© 2002 American Thoracic Society
Evidence of a Sleep-Specific Blunted Cortical Response to Inspiratory Occlusions in Mild Obstructive Sleep Apnea SyndromeDepartment of Psychology, University of Melbourne; Austin and Repatriation Medical Centre, West Heidelberg, Victoria, Australia; Human Sleep Research Program, SRI International, Menlo Park, California Correspondence and requests for reprints should be addressed to Dr. Ian M. Colrain, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025. E-mail: ian.colrain{at}sri.com
Obstructive sleep apnea syndrome (OSAS) patients have elevated non–rapid eye movement (REM) sleep arousal thresholds to inspiratory loading. To test the hypothesis that this is due to sleep-specific dampening of cortical responses to inspiratory effort, respiratory-related evoked potentials (RREPs) were evaluated in six mild OSAS patients and six age- and body mass index–matched controls during wakefulness and Stage 2 non-REM sleep. Electroencephalogram was recorded from six scalp sites (Fz, FCz, Cz, CPz, Pz, and O2). Electrooculogram, electromyogram, and mask pressure signals were also recorded. During sleep, pharyngeal pressure was recorded using a Millar pressure catheter placed 2 cm below the glottis. The RREP waveform was broadly similar in the two groups during wakefulness, but was markedly different during Stage 2 non-REM sleep. During wakefulness, only the N1 component showed reduced amplitude in the OSAS group. During sleep, the occlusion stimulus elicited fewer K-complexes in the OSAS patients. In addition, the N550 component in the average of K-complex responses was smaller in amplitude in the OSAS group. The data suggest that patients with mild OSAS have a "blunted" response to the respiratory occlusion stimulus. This appears not to be related to compromised mechanoreceptor function, as the RREP was normal in the patients when they were awake.
Key Words: apnea • sleep • respiratory-related evoked potential • K-complex • P300
The presence of obstructive apneas during sleep can lead to excessive daytime sleepiness caused by persistent arousals after obstructive events. The consequent pathology is referred to as obstructive sleep apnea syndrome (OSAS). The cause of these arousals is the increased mechanical effort required to breathe against an obstructed or flow-limited airway (1). This effort can be measured directly by muscle electromyogram (EMG) activity (2) or indirectly via an increase in negative intrathoracic pressure (3, 4). OSAS patients have been shown to have a higher arousal threshold when compared with controls, requiring both a greater effort and larger negative intrathoracic pressure to produce an awakening (1). There are several possible explanations for this higher arousal threshold (1). First, OSAS patients may have damaged pressure detection mechanisms. Second, these patients may experience habituation to the repeated stimulation of pressure detectors with multiple apneic events. Third, OSAS patients may have a raised response threshold during sleep. This latter possibility could be due to an intrinsic property of the nervous system of OSAS patients, predisposing them to the disease. Alternatively, it may be because of an adaptation to assist them to maintain longer periods of uninterrupted sleep, such as might occur as a consequence of the sleep disturbance that is characteristic of OSAS. It is possible to assess the cortical response to elevated inspiratory effort using the respiratory-related evoked potential (RREP) protocol, the RREP being the averaged cortical response to repeated presentation of a respiratory stimulus. A number of studies have investigated the RREP in normal awake subjects. The pattern of electroencephalogram (EEG) response includes a short-latency positive component, P1 (5–10), which is maximal over parietal scalp regions (11–16) and is produced by bilateral activation of primary somatosensory cortex (17). There is also a short-latency negative component, Nf. This is maximal over frontal scalp sites (11–16) and is produced by bilateral activation of the supplementary motor area (17). Late components include an N1 and P300 (7, 12–15, 18–23). These are thought to relate to attention and higher cognitive processing of stimuli. During non–rapid eye movement (REM) sleep, the early RREP components are maintained, whereas the N1 is diminished and the P300 is not normally elicited (12, 21). However, two large-amplitude negative waves, peaking at approximately 350 and 550 ms, are elicited in sleep (N350 and N550, respectively) (12). The loss of the P300 and the occurrence of the N350 occur with the onset of theta activity during Stage 1 sleep (21). Furthermore, the N350 component persists into Stage 2 sleep where it is largely produced by averaging Vertex Sharp Waves in the individual stimulus responses (24, 25). The Stage 2 and slow wave sleep RREP are dominated, however, by another later and larger negative component, the N550 (12, 21, 24–26). This is produced by