Abstract
Children with the obstructive sleep apnea syndrome (OSAS) have impaired respiratory afferent cortical processing during sleep that persists after treatment of OSAS. However, it is unknown whether this impairment is present during wakefulness and, if so, whether it improves after OSAS treatment. We hypothesized that children with OSAS, during wakefulness, have abnormal cortical processing of respiratory stimuli manifested by blunted respiratory-related evoked potentials (RREP) and that this resolves after OSAS treatment. We measured RREP during wakefulness in 26 controls and 21 children with OSAS before and after treatment. Thirteen participants with OSAS repeated testing 3–6 mo after adenotonsillectomy. RREP were elicited by interruption of inspiration by total occlusion and 30 and 20 cmH2O/l per s resistances. Nf at Fz latency elicited by occlusion was longer in children with OSAS at baseline compared with controls (78.8 ± 24.8 vs. 63.9 ± 19.7 ms, P = 0.05). All other peak amplitudes and latencies were similar between the two groups. After OSAS treatment, Nf at Fz latency elicited by 30 cmH2O/l per s decreased significantly (before, 88 ± 26 vs. after, 71 ± 25 ms, P = 0.02), as did that elicited by 20 cmH2O/l per s (85 ± 27 vs. 72 ± 24 ms, P = 0.004). The amplitude of N1 at Cz elicited by occlusion increased from −3.4 ± 5.6 to −7.4 ± 3 μV (P = 0.049) after treatment. We concluded that children with OSAS have partial delay of respiratory afferent cortical processing during wakefulness that improves after treatment.
Keywords: respiratory, evoked potentials, children, wakefulness, obstructive sleep apnea syndrome
the cortical processing of respiratory afferent stimuli during sleep, elicited by upper airway occlusion and measured by respiratory-related evoked potentials (RREP), is abnormal in children with the obstructive sleep apnea syndrome (OSAS) and does not resolve after OSAS treatment (16, 18). Considering that adequate upper airway neuromotor tone is critical to maintain upper airway patency during sleep (19, 26), this finding implies that children with OSAS are not able to perceive episodes of upper airway occlusion. Therefore, they cannot activate the upper airway reflexes and increase the upper airway neuromotor tone during sleep. The persistence of this impairment after treatment suggests that children with OSAS have either a primary or secondary but irreversible respiratory afferent cortical processing deficit during sleep. To further elucidate the extent of this impairment, it is important to determine the respiratory afferent cortical processing during wakefulness, as children with OSAS do not obstruct while awake. The upper airway loading, such as that caused by enlarged tonsils and adenoid and/or obesity, is present during wakefulness and sleep. However, the upper airway neuromotor tone is increased during wakefulness and able to secure upper airway patency (3). The presence of deficits in the cortical processing of respiratory afferent stimuli even during wakefulness would indicate a more severe sensory deficit. Similarly, it is critical to determine reversibility after OSAS treatment to clarify whether any deficits are primary or secondary.
We hypothesized that, during wakefulness, children with OSAS have abnormal cortical processing of respiratory afferent stimuli measured by RREP compared with normal controls, and, on the basis of our previous data during sleep (18), this does not normalize after OSAS treatment. Cortical neural activation measured by RREP can be obtained by different mechanical loads, such as inspiratory occlusion, inspiratory resistive loads, and expiratory occlusion (9, 14, 15, 37). To further clarify the extent of the deficit, we evaluated RREP elicited by occlusion and two levels of resistive load: 30 and 20 cmH2O/l per s.
METHODS
RREP were obtained from surface EEG during wakefulness. Children with OSAS underwent surgical treatment (adenotonsillectomy) per standard clinical care, followed 4–6 mo later by repeat RREP testing.
The Institutional Review Board at the Children's Hospital of Philadelphia approved the study. Informed consent was obtained from the parents/legal guardians of the subjects and assent from subjects older than 7 yr of age.
Study group.
