Effects of sodium cyanide and nicotine on upper airway resistance in anesthetized dogs

The purpose of this study was to determine whether pharmacologic interventions which increase respiratory drive could also reduce flow resistance in the upper airway. Studies were performed in twelve anesthetized supine dogs. In six animals breathing spontaneously through the intact upper airway, intravenous administration of respiratory stimulants (sodium cyanide and nicotine) produced a dose-related decrease in upper airway. In nine animals, upper airway resistance was measured across the isolated upper airway. The stimulants produced a dose-related decrease in upper airway resistance. In both preparations inspiratory resistance fell at lower doses than expiratory resistance. Eventually a dose could be given which resulted in comparable, minimal values of resistance during both inspiration and expiration. Mechanisms for changes in resistance were clarified using lateral radiographs of the neck and transbronchoscopic views of the upper airway. Pharmacologic challenge resulted in a change in the route of airflow (from nose only to nose-and-mouth breathing) as well as a change in caliber of the airway at the level of the naso-pharynx and hyoid apparatus. In anesthetized dogs, respiratory stimulants will decrease upper airway resistance by increasing activation of upper airway muscles which may enlarge the airway, change the route of flow, and thus overcoming collapsing forces produced by increased chest wall muscle activation.     

Functional contribution of mandibular advancement to awake upper airway patency in obstructive sleep apnea

In the narrowed upper airway of patients with obstructive sleep apnea (OSA), a neuromuscular compensatory mechanism augments the activity of the upper airway dilator muscles in defense of upper airway patency, particularly during inspiration. We hypothesized that mechanical enlargement of the upper airway by a mandibular advancement oral appliance would permit a reduction in this neuromuscular compensation during wakefulness. To test this hypothesis, we focused on changes in the cross-sectional (CS) area of the upper airway before and after emplacement of a ventrally titrated oral appliance in 12 awake OSA patients. The CS areas at the end of tidal expiration (CS area-EET) and at the nadir of intraluminal pressure during inspiration (CS area-IN) were obtained using videoendoscopy. The median apnea–hypopnea index decreased with mandibular advancement. Before mandibular advancement, there was no difference between CS area-EET and CS area-IN in the velopharynx, oropharynx, and hypopharynx. This indicates that upper airway dilator muscle activity increased during inspiration to counteract the intraluminal negative pressure of the upper airway. After mandibular advancement, CS area-EET increased in the velopharynx, oropharynx, and hypopharynx, but CS area-IN was unchanged at any level and was less than CS area-EET in the velopharynx and oropharynx. These findings suggest that mandibular advancement enlarges the upper airway and may reduce upper airway dilator muscle activity during inspiration. We conclude that oral appliances act to return the upper airway towards a normal configuration and pattern of muscle function in OSA patients.     

The upper airway in pregnancy and pre-eclampsia

Snoring is common in pregnancy, and snoring pregnant women have increased rates of pre-eclampsia. Patients with pre-eclampsia show upper airway narrowing during sleep. The present study aimed to compare upper airway dimensions in pregnant and nonpregnant women and in patients with pre-eclampsia. A total of 50 women in the third trimester of pregnancy and 37 women with pre-eclampsia were recruited consecutively from the antenatal service and matched with 50 nonpregnant women. Upper airway dimensions were measured using acoustic reflection. Comparisons were made by analysis of variance and Student-Newman-Keuls tests. Snoring was reported by 14% of nonpregnant women, 28% of pregnant women, and 75% of pre-eclamptic women (p < 0.001). When seated, pregnant women had wider upper airways than nonpregnant women (p < 0.02), but there was no difference when supine. Oropharyngeal junction area in the seated position was less (p < 0.01) in the women with pre-eclampsia (mean +/- SD: 0.9 +/- 0.1 cm2) than either nonpregnant (1.1 +/- 0.1 cm2) or pregnant women (1.3 +/- 0.1 cm2). Supine oropharyngeal junction area was less in the women with pre-eclampsia than in the nonpregnant women (0.8 +/- 0.1 versus 1.0 +/- 0.1 cm2; p = 0.01) but similar in women with pre-eclampsia and pregnant women (0.9 +/- 0.1 cm2; p > 0.3). The study showed that women with pre-eclampsia have upper airway narrowing in both upright and supine postures. These changes could contribute to the upper airway resistance episodes during sleep in patients with pre-eclampsia, which may further increase their blood pressure.     

Lung sound analysis of upper airway obstruction]

The frequency spectrum of stridor was studied by the computer program in the patients with upper airway obstruction. The results showed that the peak frequency of respiratory sound increased significantly, the frequency spectrum got wider and removed to the high frequency area above 200Hz, the E ratio was smaller than 1. These changes were more apparent during inspiration than those during expiration. It is concluded that the stridorous sound could be determined exactly and quantitatively, and differentiated from wheezing by the spectral analysis.     