including K-complexes in the average of responses to individual stimuli (26). K-complexes are large (up to 200 µV) biphasic waveforms that are readily observable in the ongoing EEG. Only one study has investigated the RREP in apneic patients—and then only during wakefulness. Harver and colleagues (27) found that in response to midinspiratory occlusions applied during wakefulness, the P300 component was smaller in patients with apnea compared with controls; however, as this study was published in only abstract form, no information was given regarding detailed methodology, apnea severity, or RREP descriptive statistics. As such, no comprehensive RREP study has been performed on patients diagnosed with OSAS during wakefulness. In addition, no evoked potential studies have been performed on OSAS patients during sleep. The most likely stimulus for the RREP is the mechanoreceptor response to the increase in inspiratory force that is generated by the increased inspiratory effort associated with application of the occlusion stimulus (28–31). As indicated previously here, the increase in respiratory effort observed during apneic events in OSAS patients is also the most likely stimulus for the repeated arousals seen in these patients during sleep (1). Thus, the pattern of EEG response seen in the RREP should provide a window into the underlying nature of the effort/arousal relationship in apnea. The aim of this study was to test the three hypotheses identified previously here, as to the elevated arousal threshold observed in OSAS patients. The research strategy was to compare the RREP response with midinspiratory occlusion stimuli presented during periods of both wakefulness and Stage 2 non-REM sleep in a group of patients diagnosed with mild OSAS and a group of age- and body mass index (BMI)-matched control subjects. The three hypotheses were as follows: (1) OSAS patients have impaired upper airway mechanoreceptor function. This hypothesis predicts that OSAS patients would have abnormal or absent RREP components during both wakefulness and non-REM sleep compared with control subjects. (2) OSAS patients habituate their response to increased effort as a consequence of repeated stimulation. This hypothesis predicts that OSAS patients (and possibly control subjects) would display a reduction in RREP component amplitudes at the end of the recording session when compared with the beginning. (3) OSAS patients have a sleep-specific increase in response threshold. This hypothesis predicts that OSAS patients would have a smaller sleep RREP response when compared with control subjects, but not differ in the wakefulness response.
Subjects and Design A total of nine patients diagnosed with mild OSAS (respiratory disturbance index [RDI] of between 5 and 15 events per hour) and eight age- and BMI-matched control subjects were tested in the study. Three of the OSAS patients and two of the control subjects experienced difficulty falling asleep while wearing the respiratory apparatus and electrocaps. As such, only the results from six OSAS patients (mean age, 38.83 ± 4.75; mean BMI, 26.87 ± 2.93; and mean RDI, 9.62 ± 3.65) and six age- and BMI-matched control subjects (mean age, 36.83 ± 4.49; mean BMI, 24.45 ± 1.98) are presented. Epworth Sleepiness Scale data and Multiple Wakefulness Data were collected from the OSAS patients. The Epworth Sleepiness Scale scores ranged from 8–17 (mean, 10.6 ± 3.8). The Multiple Wakefulness Data scores ranged from 14.38 to 40 minutes (mean, 31.48 ± 10.5). OSAS patients were recruited from the Sleep Disorders Clinic of the Austin and Repatriation Medical Centre. As the study involved the application of short respiratory interruptions, it was necessary to recruit patients who despite their OSAS diagnosis, also demonstrated periods of unobstructed breathing during sleep. As such, only patients diagnosed with mild OSAS were used in the study. Patients were tested after their initial diagnostic study at the Austin and Repatriation Medical Centre, but before any continuous positive airway pressure intervention for OSAS. This was possible because of an approximate 6- to 8-week delay between diagnosis and implementation of continuous positive airway pressure. The control group was recruited from the university and Austin and Repatriation Medical Centre staff populations and was screened for possible sleep and respiratory problems. Specifically, they reported an absence of snoring and low levels of daytime sleepiness, as well as being screened for other respiratory pathology. Subjects were studied for one night in the sleep laboratory at the University of Melbourne. Midinspiratory occlusions of a 1-second duration were applied during periods of both wakefulness and stable Stage 2 non-REM sleep. Individual trials were then subjected to evoked potential averaging, and the RREP response was determined. The University of Melbourne's Human Ethics Committee approved the study, and subjects gave written informed consent before participation.
