruitment of GGEMG in the older men was not seen in the CPAP condition (F = 3.6, P < 0.05 for age CPAP breath no. interaction). Pharyngeal resistance was higher during wakefulness in the older men and rose more at the to transition on the control night (Fig. 7B, F = 5.1, P = 0.03 for age state interaction). This increase in UAR at the to transition in the older men was not seen on the CPAP night (Fig. 7B).
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Figure 7. Breath-by-breath mean (± S.E.M.) peak GGEMG (A, percentage of swallow) and upper airway resistance (UAR; B, Rph-Max, cmH2O l-1 s-1) in younger and older men during basal breathing and nasal CPAP across the GGEMG was higher in the middle-aged men during wakefulness and was reduced more by the application of nasal CPAP. Resistance was higher in the older men during wakefulness (control) and increased more at the | ||
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DISCUSSION |
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The findings of the present study both confirm a number of previous findings and make novel observations regarding the control of upper airway patency and muscle activation in younger and older men, both during wakefulness and during the transition to sleep. First, as seen in previous studies, we found a reduction in DIAEMG, TPEMG and GGEMG at the to transition, along with a reduction in minute ventilation and a rise in UAR resistance (Worsnop et al. 1998, 2000). Second, we confirmed that during basal breathing (control night), after the initial fall in GGEMG, there is subsequent recruitment of muscle activity, such that by breath +5 after the to transition GGEMG has largely recovered to stable levels. No such recruitment was seen in TPEMG, consistent with our previous findings.
In addition, we have demonstrated a number of novel findings. First, we showed that the application of nasal CPAP led to a significant reduction in GGEMG during wakefulness along with a reduction in UAR. Second, although CPAP did not alter the magnitude of the reduction in GGEMG in the first two breaths following the transition, it did prevent the rise in UAR seen at the transition, and did block the subsequent recruitment of GGEMG. Third, CPAP had a significant effect on TPEMG during wakefulness, but no effect was seen during the transition from wakefulness to sleep. Taken together, these findings point to several mechanisms controlling these two upper airway muscles in normal humans, including the effect of state on control mechanisms.
First, the reduction in GGEMG during the application of nasal CPAP is likely to be due to removal of a 'negative pressure' stimulus to muscle activation as CPAP splints the airway open and reduces the pressure drop across the pharyngeal airway. However, the decrement in muscle activity during the initial portion of the to transition was not different on the CPAP night than it was on the control night. This implies that in these healthy men, the reduction in GGEMG seen immediately at the to transition is not due to loss of this negative pressure responsiveness, but rather due to the removal of a separate intrinsic 'wakefulness' drive to this muscle. While changes in ventilation and CO2 may contribute to the changes in GGEMG seen at the to transition, the changes in ventilation were identical on the two nights (Fig. 3) and thus cannot explain the differences in the pattern of muscle activation. Indeed, GGEMG maintained the ability to respond to negative pressure immediately after the transition as UAR increased in the control condition, GGEMG was recruited. Thus, after a normal to transition, GGEMG began to recruit, as pressure in the pharynx became more negative. This recruitment did not occur on the CPAP night, as UAR did not rise on the transition from wakefulness to sleep. These findings corroborate those of Shea et al. (1999), who were unable to find a reduction in the magnitude of the GGEMG response to pulses of negative pressure administered during the first five breaths after the onset of , when compared with the response seen during stable wakefulness. This is different than what is seen during stable NREM (non rapid eye movement) sleep, when GGEMG shows less ability to respond to negative pressure stimulation, whether applied as pulses, in the form of inspiratory resistive loading, or using an iron-lung device to generate negative pressure in the pharynx. The correlation between GGEMG activity and epiglottic pressure seen during wakefulness and immediately following the transition is also consistent with this muscle responding in a reflex manner to local conditions during this time. Further, the subsequent decrement in this relationship during pre-arousal NREM sleep suggests that responsiveness of the muscle to negative pressure is somewhat diminished by this time.
