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J Physiol (2003), 550.3, pp. 899-910
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2003.038810
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ABSTRACT |
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Pharyngeal dilator muscles are clearly important in the pathogenesis of obstructive sleep apnoea syndrome. Substantial data support the role of a local negative pressure reflex in modifying genioglossal activation across inspiration during wakefulness. Using a model of passive negative pressure ventilation, we have previously reported a tight relationship between varying intrapharyngeal negative pressures and genioglossal muscle activation (GGEMG) during wakefulness. In this study, we used this model to examine the slope of the relationship between epiglottic pressure (Pepi) and GGEMG, during stable NREM sleep and the transition from wakefulness to sleep. We found that there was a constant relationship between negative epiglottic pressure and GGEMG during both basal breathing (BB) and negative pressure ventilation (NPV) during wakefulness (slope GGEMG/Pepi 1.86 ± 0.3 vs. 1.79 ± 0.3 arbitrary units (a.u.) cmH2O-1). However, while this relationship remained stable during NREM sleep during BB, it was markedly reduced during NPV during sleep (2.27 ± 0.4 vs. 0.58 ± 0.1 a.u. cmH2O-1). This was associated with a markedly higher pharyngeal airflow resistance during sleep during NPV. At the transition from wakefulness to sleep there was also a greater reduction in peak GGEMG seen during NPV than during BB. These data suggest that while the negative pressure reflex is able to maintain GGEMG during passive NPV during wakefulness, this reflex is unable to do so during sleep. The loss of this protective mechanism during sleep suggests that an airway dependent upon such mechanisms (as in the patient with sleep apnoea) will be prone to collapse during sleep.
(Received 6 January 2003; accepted after revision 7 May 2003; first published online 13 June 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). This 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, 1999; Lavie, 2000; Peppard, 2000). Numerous studies have demonstrated that the pharyngeal airway of the apnoea patient is anatomically small when compared with that of controls, and is thus potentially more vulnerable to collapse (Haponik et al. 1983; Horner et al. 1989; Schwab et al. 1995).
There is substantial evidence in both animals and humans that upper airway dilator muscles play an important role in maintaining airway patency (van Lunteren, 1993). Many of the pharyngeal dilator muscles are known to demonstrate inspiratory phasic activity, the onset of which precedes diaphragmatic activity, thus 'preparing' the pharyngeal airway for the development of negative pressure during inspiration (Strohl et al. 1980). We have previously shown in patients with OSA during wakefulness that there is augmented activity of the genioglossus (GGEMG) muscle as well as other pharyngeal dilator muscles when compared to 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.
The best studied pharyngeal muscle is the genioglossus. At least four sources of input are potentially important in controlling this muscle's activation. First, the genioglossus receives input from the brainstem respiratory central pattern generator (CPG) (Bianchi et al. 1995). The presence of 'pre-activation' (hypoglossal nerve firing 50-100 ms prior to the phrenic nerve) supports the presence of pre-motor inputs to the hypoglossal motor nucleus in the medulla. Second, chemoreceptive inputs are important in influencing hypoglossal motor nerve output (Onal et al. 1981a,b). However, whether this is a direct effect, or is mediated by the the CPG or via negative pressure mechanisms is not clear (Shea et al. 2000). Third, a 'wakefulness' drive is present in the respiratory system and may be important in controlling upper airway muscle activation as well.