Procedures
Application of respiratory stimuli. During the sleep session, two additional measures were added. First, a silicone rubber seal (Hans Rudolph Ultimate Seal) was placed between the mask and the face of the subject to eliminate the possibility of a mask leak. Second, pharyngeal pressure was also monitored (in addition to mask pressure) from a second port on the breathing mask using a Millar catheter (MPC-500). After recording the wakefulness data, the Millar catheter was inserted via one of the nares and positioned approximately 2 cm below the level of the glottis. Pharyngeal recording was conducted in five of the OSAS patients and five of the control subjects. Pharyngeal pressure was not recorded in one OSAS patient and one control subject because of difficulties associated with their ability to tolerate the Millar catheter.
Measurement of EEG, sleep state, and digital recording. All EEG sites, the pneumotachograph airflow signal, and mask and pharyngeal pressure signals were continuously recorded on a Neuroscan system at a sampling rate of 1,000 Hz. The Cz and Fz EEG, EOG, EMG, and airflow signals were also recorded on a Compumedics system at a sampling rate of 500 Hz. The latter signals were used to determine sleep state using standard criteria (32).
Identification of occlusion trials. During wakefulness, individual trials were excluded from the analysis if they were affected either by body movements or eye blink artifact. In addition, during sleep, individual trials were excluded from the analysis if they demonstrated an arousal response according to ASDA criteria (33).
RREP component definitions. The only sleep RREP component analyzed in this study was the N550. This component was defined as the late-latency–negative component that appeared between 500–800 ms in response to the occlusion stimulus. As the N550 is comprised of a high-amplitude phasic event, the K-complex (12, 21, 24–26), the sleep data were averaged both over all trials (irrespective of the occurrence of a visually identified K-complex) and over trials that contained a visually identified K-complex. The rationale and methods for these procedures have been described in detail in a previous publication (25). Briefly, K-complexes were visually identified in the raw EEG using Rechtschaffen and Kales' criteria: "A waveform having a well delineated negative sharp wave which is immediately followed by a positive component. The total duration of the complex should exceed 0.5 sec" (32). An amplitude criterion was also implemented in that the negative wave had to have an amplitude of at least 75 µV (34, 35) at the Fz electrode site. The N350, which is based on the vertex sharp wave (24, 25), was not analyzed, as the stimulus elicited too few vertex sharp waves in the patient group.
Statistical Analyses During wakefulness, the amplitude and latency of the Nf, P1, N1, P2, and P300 components between the OSAS and control groups were compared using a series of two-groups by six-sites (Fz, FCz, Cz, CPz, Pz, O2) ANOVAs with repeated measures on the second factor. In addition, a series of independent sample t tests was conducted at the scalp site, where each component was maximal in amplitude. During sleep, the probability of a K-complex being elicited by the occlusion stimulus in the two groups was investigated using an independent-samples t test. The amplitude of the N550 component was assessed by a two-groups by six-sites ANOVA and by a t test at Fz, where the amplitude of this component was maximal. As noted previously here, this analysis was conducted first on all trials, irrespective of whether a K-complex occurred, and second on only those trials on which a K-complex occurred. In the latter analysis, the RREP for K-complex trials was also compared with trials on which neither a K-complex nor a vertex sharp wave occurred. A final analysis investigated whether either the frequency of K-complex elicitation or the amplitude of the N550 component for K-complex trials habituated over the duration of the study session. To achieve this, the total number of trials performed on each subjects' study night were divided into four equal quartiles. A 2 (group) x 4 (quartile) ANOVA was conducted on the data from the Fz site, for both the number of K-complexes elicited and on N550 amplitude in the all K-complex phasic response condition.