The tensor palatini appears to be controlled in a somewhat different manner than the genioglossus. In our study, although the application of nasal CPAP did lead to a significant reduction in TPEMG during wakefulness, there was no change in the pattern or magnitude of TPEMG reduction seen at the to transition on nasal CPAP. Furthermore, there was no correlation between epiglottic pressure or UAR and TPEMG. Thus, it appears that neither epiglottic pressure nor UAR immediately impact TPEMG. This is consistent with previous findings from our group, where TPEMG did not change with either inspiratory resistive loading or the addition of CO2 during wakefulness (Malhotra et al. 2000). The effect of sleep on TPEMG was also greater than that seen for either GGEMG or for DIAEMG. While the drop in muscle activity for all three muscles was quite similar during the two breaths following the transition, after this point TPEMG continued to decline as sleep deepened. This was quite different from that which occurred for DIAEMG and GGEMG, both of which tended to recover after the initial fall at the to transition. The tensor palatini usually (although not always) shows a primarily tonic pattern of activity, without clear phasic respiratory modulation. Work from Orem et al. (1985, 1990) has suggested that those respiratory group neurons with primarily a tonic pattern of activation are those most affected by sleep, during which they exhibit a much larger decrement in neuronal firing rate than neurons which demonstrate a clear respiratory phasic pattern of activity. However, it is also possible that our inability to find a relationship between TPEMG and epiglottic pressure during wakefulness or sleep may have been due to a relative lack of power given the small number of subjects studied. However, if such a relationship exists, it is likely to be less robust than was seen for GGEMG.
Our findings in the younger vs. middle-aged men are also novel. We found that older men had greater UAR and GGEMG during wakefulness when compared with the younger men in this study. We also found that CPAP had a greater effect on UAR and GGEMG in these middle-aged men, causing greater falls in both variables as compared with younger subjects. A greater rise in UAR was seen at the to transition in the older men, and associated with this rise, they showed substantial recruitment of GGEMG, which was not present in the younger men. Unlike our previous study however, we did not demonstrate a greater fall in muscle activity in the older men at sleep onset (Worsnop et al. 2000).
Taken together, these findings are most consistent with the hypothesis that upper airway changes associated with normal ageing are primarily anatomic, rather than related to a change in the way in which the upper airway muscles are controlled during wakefulness, or the effect of the to transition on these muscles. If ageing leads to a smaller or more collapsible pharyngeal airway, this would in turn lead to a rise in UAR, and through reflex mechanisms, increased genioglossal muscle activation in order to defend upper airway patency. With a reduction in UAR (i.e. with CPAP) there should then be a greater fall in muscle activation in the older men, to levels equivalent to that seen in the younger men. This is precisely what we found in this study. The fact that we did not find a significant difference in TPEMG in the older men, despite higher UAR, is consistent with the hypothesis that this muscle is less responsive to a negative pressure stimulus than is the genioglossus. Our data do not suggest that the sleep onset mechanism per se has a greater effect in older men, as the reduction in upper airway and diaphragm EMG was not greater in older men at the to transition while on nasal CPAP. These age-related changes may be important in understanding the increased prevalence of OSA in middle-aged individuals. If, with ageing, despite no change in BMI there is a narrowing of the pharyngeal airway, or a change in collapsibility (possibly secondary to changes in tissue characteristics), the propensity to develop sleep apnoea is likely to be greater.
It is not clear why we did not reproduce the findings of Worsnop et al. (2000), in which a greater reduction in upper airway muscle activity at the to transition was seen in the middle-aged men. Although the Worsnop experiment was conducted in Melbourne, and this one in Boston, the techniques and measurements were largely identical. One difference, however, was in the type of subject recruited in the middle-aged group. In the study by Worsnop et al. (2000), the majority of the middle-aged men were highly conditioned athletes and perhaps were not representative of typical middle-aged men in that they may have had more stable upper airways. Thus at sleep onset, if they did not need to recruit upper airway muscle activity, the full effect of the loss of wakefulness may have been seen. However, if this were the case, we should have seen a similar phenomenon on our CPAP night, when UAR did not rise at the to transition. This was not the case. Thus we cannot fully explain the difference in the two studies.