Subjects with OSAS and controls, aged 6–16 yr, underwent baseline polysomnography using standard pediatric techniques and scoring (20). OSAS was defined as having an apnea hypopnea index (AHI) ≥2/h, and controls were included if they were asymptomatic and had an AHI <1.5/h (30, 33, 35, 39). Exclusion criteria included craniofacial anomalies, genetic syndromes, history of adenotonsillectomy or upper airway surgery, continuous positive airway pressure (CPAP) use, persistent asthma, and positive pediatric sleep questionnaire (for controls only). Subjects with OSAS were recruited after a clinical polysomnogram, and healthy nonsnorer controls were recruited from the community by means of advertisements.
Wakefulness RREP.
Wakefulness RREP were performed while participants were watching a movie and listening to the audio with earbuds. Surface electrodes were placed at Fz, Cz, Pz, M1, and M2 to record scalp EEG activity and recorded with a Rembrandt polysomnography system (Embla, Broomfield, CO). Participants were monitored visually via video and via EEG to avoid sleep intrusion. Subjects breathed through a snug oronasal mask (Profile Lite; Respironics, Andover, MA) connected to a nonrebreathing valve (Series 1410; Hans Rudolph, Shawnee, KS). The mask exhalation port was occluded to avoid leaks. Inspiratory flow was measured using a pneumotachometer (Series 3830, Hans Rudolph) and a differential pressure transducer (Model 1110, Hans Rudolph) between the valve and the mask. Pressure within the mask was measured using a pressure transducer (Model 1110, Hans Rudolph). The above parameters were recorded with the Rembrandt polysomnography system (Embla) at a sampling EEG rate of 200 Hz and respiratory pressure and flow rate of 50 Hz. Data from the Rembrandt system were converted into European Data Format (EDF) and then read into Scan 4.3 software (Compumedics NeuroScan, El Paso, TX). There was no downsampling when converting Rembrandt-acquired data to EDF and Scan 4.3. EEG activity was referenced to M1 and M2, band pass filtered (0.3–30.0 Hz), epoched (500 ms before to 1,500 ms after the initiation of each occlusion), and averaged. Occlusions with EEG artifacts and mask leak were excluded. The mouth pressure change was measured at the point of peak pressure. This typically occurred 90 ± 5 ms after the stimulus.
A resistive load application system was connected to the valve inspiratory port. This consisted of a four-way gatlin-shape valve (Series 2550, Hans Rudolph) and balloon controller (Series 2550, Hans Rudolph). This type of valve has one common flow port (mouth side) that communicates with three inlet ports housing an occluder balloon. Considering that the OSAS is characterized by obstructive hypopneas and obstructive apneas, we decided to use one complete occlusion and two different resistance levels to mimic obstructive apneas and obstructive hypopneas. Each inlet port had a known resistance attached to it: 0 (no resistance), 20 (R20), or 30 (R30) cmH2O/l per s (Series 7100 linear flow resistance standards, Hans Rudolph). The resistance of the circuit was 2.9 cmH2O/l per s. The valve system was hidden from the subject's view, and valve balloon activation could not be heard by the subject. Any pressure pulses caused by the valve balloon activations were prevented from reaching the subject's mask by inserting a damping device (1-l empty plastic bottle) between the subject and the valve. Complete occlusions and the R30 and R20 loads were presented in random order for 300-ms duration interruptions during early inspiration. These were triggered when inspiratory flow reached a predetermined threshold of 50 ml/s. A random number (∼2 to 15) of uninterrupted breaths was allowed between subsequent load applications. Each load, when applied, was presented by inspiratory air flow shunted through one of the two gatlin valve inlets with the two resistors or blocked completely for the occlusive load. Subjects received a minimum of 100 load interruptions of each for occlusion, R30, and R20. Data collection lasted ∼2 h. Participants' breathing patterns were monitored throughout data collection using Powerlab.