Intrathoracic Pressure Responses Figures 1 and 2A illustrate the grand average waveform of the mask pressure signal for the average of all occlusion trials in both the OSAS and control groups during wakefulness and sleep, respectively. They illustrate that the negative mask pressure generated in response to the midinspiratory occlusion stimulus was essentially identical in the two groups during wakefulness (-3.6 ± 1.2 and -3.6 ± 0.6 cm H2O for OSAS and control subjects, respectively) but smaller (less negative) during sleep in the patients (-2.2 ± 0.3 and -4.4 ± 1.3 cm H2O, respectively). The interaction effect, F(1, 10) = 11.43, p < 0.01, and main effect of groups, F(1, 10) = 5.90, p < 0.05, were significant, but not the effect of sleep–wake state, F(1, 10) = 0.97, p > 0.05. Thus, OSAS patients had a smaller (less negative) mask pressure during sleep, but not during wakefulness.
Figure 2 illustrates the grand average waveform for the mask (Figure 2A) and pharyngeal (Figure 2B) pressure signals for the average of all midinspiratory occlusion trials in the OSAS and control groups during sleep. Pharyngeal pressure was larger (more negative) in the OSAS patients (-5.4 ± 1.2 cm H2O) compared with control subjects (-4.4 ± 1.2 cm H2O). In contrast, as noted in the previously mentioned analysis, Figure 2A indicates that the OSAS patients had smaller (less negative) mask pressure values than subjects in the control group. A two-factor ANOVA, with repeated measures on the wake–sleep factor, revealed that there was a significant main effect of pressure type for intrathoracic pressure amplitude, F(1, 4) = 97, p < 0.001. This indicated that the pressure generated in response to the occlusion stimulus was larger (more negative) when measured at the epiglottis than when measured at the mask. There was not a significant difference between the groups, F(1, 4) = 0.43, p > 0.05. However, a significant pressure type by group interaction, F(1, 4) = 8.16, p < 0.05, indicated that the pharyngeal-to-mask pressure difference was significantly greater in the OSAS group than control group.
RREP Responses
Early-latency components.
Late-latency components. Values for the late-latency components are presented in Table 2 and Figure 3. An ANOVA between groups and over sites did not reveal any significant group or group by site interaction effects for the amplitude of the N1, P2, or P300 components; however, the N1 component was significantly smaller in the OSAS patients at the maximal N1 site, Cz, as indicated by an independent groups t test, t(1, 10) = 2.35, p < 0.05; however, neither P2, t(1, 10) = -0.40, p > 0.05, nor P300, t(1, 10) = -1.14, p > 0.05, were significantly different at their maximum sites of Cz and Pz, respectively. Furthermore, a latency difference was not observed between the two groups for N1, t(1, 10) = -0.65, p > 0.05; P2, t(1, 10) = -0.61, p > 0.05; or P300, t(1, 10) = 0.44, p > 0.05 (see Figure 3). Again, components were maximal at sites anticipated on the basis of previous research (13–15, 18, 21).
Stage 2 sleep. The average number of midinspiratory occlusion trials presented to each group during Stage 2 sleep was 223 ± 13 in the OSAS group and 222 ± 17 in the control group. The percentage of occlusion trials that produced an arousal was significantly greater in the control group (9.38 ± 1.99%) compared with the OSAS group (4.74 ± 2.29%), t(10) = 3.65, p < 0.01.
Late-latency components: all-trial average.
As noted previously here, the RREP N550 component is related to K-complex elicitation (24–26). Therefore, the smaller amplitude N550 in the OSAS group in the all-trial average in this study may be due to either a reduction in the number of trials in which K-complexes were elicited or to differences in the amplitude of elicited K complexes. The probability of the stimulus eliciting a K-complex was indeed lower in the OSAS group (0.06 ± 0.02 and 0.18 ± 0.04 for the OSAS and control groups, respectively, t[1, 10] = -7.4, p < 0.01); however, the amplitude of K-complexes was also smaller. Figure 5 illustrates the Fz Stage 2 RREP, for trials on which a K-complex occurred and trials on which neither a K-complex nor a vertex sharp wave was observed. Figure 5 (Table 3) reveals that the N550 was smaller in the OSAS group compared with control group. Statistically, there were significant group, site, and group-by-site effects. Furthermore, an independent samples t test revealed that this difference was significant at the maximal site, Fz, t(1, 10) = 2.7, p < 0.05. Although Figure 5 illustrates that the N550 component appeared slightly later in the OSAS compared with control group, this difference was not significant, t(1, 10) = 0.85, p < 0.05. Finally, Figure 5 also reveals that the waveform for trials on which no phasic event occurred had no discernible components present in either group.