Our study had a number of limitations, which are important to recognize in interpreting the results. First, the application of nasal CPAP leads to a number of changes other than simply lowering UAR. Lung volumes are increased, airway shape may be changed, and the application of positive pressure may directly stimulate positive pressure receptors that have been identified in the trachea. Thus the effects of CPAP are likely to be more complex than the simplified view presented here. Indeed, we and others have shown that increasing lung volume by methods other than nasal CPAP will lead to a decrease in UAR and a subsequent decrement in GGEMG (Begle et al. 1990). Thus it is certainly possible that CPAP exerted its effects via changing lung volume, although if it did so, the primary stimulus might very well be via decreasing UAR and the associated epiglottic pressure change during inspiration. In addition, though positive pressure receptors have been shown to exist in the trachea, their function remains unclear, as does the effect of stimulating these receptors on GGEMG. Thus, although the application of CPAP leads to complex changes, we believe that our interpretation of the findings to be the most probable. Second, we did not perform formal sleep studies on any of our subjects to completely rule out OSA. Thus, it is theoretically possible that some of the older participants could have mild sleep-disordered breathing and high UAR. We think this unlikely as all were thin and did not report snoring. Furthermore, all were studied during sleep on a baseline night, in the supine posture, with a catheter placed in the airway and a mask in place, all of which would increase the load on the upper airway. This should have increased the chance of upper airway collapse, yet none demonstrated sleep-disordered breathing. We did not study REM sleep, so it remains possible that some degree of unrecognized OSA could be present during this stage in some of these individuals. Again, even if true, this is unlikely to alter our conclusions. Third, we used surface electrodes to quantify diaphragm muscle activity and it is likely that these electrodes were not recording pure DIAEMG. We did not believe it was justified in these studies to use oesophageal diaphragm electrodes, as we were only interested in the diaphragm as a representative pump muscle. Fourth, our method of quantifying GGEMG and TPEMG to allow comparisons between subjects and between nights (percentage of swallow activity) could be challenged. We used this methodology as it produced a highly reproducible, effort-independent maximal value for each subject. The general stability of the magnitude of the EMG increase with swallowing across the night is reassuring in terms of lack of change in electrode position within the muscle and amplifier gain stability. In addition, the availability of numerous swallows over the course of both nights allowed us to average a number of these values to produce our maximum. For this methodology to have produced artifactual results, CPAP would have to increase the swallow EMG signals, such that it would have appeared that the basal activity was lowered as a percentage of this swallow. We know of no reason why this should be the case. Finally, all of these studies were conducted in men, and whether these results can be generalized to females is unclear.
In summary, we first found that the application of nasal CPAP led to a reduction in waking GGEMG as well as in TPEMG, and this reduction was greater in middle-aged than in young men. This observation, combined with the finding of higher waking GGEMG in older men, suggest that the primary difference between these two groups is an anatomical one, with older men having a higher resistance upper airway leading to increased GGEMG. This result may have pathophysiological importance in understanding the increased prevalence of OSA in middle-aged men. Second, CPAP did not have an effect on the magnitude of the initial fall in muscle activity seen at sleep onset, suggesting that this is due primarily to removal of a 'wakefulness stimulus' rather than inability of these muscles to respond to resistance or negative pressure. Finally, CPAP prevented the recruitment of GGEMG during sleep onset, suggesting that this recruitment occurs in response to rising UAR at this time. Thus some ability to respond to local airway stimuli must still be present at this time.
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Acknowledgements
This work was supported by NIH NCRR GCRC MO1 RR02635, 1 P50 HL60292, RO1 HL48531, K23 HL04400 as well as NH&MRC grant 209119. Dr Fogel is a recipient of the Pickwick Fellowship from the National Sleep Foundation. Dr Malhotra is receiving grants from the Medical Research Council of Canada and the American Heart Association. The authors thank Yvonne J. Gilreath for administrative assistance.
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