Flow monitoring, randomization, and load-valve control were performed by a custom program written in Testpoint (Superlogics, Natick, MA). All amplitudes were expressed relative to the average of activity in the 200-ms prestimulus baseline period. Latencies were expressed relative to the start of the change in mask pressure following load onset.
Statistical analysis.
Statistical analysis was performed with SPSS software version 17.0 for Windows (SPSS, Chicago, IL) and Stata 13.0 (StataCorp, College Station, TX). The Kolmogorov-Smirnov test was used to test for normality. Categorical data were compared using the Fisher exact test. Continuous data were compared using the paired or unpaired Student's t-test or Mann-Whitney rank-sum test or Wilcoxon matched-pairs signed-ranks tests, as appropriate. Multilevel mixed-effects regression models were used to further analyze RREP amplitudes and latencies. The multilevel models included random effects for condition (OSAS at baseline and controls for the baseline data and OSAS before and after treatment for the posttreatment data) and patient and therefore took into account the correlation between the three challenges (occlusion, R30, and R20) per electrode site. A P value <0.05 was considered statistically significant. Data were presented as means ± SD if normally distributed and as median (interquartile range) if not.
RESULTS
Study group.
Twenty-one subjects with OSAS and 26 age-matched controls were studied (Table 1). Subjects with OSAS had greater body mass index (BMI) z-scores. However, the proportion of obese subjects was similar between the two groups. There was a wide range of severity of OSAS. Thirteen participants were reevaluated after surgical treatment.
Table 1.
Study group demographics and polysomnography results
| OSAS (Baseline) | Controls | P Value | |
|---|---|---|---|
| n | 21 | 26 | |
| Age, yr | 9.8 ± 3 | 11.1 ± 2.8 | NS |
| Males, n (%) | 13 (61.9) | 11 (42.3) | NS |
| Body mass index z-score | 1.9 (1.3–2.2) | 1 (0.2–1.7) | 0.02 |
| Obese, n (%) | 12 (57) | 8 (30.7) | NS |
| Apnea hypopnea index, n/h | 14.9 (5.6–27.2) | 0.5 (0.1–0.7) | <0.001 |
| SpO2 nadir, % | 88 (84–91) | 94 (92–95) | <0.001 |
| Time with SpO2 <90%, % TST | 0.2 (0–0.8) | 0 (0–0) | <0.001 |
| Peak ETCO2, mmHg | 56.7 ± 3.7 | 52 ± 2.9 | <0.001 |
| Time with ETCO2 ≥ 50 mmHg, %TST | 13 (5.3–32) | 0.1 (0–1.1) | <0.001 |
Data are means ± SD, median (interquartile range, IQR), or n (%).
OSAS, obstructive sleep apnea syndrome; SpO2, oxyhemoglobin saturation; TST, total sleep time; ETCO2, end-tidal CO2 measurement.
RREP stimulus intensity.
The magnitude of the mask pressure changes elicited by occlusion, R30, and R20 did not differ between OSAS and controls and between OSAS before and after treatment (Table 2, Figs. 1, 2, and 3).
Table 2.
Pressure change measured at the mask elicited by occlusion, R30, and R20 in children with OSAS before and after treatment and controls
| OSAS at Baseline | Controls | OSAS After Treatment | |
|---|---|---|---|
| Stimuli | |||
| Occlusion, cmH2O* | −4.4 ± 1.0 | −4.3 ± 1.3 | −4.6 ± 1.6 |
| R30, cmH2O* | −3.0 ± 0.8 | −3.3 ± 0.9 | −3.3 ± 1.1 |
| R20, cmH2O* | −2.6 ± 0.6 | −2.7 ± 0.1 | −2.7 ± 0.8 |
Data are shown as means ± SD.
R30, resistance of 30 cmH2O/l per s; R20, resistance of 20 cmH2O/l pers.