Finally, an analysis was performed to investigate any possible habituation in either K-complex elicitation or N550 amplitude (for trials on which a K-complex occurred) across the data collection session for each subject. The number of K-complexes and the amplitude of the N550 component in each of the four quartiles are represented graphically in Figures 6A and 6B , respectively. Figure 6 revealed that for each quartile, the occlusion stimulus elicited more K-complexes and a larger amplitude N550 component in the control subjects. This was confirmed by a significant main effect of group, for K-complex frequency, F(1, 10) = 77.1, p < 0.001, and N550 amplitude, F(1, 10) = 5.09, p < 0.05. There was no main effect of quartile for K-complex elicitation frequency, F(3, 30) = 2.15, p > 0.05, or N550 amplitude F(3, 30) = 1.87, p > 0.05. There was no group by quartile interaction for either variable.
The data revealed that during wakefulness, a similar cortical response was observed to the midinspiratory occlusion stimulus in a group of patients diagnosed with mild obstructive sleep apnea and a group of age- and BMI-matched control subjects. Although there was a difference in N1 amplitude between the two groups, when assessed at the site of the maximal amplitude, no other amplitude or latency differences were observed for the remaining early- or late-latency wakefulness RREP components. In contrast, the cortical response during Stage 2 sleep was markedly different between the OSAS and control groups. OSAS patients demonstrated a smaller amplitude evoked response during sleep that appeared to be due to both a reduction in the number of elicited K-complexes and a reduction in the amplitude of K-complexes, as reflected in the N550 component of the average of trials that contained only K-complexes.
Wakefulness The wakefulness early-latency RREP response, the Nf and P1 components, demonstrated similar amplitudes and latencies in the two groups. These components are believed to reflect cortical activation by the afferent signal (5), with Nf being produced bilaterally in the supplementary motor area and P1 bilaterally in primary somatosensory cortex (17). The evoked RREP is most likely due to stimulation of respiratory muscle afferents in the airway, lungs, and chest wall that occur in association with intrathoracic pressure changes in response to the occlusion stimulus. It is therefore likely that any impairment in mechanoreceptor function in the OSAS patients would translate to a deviation from the "normal" wakeful RREP response. The similarity of the evoked early-latency RREP between the OSAS patients and the control group in this study would therefore suggest that OSAS patients have relatively intact or unimpaired respiratory mechanoreceptor function. It would also suggest that their sleep-disordered breathing is not due to a problem associated with afferent transmission of respiratory information to the cortex. It should be noted that the early-latency wakefulness RREP components reported in this study appeared approximately 20–40 ms later than those reported in previous research (12–17). This relative delay was most likely due to the different methods used to apply the midinspiratory occlusion and resistive loads. Previous research presented stimuli using a gas-activated valve trigger that had a very rapid rise time. In contrast, the rise time of the occlusion using the hand held stopcock in this study was slower. For the most part, the late-latency wakefulness RREP response was very similar in both the OSAS and control groups. The N1 component in the OSAS group was smaller than that of the control group, although only when compared specifically at its maximum site; however, P2 and P300 amplitude differences were not observed between the two groups. In addition, no N1, P2, or P300 latency differences were observed between the OSAS and control groups. These data further support the notion that OSAS patients have relatively intact or unimpaired respiratory mechanoreceptor function. The N1, which was smaller in the OSAS compared with the control group, is influenced by both sensory input and cognitive factors (36); however, it is unlikely that the difference in N1 was due to a variation in sensory processing. This is because mask pressure did not vary between the groups during wakefulness and because the earlier short-latency RREP components that are affected by sensory factors were not different between the groups. In the cognitive domain, N1 is modulated by a variation in levels of attention and arousal (36). Gora and colleagues (21) reported that the RREP N1 decreased significantly after the onset of Stage 1 sleep. This was recently confirmed for the auditory N1 by Colrain and colleagues (37). In other studies of drowsiness (38), the auditory N1 was significantly reduced as soon as reaction times started to