Finally, substantial evidence supports a major contribution from local mechanisms in the modulation of pharyngeal dilator muscle activation, although the precise stimulus and receptors involved remain unclear (Horner, 1991a,b; Fogel et al. 2001). Most data suggest that intrapharyngeal negative pressure is the primary stimulus to phasic pharyngeal dilator muscle activation during wakefulness (Mathew et al. 1982a,b). First, 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. 1991a,b). The time course of this response (maximal response within 200 ms) suggests that it is a neural reflex. Second, we have recently shown that peak phasic genioglossus (GG) activity correlates closely with the peak negative epiglottic pressure generated during inspiratory resistive loading in healthy controls (Malhotra et al. 2000). Finally, using an iron lung model of passive ventilation, data from our laboratory demonstrate that during inspiration, there is an extremely tight correlation between epiglottic negative pressure (Pepi) and GGEMG (Akahoshi, 2001; Malhotra et al. 2002). Using this iron lung model, we can substantially attenuate or eliminate the pre-activation of pharyngeal dilator muscles and show a marked reduction or elimination of phasic diaphragm EMG (DiaEMG) activity (Akahoshi, 2001). Therefore, this model can serve as a useful tool to investigate the relative influences of intrapharyngeal stimuli while minimizing CPG input (Zhou et al. 2000). During wakefulness, even in the absence of CPG input, GGEMG increases as intrapharyngeal pressure becomes more negative during iron lung ventilation. The responsiveness of the GGEMG (slope of GGEMG/Pepi) was found to be remarkably constant in a given individual over a range of epiglottic pressures and was not independently influenced by changes in PO2, PCO2 or airflow(Akahoshi, 2001; Malhotra et al. 2002). Furthermore, we have recently shown that the slope of this relationship (GGEMG/Pepi) was similar in patients with OSA and age-matched controls, suggesting that the intrinsic relationship between pressure and muscle activation was not different in patients with OSA during wakefulness (Fogel et al. 2001). The data from this iron lung model suggest that during wakefulness genioglossal muscle activation is directly proportional to intrapharyngeal pressure, probably secondary to activation of a local 'negative-pressure reflex' (NPR).
The effect of sleep on genioglossal muscle activation is more complex. The bulk of data suggest that in normal individuals there is an initial drop in genioglossal muscle activation at sleep onset, but that muscle activity recovers to waking levels or above during stable NREM sleep (Worsnop et al. 1998, 2000). However, data from our laboratory and others suggest a marked diminution in the ability of the genioglossus to respond to either brief pulses of negative pressure, elevated CO2 levels or inspiratory resistive loading during stable NREM (Wheatley et al. 1993; Horner et al. 1994; Malhotra et al. 2000). Whether the recovery of GGEMG during NREM sleep in normal individuals is due to local activation of the muscle (negative pressure, CO2, etc.) or is due to increased output of the CPG is unclear. An increase in CPG output during stable NREM sleep is suggested by the fact that DiaEMG also recovers to baseline levels after an initial decrement at sleep onset (Worsnop et al. 1998). Thus the true effect of sleep on the NPR, as well as the time course of the change in this reflex has not been well delineated.
In this study, we used the iron lung negative pressure ventilation protocol to study the relationship between negative pressure and genioglossal muscle activation during wakefulness as compared with stable NREM sleep in normal healthy humans, while minimizing the confounding influence of CPG activation. We hypothesized that during NREM there would be a reduction in the NPR, and thus there would be a marked decrement in genioglossal muscle activation during passive ventilation (in the absence of diaphragm activity) and that this would be associated with an increase in pharyngeal resistance. We further wished to explore the time course of the change in muscle activation during the transition from wakefulness to sleep.
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METHODS |
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Sixteen healthy volunteers (9 males) without sleep complaints were studied. The mean age was 31.0 ± 2.3 (S.E.M.) years and mean body mass index, 23.1 ± 0.53 kg m-2. Written informed consent was obtained from each subject, with the protocol having the prior approval of the Human Subjects Committee of the Brigham and Women's Hospital. All procedures used conformed with the standards of the Delaration of Helsinki. Four subjects were unable to sleep during the protocol and thus data from twelve subjects (seven males) were analysed.
Equipment and techniques
All studies were performed on subjects in the supine posture as they lay within a negative pressure chamber (Porta-Lung, Model PL4, Denver, CO, USA), attached to a negative pressure ventilator (Respironics Model NEV-100, Murraysville, PA, USA) which was activated only for the mechanical ventilation conditions (see below). Subjects were instrumented with two channels of electroencephalography (EEG), two channels of electro-oculography (EOG) and chin EMG for monitoring and staging of sleep.
Airway mechanics. Subjects wore a nasal mask (Healthdyne Technologies, Marietta, GA, USA) connected to a non-rebreathing valve. Inspiratory and expiratory airflow was 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. The inspiratory flow signal was integrated to yield tidal volume. 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 with a perforated catheter surrounding the mask-face interface, which continuously sampled for CO2. In addition, end-tidal PCO2 (PETCO2) was monitored from the mask using an infrared analyser (Capnograph Monitor, BCI, Waukesha, WI, USA).