Physiologic correlates of airway collapse in chronic airflow obstruction

Forty percent of 89 patients with chronic airflow obstruction (CAO) demonstrated maximum expiration flow-volume (MEFV) patterns consistent with sudden collapse or marked narrowing of large central airways. In contrast, 43 percent of the CAO patients demonstrated a curvilinear (C) pattern; the remainder (17 percent) were intermediate. Volume displacement plethysmography indicated that the airway collapse (AC) pattern was influenced by, but was not solely, a gas compression artifact. Airway collapse patients had more obstruction and hyperinflation than C patients and also had decreased diffusing capacity, absence of density dependence, reduced lung recoil, and no effort dependence of airflow. Bronchodilator administration in AC patients typically produced large reduction of residual volume and increase of vital capacity, with a smaller increase of airflow. These data suggest that AC patients have significant, partially reversible peripheral airways obstruction plus emphysema. Possible determinants of AC include reduced central airway support, increased peripheral resistance, loss of lung recoil, and increased pleural pressures during forced expiration. The MEFV contour appears to evolve from normal to curvilinear to the AC pattern as the severity of airflow obstruction worsens.     

Phasic changes in upper airway impedance

To identify within breath variations in the mechanical properties of the isolated upper airway, we examined changes in impedance spectra over the course of the respiratory cycle. Changes were evaluated with a modified forced oscillation technique applied to the isolated, sealed upper airways of nine anesthetized mongrel dogs. Upper airway impedance spectra were studied during sequential 350 msec epochs. We found spectral changes which were reproducible within the respiratory cycle. Impedance spectra revealed that during mid-inspiration at the point of peak upper airway muscle activity, the low frequency real part decreased and the imaginary part was less negative and less steep. During late inspiration and early expiration the impedance values returned to their end-expiratory values. The only significant change in parameter estimates from a three-parameter model indicated an increase in compliance. Since these changes correlated not only with tidal flow through the lower trachea and lung but also with upper airway muscle activation, we reasoned that changes in impedance could have resulted from an increase in upper airway size. Therefore, we used a sealed speaker system and, while the animal was apnoeic, evaluated impedance at two different airway pressures and the resultant volumes. The changes in impedance spectra with a volume increase were similar to those seen during spontaneous breathing efforts. We conclude that the mechanical properties of the upper airway change during the respiratory cycle and that these changes correlate with the respiratory activation of upper airway muscles. We suspect that these changes in input impedance could reflect a change in the size of the airway rather than a true increase in elasticity.     

Effects of electrical stimulation of the genioglossus on upper airway resistance in anesthetized dogs

We examined the relationship between the frequency of stimulation of the genioglossus and upper airway resistance in six anesthetized dogs in the supine position. The upper airway was isolated from the lower airway by transecting the cervical trachea, and the pressure flow relationship of the upper airway was obtained by applying constant negative pressure (5, 10, and 20 cm H2O) to the proximal cut end of the trachea. Electrical stimulation of the genioglossus was performed at a constant voltage (10 to 20 V) and at various frequencies (as high as 100 Hz). Upper airway resistance (Rua) during both inspiration and expiration increased with an increase in tracheal negative pressure, and at each tracheal negative pressure Rua was significantly reduced by stimulation of the genioglossus. The effects of genioglossal muscle stimulation were nonlinearly dependent on the stimulating frequency. Below 50 Hz, Rua decreased markedly as the stimulating frequency was increased, but above 50 Hz, Rua plateaued at a minimum value. These findings suggest that at a stimulating frequency of more than 50 Hz, upper airway patency is stably maintained in anesthetized dogs.     

Palate and hypopharynx--sites of inspiratory narrowing of the upper airway during sleep

In order to determine the specific site of inspiratory narrowing within the upper airway during sleep, we measured supralaryngeal, oropharyngeal, and nasopharyngeal pressures and inspiratory flow in 11 healthy nonsnoring male subjects awake and in NREM sleep. Resistance was calculated at 0.01 L/s, a point along the linear portion of the pressure-flow relationship, and at peak inspiratory pressure, a point within the curvilinear section of the pressure-flow relationship. During sleep, nasal resistance increased minimally. At peak inspiratory pressure, both transpalatal and hypopharyngeal resistances increased more than 700% in NREM sleep. At 0.01 L/s inspiratory flow, transpalatal and hypopharyngeal resistances increased 200 and 400%, respectively. Six subjects had a greater increase in transpalatal than hypopharyngeal resistance, and five subjects had a greater increase in hypopharyngeal than transpalatal resistance. Three subjects in each of these two subgroups had an increase in resistance exclusively across the palate or the hypopharynx. The site of increased resistance during sleep was not predictable from awake resistance measurements. From these data, we conclude that the site of inspiratory narrowing within the upper airway during sleep occurs primarily at either the level of the palate or hypopharynx and is variable among subjects. The pattern of palatal or hypopharyngeal narrowing is the same as that observed in obstructive sleep apnea patients, but quantitatively different.     