increase. Thus, the decrease in the amplitude of N1 might be due to greater fatigue or sleepiness in the patients. Consistent with this, the Multiple Wakefulness Data and Epworth Sleepiness Scale scores obtained from the patients were indicative of low to moderate levels of sleepiness. Although two patients failed to sleep in the Multiple Wakefulness Data (i.e., score of 40), others ranged down as far as 14 minutes, and the mean Epworth Sleepiness Scale was 10.6. The greater level of sleepiness is likely to be due to the sleep fragmentation commonly reported for OSAS patients. The data therefore raise the possibility that the N1 could be a sensitive index of daytime alertness in OSAS. Interestingly, this study demonstrated no P300 amplitude or latency variation between the OSAS and control groups in response to the occlusion stimulus. The presence of a P300 is believed to reflect conscious "awareness" of a stimulus (39). P300 amplitude has been theorized to be contributed to by multiple neural generators, with the activity of each generator reflecting a discrete aspect of cognitive processing, such as stimulus probability, attention, equivocation, stimulus meaning, and stimulus value or relevance (40, 41). Indeed, the RREP P300 has been shown to vary systematically with several of these parameters (13, 14, 18). These data are in contrast to the only other RREP study conducted on OSAS patients during wakefulness. Harver and colleagues (27) reported a smaller amplitude P300 in OSAS patients compared with age-matched control subjects; however, as this study was published only in abstract form, no details were given regarding detailed methods, apnea severity, or descriptive RREP statistics. This has made it difficult to draw any conclusions regarding the different results reported between the two studies. Studies conducted on OSAS patients employing other modalities have reported mixed results regarding P300 amplitude and latency to auditory and visual stimuli. There is consistency in studies of visual P300, with all studies showing no effect for amplitude, but OSAS patients having a delayed latency (42–45); however, the consistency disappears in studies of the auditory P300. Two studies reported reduced auditory P300 amplitude in patients diagnosed with severe OSAS (46, 47); however, three studies by Sangal and Sangal found no difference between OSAS patients and control subjects (43–45), this despite the same group reporting in another article that the only visual or auditory P300 measure to correlate significantly with RDI was auditory P300 amplitude (48). Three studies have reported an increased auditory P300 latency in OSAS (43, 46, 47), and two reported no difference (44, 45). The strongest effect from the previously mentioned studies seems to be an increase in P300 latency with OSAS. Variations in P300 latency are believed to reflect differences in stimulus evaluation speed (49). The delayed P300 observed in severe OSAS patients in previous EP research has therefore been interpreted as suggesting some form of brain dysfunction relating to the processing speed of cognitive information (42, 45). The lack of any difference in P300 amplitude or latency between the mild OSAS patients and age- and BMI-matched controls in this study may be due to several factors. The first is that the patients in this study had relatively mild apnea. That is, it is likely that the sleep of patients with mild OSAS is not as fragmented as the sleep of patients diagnosed with severe OSAS. A second explanation is that the relatively young age of the OSAS group (average of 38 years) means that it is likely that they have not had apnea for a long period of time. Older subjects with a longer disease history may well experience the accumulative effects of hypoxemia and sleep fragmentation that could lead to diffuse damage, that in all probability would be reflected in ERP results. Such effects would likely be permanent. In this context it should be noted that treatment with CPAP did not decrease P300 latency significantly in two studies (42, 45). In another two, significant latency reductions occurred (46, 47), but posttreatment values were still substantially later than those seen in control subjects. Finally, the failure to find a difference may relate to the nature of the paradigm employed. Typically, the P300 is elicited using an oddball task in which subjects are asked to detect a rare target stimulus occurring among a train of more frequently occurring standard stimuli. In this study, a more biologically relevant stimulus (occlusion of breathing) was employed. It is possible that such a biologically relevant stimulus was automatically detected in the waking state for both patients and controls. Thus, even though there was evidence of sleepiness in the patients, they may still have been able to detect the occlusion of inspiration.