Pressures were monitored in the mask with an open catheter attached to a pressure transducer (Validyne Corp) and in the airway at the level of the choanae and the epiglottis using pressure-tipped catheters (MPC-500, Millar, Houston, TX, USA). One nostril was decongested (oxymetazalone HCl) and anaesthetized (lignocaine (lidocaine) HCl), and the Millar catheters were inserted through this nostril and localized at the choanae and epiglottis. Prior to insertion, all three pressure signals were calibrated simultaneously in a rigid cylinder using a standard water manometer. These three signals plus flow were demonstrated to be without amplitude or phase lags at up to 2 Hz.
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. The needle was quickly removed, leaving the wires in place. This technique has been used previously in our laboratory (Wheatley et al. 1993). Diaphragm EMG (DiaEMG) was obtained from electrodes placed at the right sixth to eighth intercostal spaces, adjacent to the costal margin.
The raw EMG was amplified (Grass Instruments, Quincy, MA, USA.), band-pass filtered (between 30 and 1000 Hz), rectified, and electronically integrated on a moving time average (MTA) basis with a time constant of 100 ms (CWE, Inc., Ardmore, PA, USA). Electrocardiographic (ECG) artifacts were removed from the raw diaphragm EMG using an ECG blanker (CWE: SB-1, Ardmore, PA, USA). The EMG was amplified to provide an easily visible phasic inspiratory signal during quiet breathing in each individual and was thus quantified in arbitrary units (a.u.).
Negative pressure ventilation ('iron lung'). Subjects were studied while supine with the head outside and body within a negative pressure chamber (Porta-Lung, Model PL4, Denver, CO, USA). The ventilator was switched on only for specific parts of the experiment (see protocol below). The device was lightly sealed around the neck with a flexible twisted nylon sheet while an external negative pressure ventilator (Model NEV-100, Respironics, Murraysville, PA, USA) created negative pressure around the chest wall and abdomen, thus assisting each breath. The negative pressure ventilator could be adjusted (pressure level, respiratory rate, inspiratory time) to achieve the desired upper airway pressure and breathing frequency, so that passivity (or completely synchronous ventilation) was achieved. All subjects required some initial coaching to enable passive mechanical ventilation. This involved asking the subjects to remain completely relaxed while the investigators provided feedback on a breath-by-breath basis to achieve consistent timing and shape of the pressure and flow traces. Recordings were stopped when there was a departure from this passive pattern until adequate passivity could be achieved, or the experiment was terminated. Measurements were recorded only during steady-state conditions (Akahoshi, 2001).
Protocol. Each subject reported to the laboratory at approximately 9 pm, having fasted for at least 4 h, and the sleep staging electrodes, pressure catheters and intramuscular EMG wires were placed in position. Subjects then assumed the supine posture in the iron lung, and the nasal mask was attached. Subjects subsequently lay with eyes open in this posture, and were allowed to acclimate to the equipment. Subjects were subsequently recorded during both basal breathing (BB) and during passive breathing in the negative pressure ventilator (NPV) during wakefulness for at least 5-20 min in each condition. Respiratory rate in the iron lung was initially set at 1-2 breaths min-1 above the eupnoeic level and then adjusted for subject comfort. The amplitude of the iron lung excursions was adjusted as necessary to achieve passivity. When passive (synchronous) ventilation was achieved, data were recorded. Although we wished to develop greater negative intrapharyngeal pressure during NPV, we did not choose precise pharyngeal pressure goals as this was difficult to achieve due to variable upper airway resistance. Carbon dioxide was added to the inspiratory line when necessary to produce the desired end-tidal CO2 concentration. In order to achieve passivity PETCO2 was allowed to drop 3-4 mmHg below baseline if necessary, but not more than this. After recording wakeful data subjects were allowed to fall asleep under both baseline and NPV conditions (order randomized). If the subjects achieved greater than 10 consecutive minutes of stable NREM sleep in either condition they were awoken and allowed to fall back to sleep in order to evaluate discrete transitions from wakefulness to sleep. Therefore, each subject was studied under four different conditions (BB - wakefulness and NREM, and NPV - wakefulness and NREM). For each individual, at least 10 min of stable data were obtained in each condition.