Changes in upper airway size during tidal breathing in children with obstructive sleep apnea syndrome

We performed respiratory-gated magnetic resonance imaging to evaluate airway dynamics during tidal breathing in 10 children with obstructive sleep apnea syndrome (OSAS; age, 4.3 +/- 2.3 years) and 10 matched control subjects (age, 5.0 +/- 2.0 years). We hypothesized that respiratory cycle fluctuations in upper airway cross-sectional area would be larger in children with OSAS. METHODS: Studies were performed under sedation. Respiratory gating was performed automatically at 10, 30, 50, 70, and 90% of inspiratory and expiratory volume. Airway cross-sectional area was measured at four ascending oropharyngeal levels at each increment of the respiratory cycle. RESULTS: We noted the following in subjects with OSAS compared with control subjects: (1) a smaller upper airway cross-sectional area, particularly during inspiration; (2) airway narrowing occurred during inspiration without evidence of complete airway collapse; (3) airway dilatation occurred during expiration, particularly early in the phase; and (4) magnitude of cross-sectional areas fluctuations during tidal breathing noted in OSAS at levels 1 through 4 were 317, 422, 785, and 922%, compared with 19, 15 17, and 24% in control subjects (p < 0.001, p < 0.005, p < 0.001, and p < 0.001, respectively). CONCLUSIONS: Fluctuations in airway area during tidal breathing are significantly greater in subjects with OSAS compared with control subjects. Resistive pressure loading is a probable explanation, although increased airway compliance may be a contributing factor.     

The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade

RATIONALE: Partial neuromuscular transmission failure by acetylcholine receptor blockade (neuromuscular blockade) or antibody-mediated functional loss (myasthenia gravis), even with a magnitude of muscle weakness that does not evoke respiratory symptoms, can evoke dysphagia and decreased inspiratory airflow, and increases the risk of susceptible patients to develop severe pulmonary complications. OBJECTIVES: To assess whether impaired neuromuscular transmission predisposes individuals to inspiratory upper airway collapse, we assessed supraglottic airway diameter and volume by respiratory-gated magnetic resonance imaging, upper airway dilator muscle function (genioglossus force and EMG), and changes in lung volume, respiratory timing, and peripheral muscle function before, during, and after partial neuromuscular blockade in healthy, awake volunteers. MEASUREMENTS AND MAIN RESULTS: Partial neuromuscular blockade (train-of-four [TOF] ratio: 0.5 and 0.8) was associated with the following: (1) a decrease of inspiratory retropalatal and retroglossal upper airway volume to 66 +/- 22 and 82 +/- 12% of baseline, which was significantly more intense in the retropalatal area; (2) an attenuation of the normal increase in anteroposterior upper airway diameter during forced inspiration to 74 +/- 18% of baseline; (3) a decrease in genioglossus activity during maximum voluntary tongue protrusion to 39 +/- 19% (TOF, 0.5) and 73 +/- 29% (TOF, 0.8) of baseline; and (4) no effects on upper airway size during expiration, lung volume, and respiratory timing. CONCLUSIONS: Thus, impaired neuromuscular transmission, even to a degree insufficient to evoke respiratory symptoms, markedly impairs upper airway dimensions and function. This may be explained by an impairment of the balance between upper airway dilating forces and negative intraluminal pressure generated during inspiration by respiratory "pump" muscles.     

High-frequency oscillatory ventilation may increase airway closure

In five seated, normal subjects, we measured closing volumes using 133Xe boluses inhaled at residual volume. High frequency oscillatory ventilation (HFOV) (15 Hz, 2 cc/kg) was applied during either inspiration to total lung capacity or the subsequent expiration. Closing volume was increased (P less than 0.001) when HFOV was applied during the latter half of expiration, but not when HFOV was applied during inspiration or the first half of expiration. Subsequently, in seven subjects, we measured the regional distributions of 133Xe boluses delivered during open-glottis breath-hold at 14% vital capacity after equilibration with N2O. HFOV was applied during bolus delivery for about 16 sec. These distributions were compared with those achieved by intravenous injections of 133Xe in saline. Regional perfusion (injected isotope) exceeded regional N2O uptake at the lung bases and this was significantly accentuated by HFOV, compatible with increased basal closure. We conclude that in normal subjects at low lung volumes, HFOV may enhance airway closure, though other explanations are possible.     