Pressure changes were different between stimuli as expected. However, there were no significant differences between pressures changes elicited by occlusion, R30, and R20 in children with OSAS before and after treatment and controls.
Fig. 1.
Mask pressure changes elicited by occlusion in children with obstructive sleep apnea syndrome (OSAS) before treatment compared with after treatment and controls.
Fig. 2.
Mask pressure changes elicited by 30 cmH2O/l per s in children with OSAS before treatment compared with after treatment and controls.
Fig. 3.
Mask pressure changes elicited by 20 cmH2O/l per s in children with OSAS before treatment compared with after treatment and controls.
Baseline RREP.
The latency of Nf at Fz elicited by occlusion was significantly shorter in controls compared with children with OSAS (Fig. 4). All other amplitudes and latencies were similar between the two groups (Table 3, Figs. 5, 6, 7, 8, and 9). These results were confirmed by mixed-effect multilevel regression models.
Fig. 4.
Respiratory-related evoked potentials at Fz elicited by occlusion in children with obstructive sleep apnea before treatment compared with after treatment and controls. Nf latency is shorter in controls. The black vertical line symbolizes initiation of pressure deflection.
Table 3.
RREP during wakefulness in children with the OSAS vs. controls
| Stimuli | OSAS | Controls | P Value |
|---|---|---|---|
| Nf at Fz | |||
| Occlusion | |||
| Amplitude, μV | −7.0 ± 4.5 | −5.5 ± 3.3 | NS |
| Latency, ms | 78.8 ± 24.8 | 63.9 ± 19.7 | 0.05 |
| R30 | |||
| Amplitude, μV | −5.8 ± 3.6 | −5.4 ± 4.1 | NS |
| Latency, ms | 85.3 ± 27.4 | 70.5 ± 24.9 | NS |
| R20 | |||
| Amplitude, μV | −4.7 ± 3.9 | −3.9 ± 3.9 | NS |
| Latency, ms | 88.9 ± 30 | 79.3 ± 21.1 | NS |
| P1 at Cz | |||
| Occlusion | |||
| Amplitude, μV | 4.4 ± 5.3 | 6.4 ± 4.8 | NS |
| Latency, ms | 137.3 ± 40.3 | 130 ± 29.5 | NS |
| R30 | |||
| Amplitude, μV | 2.4 ± 5.3 | 5.4 ± 5.7 | NS |
| Latency, ms | 133.5 ± 40.7 | 132 ± 41.4 | NS |
| R20 | |||
| Amplitude, μV | 4.9 ± 4.3 | 6.6 ± 5.7 | NS |
| Latency, ms | 143.8 ± 38.9 | 145.2 ± 34.4 | NS |
| N1 at Cz | |||
| Occlusion | |||
| Amplitude, μV | −4.7 ± 4.6 | −5.9 ± 5.4 | NS |
| Latency, ms | 186.4 ± 46 | 199.2 ± 52.7 | NS |
| R30 | |||
| Amplitude, μV | −3.8 ± 4.8 | −4.8 ± 4.8 | NS |
| Latency, ms | 180.9 ± 50.5 | 194.2 ± 57.7 | NS |
| R20 | |||
| Amplitude, μV | −1.9 ± 4.2 | −3.2 ± 4 | NS |
| Latency, ms | 193 ± 44.6 | 209.5 ± 50.5 | NS |
Data are means ± SD.
RREP, respiratory-related evoked potentials.
Fig. 5.
Respiratory-related evoked potentials at Fz elicited by 30 cmH2O/l per s (R30) in children with OSAS before treatment compared with after treatment and controls. Nf latency improves in children with OSAS after treatment. The black vertical line symbolizes initiation of pressure deflection.
Fig. 6.
Respiratory-related evoked potentials at Fz elicited by 20 cmH2O/l per s in children with OSAS before treatment compared with after treatment and controls. Nf latency improves in children with OSAS after treatment. The black vertical line symbolizes initiation of pressure deflection.