Data recording and analyses
All signals (GGEMG and DiaEMG (raw and MTA), airway pressure (mask, choanal, epiglottic), PETCO2, 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 and DiaEMG-MTA, airway pressures, EEG, inspiratory flow, PETCO2) were also recorded onto computer using signal-averaging software (Spike 2; Cambridge Electronic Design Ltd, Cambridge, UK).
Analysis of stable conditions. For each of the four stable conditions, one buffered breath was generated by signal averaging all breaths in that particular condition. This was accomplished by aligning each breath to the onset of inspiration and then averaging the response profile for each variable. For analysis of stable NREM sleep we only analysed periods of sleep during which there was no evidence of arousal for the entire period. In each subject, all such periods were included, such that approximately 20-30 min of stable NREM sleep was analysed in each condition. For each buffered breath the following variables were determined: peak negative pressure (at the levels of choanae and epiglottis), peak flow, tonic GGEMG and DiaEMG (lowest level of activation during expiration), and peak phasic GGEMG (peak activation during inspiration). Phasic EMG was defined as the difference between peak phasic and tonic EMG. Pharyngeal resistance (choanae to epiglottis) and supraglottic resistance (mask to epiglottis) were calculated at peak inspiratory flow. The relationship (slope) between inspiratory GGEMG and epiglottic pressure was determined across the buffered breath (within-breath analysis) as a linear regression.
Analysis of sleep-onset effects. In order to determine the time course of changes in the relationship between negative pressure and GGEMG we also evaluated the change in muscle activation and pharyngeal resistance during normal breathing and NPV across the transition from wakefulness to sleep (
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transition). Briefly, for each subject each breath was assigned a value of or by visual analysis of the occipital EEG signal alone, by two of the authors (R.B.F., J.K.E.) independently and any disagreements resolved. An adequate - transition was defined as 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 +3, as previously described by Worsnop (Worsnop et al. 1998). Thus, every transition had breaths -3 to +2, with somewhat fewer including breaths at the far ends of the transition. The tonic, peak phasic and phasic GGEMG were calculated on a breath-by-breath basis and the arithmetic mean determined both for each position relative to the transition as well as the mean level (-5 to -1) and the mean level (+1 to +3). The limited number of breaths at each position precluded signal averaging these data. Only those individuals with at least 10 adequate transitions during both BB and NPV were used for this analysis (8 subjects).
Statistical analyses. All statistical analyses were performed with commercially available software (SigmaStat + Sigmaplot, SPSS, Chicago, USA). Standard linear regression analyses were performed to examine the slope and correlation between negative epiglottic pressure and GGEMG for our within-breath analysis from the signal-averaged (buffer) breath in each condition. A 2 
2 ANOVA for repeated measures (with the factors breathing type and sleep-wake state) was performed to determine the effects of NPV and sleep-wake state on muscle activation, airflow and upper airway resistance on the signal-averaged data. When a significant effect was found, Tukey's test was used to determine which groups were significantly different. A 2 8 ANOVA for repeated measures (with the factors breathing type and breath number) was used to compare sleep onset during basal breathing and negative pressure ventilation. Tukey's test was used to examine differences between basal breathing and negative pressure ventilation at individual breaths across the - transition. For all analyses, was set at 0.05. Results are presented as means ± S.E.M.
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RESULTS |
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Analysis of stable conditions
Complete data sets for all four conditions were obtained in 12 individuals. Figure 1 shows an example of raw data obtained during wakefulness in one individual during basal breathing and passive NPV. As can be seen, GGEMG was greater during NPV and DiaEMG was markedly reduced. Figure 2 shows an example of signal-averaged data in one individual showing the loss of GGEMG pre-activation during NPV, again consistent with a reduction in CPG activity. PETCO2 values for each condition are shown in Fig. 3. There was a significant reduction in CO2 during NPV during wakefulness when compared with BB (36.95 ± 0.57 vs. 40.18 ± 0.56 mmHg, P < 0.001) but not during NREM sleep.