Stage 2 Sleep Berry and Gleeson (1) have indicated that OSAS patients often display airway closure in response to externally applied occlusions. In this study, the midinspiratory occlusion stimulus produced a larger pharyngeal pressure response in OSAS than in control subjects. At the same time, the mask pressure response in OSAS patients was substantially less than that of the controls. These data indicate that during sleep, control subjects maintained a patent airway after external occlusion of the inspiratory line, but that OSAS patients experienced at least partial closure of the upper airway at some point between the epiglottis and the mouth. The intensity of the midinspiratory occlusion stimulus, as indicated by pharyngeal pressure, was thus greater for the OSAS patients. The early-latency P1 and Nf components have been reported to be present during Stage 2 sleep in response to midinspiratory occlusions (12, 50); however, these components, as well as the N1 component, could not be reliably detected in the grand mean averages in this study. The most likely explanation for this is that an insufficient number of stimuli were averaged to overcome the lower signal to noise ratio between the components and the background EEG experienced during Stage 2 sleep. Webster and Colrain (12), for example, typically averaged over 300 trials per subject in Stage 2 sleep. Second, although the slower rise time of the midinspiratory occlusion stimulus used in this study elicited the wakeful early-latency components, this stimulus may not have been abrupt enough to reliably elicit sleep early-latency components. Both of these explanations imply that to elicit the early-latency components during Stage 2 sleep, a larger number of trials would have to be conducted. Alternatively, the use of a more abrupt stimulus, such as that used in earlier studies (12, 50), may also assist in more reliable elicitation of the early-latency components. The data revealed that when all trials were included in the evoked potential average, the sleep RREP looked markedly different in the OSAS compared with control group. That is, the N550 in the OSAS group was much smaller in amplitude than the N550 in the control group. This was due to two factors. First, N550 is related to K-complex elicitation (21, 24–26). Thus, the lower number of K-complexes elicited in response to the occlusion in the OSAS group reduced N550 amplitude. Second, there was a reduction in K-complex amplitude. It seems unlikely that the difference in the elicitation of K-complexes was due to differences in the intensity of the occlusion stimulus, as the effective stimulus was larger (that is the intrathoracic pressure was more negative) in the OSAS group. The difference is also unlikely to be due to impaired mechanoreceptor function, as there were only minor differences in RREP components between the two groups during wakefulness. A more likely explanation may be that the OSAS group had a raised threshold to respiratory events during sleep. As pointed out by Berry and Gleeson (1), this raised threshold may be either intrinsic or due to the effects of sleep deprivation. The similar wakefulness profiles suggest that if the raised threshold to respiratory events is indeed intrinsic, its effects appear to be sleep specific. The data also revealed that the amplitude of the K-complex was smaller in the OSAS compared with control group. That is, the N550 for trials on which a K-complex occurred was significantly reduced in the OSAS compared with control group. This would suggest that not only does there appear to be a threshold effect for elicitation frequency in the OSAS group, but there also appears to be cortical dampening when a K-complex is actually elicited. The latency of the N550 observed in the study was relatively long (Table 3); however, the latency is consistent with previous studies using a respiratory occlusion stimulus. We believe this relates to the rise time of the stimulus (see Gora and colleagues for a discussion of this issue [21]). Additional analyses were conducted to determine whether either the OSAS or control groups habituated to the occlusion stimulus over the duration of the study night. This analysis revealed that there was no change in K-complex elicitation frequency or N550 amplitude across the duration of the study night for either group. These data exclude the possibility that the smaller number of K-complexes in the OSAS group was due to these patients habituating to the occlusion stimulus over the duration of the sleep session; however, it remains possible that OSAS patients have habituated to occlusions over the course of their disease and that this is the basis of the differences in the N550 component identified in this study.
Conclusions Received in original form June 1, 2001; accepted in final form August 6, 2002
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ABSTRACT
INTRODUCTION
. Electrooculogram (EOG) activity was recorded from electrodes placed slightly above or below the outer canthus of each eye. EMG activity was also recorded from electrodes placed over the submentalis muscle. 