Fig. 7.
Respiratory-related evoked potentials at Cz elicited by occlusion in children with OSAS before treatment compared with after treatment and controls. The black vertical line symbolizes initiation of pressure deflection.
Fig. 8.
Respiratory-related evoked potentials at Cz elicited by 30 cmH2O/l per s (R30) in children with OSAS before treatment compared with after treatment and controls. N1 amplitude improves in children with OSAS after treatment. The black vertical line symbolizes initiation of pressure deflection.
Fig. 9.
Respiratory-related evoked potentials at Cz elicited by 20 cmH2O/l per s (R20) in children with OSAS before treatment compared with after treatment and controls. P1 latency improves in children with OSAS after treatment. The black vertical line symbolizes initiation of pressure deflection.
Response to treatment of OSAS.
Subjects underwent surgical treatment per the discretion of their clinical physician. Sixteen participants underwent adenotonsillectomy. Of the five participants who were not surgically treated, one preferred treatment with CPAP, and four did not follow through. Thirteen children came back for RREP testing. Of the three children who underwent adenotonsillectomy but did not come back for RREP testing, two declined more research, and one returned for the posttreatment polysomnogram but declined RREP testing. There were no clinical differences between participants who were retested and those who were not (Table 4).
Table 4.
Baseline demographics and polysomnographic results for subjects with OSAS who underwent postoperative assessments vs. those who did not
| Postoperative Assessment | No Postoperative Assessment | P Value | |
|---|---|---|---|
| n | 13 | 8 | |
| Age, yr | 8.9 ± 2.5 | 11.3 ± 3.1 | NS |
| Males, n (%) | 9 (69) | 4 (50) | NS |
| Body mass index z-score | 1.7 (1.2–2.3) | 1.9 (1.6–2.2) | NS |
| Obese, n (%) | 7 (54) | 6 (75) | NS |
| Apnea hypopnea index, n/h | 20 ± 16.6 | 14.6 ± 10.7 | NS |
Data shown are means ± SD or median (IQR).
Baseline polysomnography and RREP were repeated 5 ± 2 mo after the baseline study and 3.2 ± 1 mo after adenotonsillectomy. The AHI decreased from 20 ± 16.6 to 0.9 ± 1.2 events per h (P = 0.001). Four participants had persistent mild OSAS, with AHI between 1.7 and 3.7 events per h (Fig. 10). BMI z-scores did not change before and after treatment (1.4 ± 1.2 vs. 1.5 ± 0.9, P = NS).
Fig. 10.
Change in apnea hypopnea index following surgery.
RREP after OSAS treatment.
The amplitude of N1 at Cz elicited by the R30 increased significantly after OSAS treatment. All other amplitudes did not change. The latencies of Nf at Fz elicited by the R30 and P1 at Cz elicited by the R20 were significantly shorter in the posttreatment group (Table 5, Fig. 3). All other latencies did not change. These results were confirmed by mixed-effect multilevel regression models. To clarify whether the observed changes in latencies were not due to central nervous system maturation, we calculated the median age of the OSAS group (9.5 yr). On the basis of this, we compared the pretreatment latencies of participants younger than 9.5 vs. older than 9.5 yr and found no differences. Specifically, the latency of Nf at Fz elicited by R30 in younger children was 97 ± 31 ms vs. 70 ± 11 ms in older children (P = 0.11); the latency of P1 at Cz elicited by R20 was 142 ± 46 ms in younger participants vs. 147 ± 31 ms in older participants (P = 0.821). There were no significant differences between controls and children with OSAS after treatment.
Table 5.