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Figure 1. Phasic genioglossal activation during basal breathing and negative pressure ventilation Example of raw data from one subject during basal breathing (top) and negative pressure ventilation (bottom) during wakefulness. Phasic GGEMG persists during NPV, in spite of reduced DiaEMG. | ||
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Figure 2. Loss of GGEMG pre-activation during negative pressure ventilation Signal-averaged data in one individual shows that during basal breathing (left), phasic activation of the genioglossus is seen prior to the onset of inspiratory airflow (dashed line). This pre-activation is lost during negative pressure ventilation (right). | ||
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Figure 3. PETCO2 values during the four breathing conditions The individual and mean (± S.E.M.) values for PETCO2 during basal breathing (BB) and negative pressure ventilation (NPV), both during wakefulness and NREM sleep are shown. There was a reduction in CO2 during NPV-wake compared with BB, but not during NREM sleep. * P < 0.05, NPV-wake different from all other conditions. | ||
Diaphragm activation
Table 1 shows the effects of breathing condition (BB vs. NPV) and state (wake vs. NREM) on GGEMG and DiaEMG. There was a significant reduction in phasic and peak phasic DiaEMG during NPV (phasic DiaEMG 3.19 ± 0.66 vs. 0.58 ± 0.18 a.u. BB vs. NPV P < 0.001). There was no significant in change in tonic DiaEMG during any condition. There was no significant interaction between sleep-wake state and breathing condition. Sleep-wake state did not have a significant effect on peak or phasic DiaEMG (Table 1, peak DiaEMG, 11.88 ± 2.9 vs. 11.61 ± 3.3 a.u., BB, wake vs. NREM).
Genioglossal activation
As can be seen in Table 1, the effects of NPV on both peak and phasic GGEMG were state dependent (P < 0.01) such that peak GGEMG was highest during NPV and wakefulness and lowest during NPV and stable sleep (35.71 ± 6.1 vs. 14.78 ± 3.5 a.u. P < 0.001 for interaction effect). Figure 4 shows an example of raw data from one individual during stable NREM sleep with BB or NPV. As can be seen, with NPV during sleep there is a marked reduction in GGEMG despite markedly increased epiglottic negative pressure and much higher pharyngeal resistance. In this otherwise normal individual, flow limitation developed during NREM sleep while on NPV. There was also a significant effect of sleep-wake state on GGEMG, but this appeared to be due primarily to the reduction in GGEMG with NPV during NREM as there was no significant difference between peak GGEMG during wake and NREM sleep during BB (Table 1, 22.77 ± 4.1 vs. 24.50 ± 4.6 a.u., P = n.s.). Figure 5 shows an example of the linear regression slope of GGEMG vs. Pepi in one individual across all four conditions. As seen in Fig. 5 and Table 1, the relationship between epiglottic pressure and GGEMG was constant across all three conditions except for NREM sleep during NPV, when there was a marked reduction in this slope (0.58 ± 0.1 a.u. cmH2O-1, P < 0.01 vs. both NPV-wake and BB-NREM).
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Figure 4. Loss of phasic GGEMG with NPV during stable NREM sleep Raw data from one individual shows that during stable NREM sleep and BB, phasic GGEMG activity is still seen. However, during NPV, phasic GGEMG is largely absent, despite more negative intrapharyngeal pressure, and the development of inspiratory airflow limitation (bottom). | ||
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Figure 5. The relationship between GGEMG and negative epiglottic pressure The relationship between GGEMG and Pepi during the four stable breathing conditions is shown using signal-averaged data from one subject. As can be seen, the slope of the GGEMG/Pepi regression line is relatively constant except during NPV-NREM, when the slope is markedly reduced. | ||
Pharyngeal mechanics
Peak inspiratory flow plus pharyngeal and supraglottic resistances are presented in Table 2. As expected, flow increased during NPV-wake compared with BB-wake and was decreased during NREM sleep under both ventilatory conditions. The interaction term was again significant, as the effect of NPV depended on sleep-wake state. Pharyngeal and supraglottic resistances were increased during NPV compared to BB during both wake and NREM sleep (Table 2). However, the effect was most marked during NPV-NREM when resistance was markedly increased compared to all other conditions (all P values < 0.001).
Sleep-onset effects
There were eight individuals (4 male) in whom there were at least 10 - transitions during both BB and NPV conditions that could be analysed. Figure 6 shows an example of a transition from wakefulness to sleep during BB and NPV. As seen in the stable state data, tonic and peak GGEMG were greater during NPV prior to the transition from wakefulness to sleep. The reductions in tonic, peak and phasic GGEMG from to were greater during NPV than they were during BB (Fig. 7) (tonic GGEMG, 1.92 ± 0.7 vs. 3.74 ± 1.1 a.u., P = 0.025; peak GGEMG, 4.00 ± 0.9 vs. 13.44 ± 3.0 a.u. P < 0.01). However, even at breath +2 following the transition, peak GGEMG showed a strong trend to be greater during NPV than during BB (32.07 ± 6.3 vs. 25.49 ± 4.6 a.u., P = 0.08), whereas tonic GGEMG was no longer greater (12.98 ± 2.5 vs. 11.42 ± 2.1 a.u., P = n.s.). This is in contrast to stable sleep when GGEMG had fallen to its lowest levels during NPV. There was also a trend for the slope of the GGEMG/Pepi relationship to fall during NPV across the transition (2.04 ± 0.37 vs. 1.34 ± 0.29 a.u. (cmH2O)-1, P = 0.08). No such change in slope at the - transition was seen during BB (data not shown). The rise in pharyngeal resistance was also greater during sleep onset during NPV (0.17 ± 0.2 vs. 1.04 ± 0.4 cmH2O l-1 s-1, P = 0.03, Fig. 6). There was no significant change in DiaEMG at the - transition seen in either breathing condition (data not shown).
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Figure 6. Sleep onset during basal breathing and negative pressure ventilation Raw data in one individual shows a transition from | ||
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Figure 7. Change in GGEMG and pharyngeal resistance during the Mean data for the entire group showing the change in peak GGEMG (top) and pharyngeal resistance (bottom) during BB (continuous line) and NPV (dashed line). The reduction in GGEMG was greater during NPV (although peak GGEMG during NPV was still greater than BB at breath +2). In addition, pharyngeal resistance was higher during | ||
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DISCUSSION |
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The findings of the present study substantially improve our understanding of the control of genioglossal muscle activation in normal humans, during wakefulness and NREM sleep. First, we confirmed our previous observations that with NPV during wakefulness, there is a marked increase in GGEMG, which parallels the rise in pharyngeal negative pressure (Akahoshi, 2001; Fogel et al. 2001; Malhotra et al. 2002). Thus, the slope of the GGEMG-Pepi relationship remains constant between BB and NPV during wakefulness, despite a marked decrement in DiaEMG (and presumably CPG activity) during NPV. Second, we confirmed prior observations that in normal individuals, both GGEMG and DiaEMG are relatively well maintained during stable NREM sleep when compared to wakefulness (Worsnop et al. 1998). In addition, we found that the slope of the GGEMG-Pepi relationship was similar for wakefulness and NREM sleep during BB.
The major novel observation of this study is that with NPV during stable NREM, there was a marked reduction in GGEMG compared with both NPV during wakefulness and BB during NREM. Associated with this fall in muscle activation was a large rise in pharyngeal and supraglottic resistance, and in some of these otherwise normal individuals the development of airflow limitation. The GGEMG/Pepi slope was reduced by more than 60 % during NPV-NREM sleep when compared with all other conditions.
This finding has a number of implications. First, it suggests that during NREM sleep, when the negative pressure reflex is substantially reduced, the genioglossus is minimally able to respond to increasing pharyngeal pressure and pharyngeal resistance. Thus, if the upper airway is dependent upon this reflex to maintain patency then collapse to some extent must ensue (as occurs in the apnoea patient). Our results are also consistent with previous small series and case reports showing upper airway obstruction and the induction of OSA in some normal individuals during negative pressure ventilation (Levy et al. 1989, 1992; Hill et al. 1992).