RREP during wakefulness in children with the OSAS before and after treatment
| Stimuli | Before | After | P Value |
|---|---|---|---|
| Nf at Fz | |||
| Occlusion | |||
| Amplitude, μV | −6.4 ± 4.5 | −7.6 ± 5.8 | NS |
| Latency, ms | 78.9 ± 27.4 | 72.3 ± 25.6 | NS |
| R30 | |||
| Amplitude, μV | −3.8 ± 4 | −6 ± 3.7 | NS |
| Latency, ms | 88 ± 26 | 71 ± 25 | 0.02 |
| R20 | |||
| Amplitude, μV | −3.8 ± 3.5 | −5.8 ± 5.8 | NS |
| Latency, ms | 82 (72–121) | 60 (57–75) | 0.004 |
| P1 at Cz | |||
| Occlusion | |||
| Amplitude, μV | 3.1 ± 6.7 | 2.5 ± 6.3 | NS |
| Latency, ms | 135.5 ± 42 | 124.4 ± 37 | NS |
| R30 | |||
| Amplitude, μV | 2.5 ± 5 | 0.6 ± 4 | NS |
| Latency, ms | 140 ± 44 | 126 ± 30 | NS |
| R20 | |||
| Amplitude, μV | 3.8 ± 5.4 | 2.2 ± 3.1 | NS |
| Latency, ms | 145 ± 41 | 123 ± 44 | 0.003 |
| N1 at Cz | |||
| Occlusion | |||
| Amplitude, μV | −3.7 ± 4.9 | −7.9 ± 5.6 | NS |
| Latency, ms | 177.2 ± 42 | 175.8 ± 52 | NS |
| R30 | |||
| Amplitude, μV | −3.4 ± 5.6 | −7.4 ± 3 | 0.049 |
| Latency, ms | 179.6 ± 47 | 173.4 ± 46 | NS |
| R20 | |||
| Amplitude, μV | −3.7 ± 3.9 | −6 ± 3.8 | NS |
| Latency, ms | 186 ± 40 | 174 ± 57 | NS |
Data are means ± SD or median (IQR).
DISCUSSION
This study has shown that untreated children with OSAS have delayed processing of respiratory afferent information elicited by occlusion during wakefulness compared with controls. After OSAS treatment, children with OSAS exhibited a significant shortening in the processing time of respiratory afferent information elicited by resistive loads. The magnitude of the cortical neural activation, measured by peak amplitudes, obtained by occlusion and resistive loads was similar in children with OSAS at baseline and controls. However, children with OSAS after treatment showed a significant increase in the amplitude of N1 at Cz elicited by R30. These data suggest that children with untreated OSAS have a delay of respiratory afferent processing that improves after treatment. Therefore, OSAS is associated with reversible changes during wakefulness in children.
RREP and OSAS.
RREP have been used to study the cortical neural activation triggered by respiratory stimuli in various diseases such as asthma, central hypoventilation syndrome, and OSAS (9, 10, 16–18). The airway obstruction provoked by occlusion or loading activates the mechanoreceptors that transduce this signal to the somatosensory cortex (24). In addition, a relationship between the inspiratory load detection threshold, magnitude estimation, and the RREP has been described (7, 21). Furthermore, the RREP peak amplitudes are directly related to the magnitude estimation of the resistive loads (21, 22). Hence, the RREP are objective neural measures of the perceptual response to respiratory loads.
OSAS is characterized by repetitive episodes of upper airway occlusion during sleep but airway patency during wakefulness. However, upper airway loading, for instance, secondary to adenotonsillar hypertrophy is present during wakefulness and sleep. The upper airway collapse during sleep is thought to be due to an imbalance between upper airway loading and neuromotor activation, which is naturally decreased during sleep (25, 27). A previous study in children during sleep demonstrated decreased arousal responses to inspiratory resistive loading, suggesting that children with OSAS had decreased loading perception during sleep (29). However, only a few reports have assessed the perception of inspiratory loads during wakefulness in subjects with OSAS. A study in adults using subjective methods showed that subjects with OSAS had decreased inspiratory effort sensation during wakefulness that improved after CPAP treatment (34). Studies recording the RREP in response to negative pressure pulse stimuli in adults with OSAS compared with controls demonstrated that RREP latencies were delayed in adults with OSAS (10, 11). Those participants were not tested after OSAS treatment. Our data corroborated this finding in children and provide evidence that RREP latencies with airway-resistive loading decreased after OSAS treatment. This suggests that OSAS in children is associated with a delay in neural cortical activation to airway-resistive loading during wakefulness that improves after treatment. Importantly, our results suggest neuroplasticity in respiratory sensory processing in OSAS children during wakefulness.