Second, these findings suggest that the normal recruitment of genioglossal muscle activity seen during NREM (that which occurs after the initial fall at the - transition) may be due to recruitment of central pattern-generating neurons, rather than activation of local upper airway receptor mechanisms. If true, this observation would also help explain previous discordant findings. It has been difficult to reconcile the fact that there is recruitment of GGEMG during NREM sleep in normal individuals with the fact that this muscle is largely unresponsive to brief stimuli applied during this state, such as pulses of negative pressure or the addition of an inspiratory resistive load. These results suggest that during wakefulness GGEMG can be maintained by either CPG neurons, local reflex mechanisms or both, but that during NREM sleep, only CPG mechanisms are functional. In these individuals, the GGEMG-Pepi relationship was similar during BB in wakefulness and NREM sleep. One might thus speculate that in these individuals, there is little activation of the negative pressure reflex during normal quiet breathing and GGEMG is largely due to output from the CPG. During NPV with an increase in Pepi there is recruitment of this reflex activation at the same time that there is a reduction in CPG output, thus GGEMG is maintained. During NREM sleep, we would speculate that the negative pressure reflex fails, and thus in the absence of CPG output, GGEMG is unable to respond to the generation of negative pressure. The degree of airway collapse would then be dependent on the passive characteristics of the airway in this setting.
An alternative explanation of these results would be that CPG neurons are not directly responsible for GGEMG activity during NREM sleep, but rather that input from these neurons has a 'permissive' function at the hypoglossal nucleus, thus allowing the genioglossus to respond to local conditions such as an increase in negative pressure in the pharynx. Thus, by inhibiting these neurons with NPV and mild hypocapnia during sleep, we removed this permissive input to the hypoglossal nucleus and thus the muscle was unable to respond. While we cannot eliminate this possibility we believe it is a less likely explanation than that outlined above. As seen in the results, DiaEMG was markedly reduced with NPV during wakefulness, yet GGEMG was highest during this condition, with a similar slope to BB, and was lowest with NPV during NREM sleep. Thus, for this explanation to be correct, the requirement for 'permissive' CPG input would have to be state dependent. We know of no data to support this concept. Finally, more complex relationships between CPG output, CO2 levels and GGEMG may exist, such that, under hypocapnic conditions during sleep, there is active inhibition of genioglossal responsiveness. Again, although theoretically possible we think this is somewhat less likely.
Our observations regarding the changes in muscle activation during NPV vs. BB across the - transition are of some interest as well. We found a larger decrement in GGEMG (peak and phasic) at the - transition during NPV compared with BB and this was associated with a greater rise in pharyngeal resistance. However, by breath +3 after the transition, GGEMG remained higher during NPV than during BB. This is in contrast to the situation seen during stable NREM sleep, where GGEMG was at its lowest level during NPV. The changes in the respiratory system that occur at sleep onset are complex, but probably include a loss of the 'wakefulness drive' and changes in tonic inputs to the respiratory system as well as changes in the ability to respond to local stimuli. If the greater peak and phasic GGEMG activity seen during NPV in the wakeful condition were due to an augmented negative pressure reflex, then a similar reduction in this reflex would lead to a greater reduction in GGEMG at sleep onset. However, the fact that peak GGEMG was still greater during NPV in the immediate post-transition period compared with BB suggests that the negative pressure reflex is not completely lost at this time. This reflex must diminish slowly over the transition from wakefulness to sleep, such that it is largely abolished by stable NREM sleep. Consistent with this hypothesis are previous data from our laboratory, in which GGEMG responses to brief pulses of negative pressure were only moderately reduced (not significantly) in the first five breaths after an - transition compared to stable wakefulness (Shea et al. 1999). The trend towards a reduction in the GGEMG/Pepi slope during NPV at the - transition would also be consistent with this hypothesis.