RREP during sleep.
We have previously demonstrated that children with OSAS have blunted RREP amplitudes and delayed latencies during sleep that do not resolve after treatment (18). Therefore, this implies that the response of the central nervous system to the mechanical stimulation of the respiratory system is functionally impaired in children with OSAS during sleep. Moreover, the lack of improvement after treatment observed during sleep represents either a primary congenital abnormality or a secondary and irreversible deficit. However, the data presented in this study showed improvement in wakefulness RREP latencies after OSAS treatment, suggesting that neural cortical activation occurs faster after OSAS treatment in the awake state. The clinical implications of this are unknown, but, considering the positive neurobehavioral changes observed after OSAS treatment (6, 28, 31, 32), it could very well represent a global abnormality of cortical neural activation in untreated OSAS. This could affect many domains, including behavior and respiratory afferent sensory processing.
RREP during wakefulness.
RREP during wakefulness have characteristic peaks: Nf, P1, N1, and P300 (4, 5). Each of these peaks is recorded in a specific cortical location. P300 is elicited when participants are asked to pay attention to the stimuli (23). Children in this study were not asked to attend to the loading, and therefore the P300 was not reported.
The short-latency peak, Nf, has the highest amplitude in Fz and is reported to be the result of neural activation in the frontal supplementary motor cortex (24). This region coordinates motor responses and has been shown to be activated in speech, another condition involving exquisite coordination of respiratory motor systems (2). The longer latency of Nf in children with OSAS suggests a delay in motor processing with airway occlusion during wakefulness. The shortening of Nf latency after treatment suggests that children with treated OSAS are able to activate cortically mediated motor processes faster.
P1 is most prominent at posterior scalp sites, such as Cz, and is thought to reflect activation of the primary somatosensory cortex (24). P1 amplitude correlates with stimulus intensity (8, 37) and with load magnitude estimation (22). P1 has been reported to be absent in children with life-threatening asthma (9) but present in those with central hypoventilation syndrome (17) and adults with OSAS (1, 10, 11). Our data showed that P1 amplitudes were similar between OSAS and controls, suggesting that children with OSAS could detect loads appropriately. Interestingly, the latency of P1 decreased significantly after OSAS treatment as did Nf. This suggests that sensory-motor cortical processing of respiratory mechanical load information is suppressed in untreated OSAS and is restored with the decreased background upper airway resistance from adenotonsillectomy surgery. It is possible that epiglottic pressure may have been more negative in children with OSAS before treatment compared with controls and OSAS after treatment, despite similar orofacial pressure measurements (11). However, with consideration that study procedures were complex for children, an epiglottic pressure catheter was not included in our setup. It is also plausible that the improvement in gas exchange abnormalities secondary to the surgery induces central neural plasticity in the sensory network, or it is possible that a combination of decreased background load and central neural plasticity are responsible for the RREP changes after surgery. Inflammation has been documented in children with OSAS, and inflammatory markers, not measured in our protocol, have been reported to improve after treatment of OSAS in children (12, 13). Hence, it is conceivable that decreased inflammation after OSAS treatment could contribute to the faster respiratory sensory transmission shown here. Alternatively, as the control group was not reevaluated, it is possible that the latency changes observed were attributable to maturational changes due to aging. However, this is unlikely over the course of only 5 ± 2 mo. To the best of our knowledge, there are no longitudinal studies evaluating RREP changes during development. However, there were no latency differences between younger vs. older participants in this study, suggesting that it would be unlikely that the latency differences were attributable to aging. Similarly and to the best of our knowledge, there are no day-to-day RREP measurement variability data during wakefulness in children. Further research is warranted.