These findings may have relevance to the patient with OSA as well. We and others have shown an augmented GGEMG in apnoea patients during wakefulness compared with normal individuals (Mezzanotte et al. 1992; Fogel et al. 2001). In addition, the application of nasal continuous positive airway pressure during wakefulness (which should abolish the stimulus for the NPR) leads to a much greater reduction in GGEMG in apnoea patients. These findings are consistent with an augmented activation of the negative pressure reflex in the apnoea patient. At sleep onset we have also shown a greater reduction in GGEMG in OSA patients thus mimicking the results reported here in normal individuals during NPV (Mezzanotte et al. 1996). Thus, like the apnoea patient, these normal individuals have an augmentation of the negative pressure reflex during NPV, and given a similar reduction of this reflex at sleep onset, a greater fall in GGEMG. It is worth noting that although the reflex does not appear to be completely lost at the wake-sleep transition, apnoea patients frequently have airway obstruction at this time. This suggests that at least in some apnoea patients, partial loss of the negative pressure reflex (and decrement in GGEMG) is enough to compromise airway patency. In the typical apnoea patient, GGEMG recruitment does not have a chance to occur as airway collapse ensues with repeated cycling between sleep (with associated occlusion of the airway) and arousal from sleep.
Our study has several potential limitations that should be recognized. First, all subjects may not have been completely passive during negative pressure ventilation. Our observations of a loss of dilator muscle pre-activation prior to the onset of airflow, and a decrement in surface diaphragmatic EMG during NPV are consistent with the concept that brainstem premotor output is decreased. However, we have used surrogate markers to infer a decrease in CPG output which, in humans, is all that is available. It is thus, certainly possible, that subjects were 'entrained' to the NPV rather than truly passive. However, we would expect this entrainment to disappear during NREM and subjects to become truly passive given the mild hypocapnia. Second, for the sake of convenience, all of the stable wakefulness data were collected earlier in the experimental protocol than were the NREM data. Thus if there was a circadian effect on genioglossal muscle activation or its responsiveness to negative pressure this might confound the results of our study. We know of no data supporting such circadian variability in GGEMG responsiveness, and in a previous study we have found waking GGEMG and muscle responsiveness to elevated CO2 to be similar at the beginning and end of the night (Pillar et al. 2000). Thus, we doubt that the effects of time of night would substantially influence the results of this study. Third, our use of mild hypocapnia during NPV may have had an effect on GGEMG. However, in a number of previous studies, we have not been able to demonstrate an independent effect of CO2 level on GGEMG (Akahoshi, 2001; Fogel et al. 2001; Malhotra et al. 2002). In all of our previous studies using this model of negative pressure ventilation, the level of GGEMG during passive NPV depended directly on the negative intrapharyngeal pressure generated, and at any given pressure was the same whether CO2 was normal, elevated or reduced. Thus, we do not believe that the mild levels of hypocapnia used in this protocol were likely to affect the results. We do admit, however, that our prior studies using NPV to examine the relationship between Pepi and GGEMG were all performed during wakefulness, and an 'unmasking' of an inhibitory effect of hypocapnia on GGEMG during sleep cannot be excluded. Fourth, we have used surface recordings to determine DiaEMG, and it is certainly possible that other chest wall muscles are contributing to the signal obtained. However, we do not believe this would change the interpretation of the results.
Finally, we have only measured the responsiveness of a single upper airway muscle in this study, the genioglossus. While we believe that there are substantial data supporting the importance of this muscle in the maintenance of upper airway patency, it may behave differently from other muscles. For example, we have previously shown that the tensor palatini, another important upper airway muscle, has less respiratory-related activity, shows a greater decrement during sleep and does not appear to respond to changes in airway negative pressure as readily as the genioglossus. Thus, our findings should not be extended to reflect the activity of all upper airway muscles.
In conclusion, we observed in normal humans during wakefulness a robust relationship between pharyngeal negative pressure and GGEMG during passive NPV that was largely abolished during stable NREM sleep. However, this relationship between negative pressure and GGEMG is not lost completely at sleep onset, but occurs more slowly during the transition from wakefulness to sleep. These findings suggest that the ability for upper airway muscles to respond to locally changing conditions is diminished during sleep. Thus an airway that is anatomically dependent on these mechanisms to remain patent will collapse during sleep.
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Acknowledgements
This work was supported by NIH NCRR GCRC MO1 RR02635, 1 P50 HL60292, RO1 HL48531 and K23 HL04400. R. B. Fogel is a recipient of the Pickwick Fellowship from the National Sleep Foundation. A. 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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