The N1 peak is localized in Cz, is related to respiratory sensory gating, and increases with attention to respiratory stimuli (24, 36, 38). The N1 scalp distribution suggested an extensive activation of the somatomotor cortex (38). Our participants watched a movie during testing and were not asked to pay attention to stimuli. However, the amplitude of N1 elicited by R30 increased significantly after OSAS treatment. This differs from our previous study during sleep that showed persistent blunting of N350 at Cz after treatment of OSAS (18). We postulate that the increase in N1 amplitude may be related to decreased background load and/or decreased sensory gating of the load stimuli after treatment of OSAS during wakefulness, as adenoid and tonsils have been removed. However, it is important to consider that OSAS results from an imbalance between anatomy and upper airway neuromotor function. Therefore, it is possible that persistent upper airway neuromotor function impairment during sleep, after treatment of OSAS, may lead to upper airway hypotonia, which may result in increased background load during sleep. Further studies using the RREP-gating paradigm during wakefulness and sleep in the same group of children may provide insight into the mechanisms for adenotonsillectomy surgery modulation of N1.
Limitations.
BMI z-score was greater in the OSAS group, but the number of obese subjects was similar between the two groups. It is possible that upper airway adipose tissue could increase the background airway resistance and contribute to the delay of the cortical neural activation in untreated OSAS subjects. However, the fact that RREP latencies decreased in the children with OSAS following surgery, despite a stable BMI, suggests that obesity did not play a major role in RREP processing. Furthermore, we have previously shown that obesity does not affect RREP amplitude or latency (16).
There were no significant differences between controls and OSAS postsurgical values. However, it is important to note that the statistical difference between these two groups was tested using unpaired tests, and the number of children with OSAS who were tested after surgery is small compared with the number of controls. Therefore, it is possible that small significant differences may have been underpowered.
It is important to note that the children who participated in the current research were studied during wakefulness only. Their clinical characteristics, however, were similar to that of participants of our previous studies during sleep (16, 18). Further research during wakefulness and sleep in the same study group is warranted.
Conclusion.
The main findings of this study are that children with untreated OSAS have delayed cortical neural activation elicited by airway mechanical loading compared with controls. After OSAS treatment, latencies in the OSAS subjects decrease to control subject values. This suggests that children with OSAS have a reversible delay of respiratory afferent sensory processing during wakefulness.
GRANTS
This work was supported by AHA 10CRP376001, NIH HL58585, NIH UL1RR024134, and Research Electronic Data Capture (REDCap).
DISCLOSURES
Dr. Marcus has received research support from Philips Respironics and Ventus unrelated to this publication. Dr. Davenport has received research support from BAE, unrelated to this publication. All other authors have nothing to disclose, financial or otherwise.
AUTHOR CONTRIBUTIONS
Author contributions: I.E.T. and C.L.M. conception and design of research; I.E.T., J.M.M., and J.H. performed experiments; I.E.T., J.M.M., J.H., P.R.G., and J.S. analyzed data; I.E.T., J.M.M., J.H., and C.L.M. interpreted results of experiments; I.E.T. and J.M.M. prepared figures; I.E.T. and P.R.G. drafted manuscript; I.E.T., J.M.M., C.L.M., J.S., and P.W.D. edited and revised manuscript; I.E.T., J.M.M., J.H., C.L.M., P.R.G., J.S., and P.W.D. approved final version of manuscript.
ACKNOWLEDGMENTS
We thank the patients and their families who participated in this study, the research coordinators Jill Maggs and Mary Anne Cornaglia, and the sleep technologists John Samuel and Jennifer Falvo at the Sleep Center of the Children's Hospital of Philadelphia for their help with this study.
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