Effect of hypercapnia on upper airway resistance and collapsibility in anesthetized dogs

The upper airway (UAW) is intrinsically unstable and susceptible to collapse when the negative inspiratory intraluminal pressure exceeds the stabilizing forces which prevent obstruction. In the present study we evaluated mechanisms by which UAW patency is maintained in the presence of increased inspiratory flows when respiration is stimulated. In seven anesthetized dogs breathing spontaneously through a low tracheostomy, the UAW was isolated by a second tracheostomy directed rostrally. UAW pressure-flow relationship and stability against collapse were evaluated during steady flow in the inspiratory direction while the animals were breathing 100% O2 or a hypercapnic gas mixture. The pressure-flow curves of the isolated UAW demonstrated the characteristic pattern of collapsible tubes. Steady state hypercapnia resulted in lower UAW resistance during both inspiration and expiration. UAW resistance decreased linearly as PCO2 and ventilation increased over the course of CO2 rebreathing. In addition, during hypercapnia the critical negative intraluminal pressure required to induce UAW collapse and obstruction increased from -4.3 +/- 0.9 to -8.5 +/- 1.5 SE cm H2O (p less than 0.01), indicating increased stability of the UAW. Since hypercapnia is known to stimulate UAW muscles, our findings suggest that increased UAW muscle activity improves UAW patency both by decreasing their resistance to airflow, and by increasing UAW walls rigidity and stability against collapse.     

Methacholine-induced volume dependence of respiratory resistance in preschool children.

Enhanced negative volume dependence of airway resistance is associated with bronchoconstriction in tracheostomized paralysed open-chest animals. Significant upper airways responses may be associated with bronchoconstriction and could thereby alter the pattern of volume dependence in spontaneously breathing subjects. The aim of the study was to test whether volume dependence of respiratory resistance (Rrs) could be demonstrated in preschool children undergoing routine methacholine challenge. The volume dependence of respiratory oscillation resistance at 12 and 20 Hz (Rrs,12 and Rrs,20) was examined in eight 4-5.5-yr-old children showing a positive response to methacholine. Multiple linear regression analysis was also used to account for flow dependence during tidal breathing (Rrs,12 or Rrs,20=K1+K2?V'?+K3V). Rrs,12 and Rrs,20 yielded similar results. Negative volume dependence was present at baseline and significantly enhanced by methacholine (p<0.01). For instance, the mean+/-SD inspiratory K3 at 20 Hz was 4.1+/-1.3 hPa x s x L(-2) at baseline and -15.0+/-4.3 hPa x s x L(-2) after methacholine, in which case it was also larger on expiration than on inspiration (p<0.05), possibly as a result of upper airway responses. A significant increase in the negative volume dependence of respiratory resistance may thus be shown in preschool children in response to methacholine. The volume dependence (K3) during inspiration may be particularly useful in detecting bronchoconstriction, because it is less likely to be affected by upper airway mechanisms than during expiration.     

Stridor: differentiation from asthma or upper airway noise

Stridor, a musical, continuous sound often attributed to upper airway narrowing, may be encountered in the recently extubated patient. Recently extubated patients and patients with documented upper airway obstruction were studied. Sounds were recorded from the neck and chest. The sound signal of patients with stridor was compared to that made by asthmatics and extubated patients with no airway obstruction. The frequency spectrum of segments of the sound signal was determined using the fast fourier transform technique. The sound signal associated with stridor had a similar frequency to that found with asthma. However, the signal was more intense over the neck than over the chest, whereas in asthmatics the reverse was true. The musical sounds in patients with stridor occurred during inspiration, whereas in those patients with asthma, they were predominantly expiratory. The major difference between stridor and asthma was the timing of the sound and the prominence of the sound over the neck.     

Effect of hypercapnia on total pulmonary resistance during wakefulness and during NREM sleep.

We investigated the effect of different levels of hypercapnia on total pulmonary resistance (RL) in 13 subjects ranging from nonsnorers with low RL to snorers with high RL and dynamic narrowing of the upper airway during inspiration. Added CO2 was adjusted to achieve a steady-state increase in PETCO2 of +2, +4, or +6 mm Hg. RL was measured at peak inspiratory flow (RLpf), at maximal resistance within breath (RLmax), and at 10 equally spaced points within inspiration in several trials. During wakefulness, hypercapnia was associated with decreased RLmax. During steady state +6 mm Hg hypercapnia, RLmax decreased by 30% (p less than 0.01). During NREM sleep, low levels of hypercapnia did not affect RL. However, +6 mm Hg hypercapnia was associated with decreased RLmax in six of eight subjects (p = 0.07), especially in subjects with high RLmax during room air breathing. The effects of hypercapnia on RLpf paralleled its effect on RLmax. We concluded that (1) the decrease in RL during awake hypercapnia suggests an increase in upper airway dimensions and stiffness, (2) the absence of increased RL during low level NREM hypercapnia (despite the increase in inspiratory flows and collapsing pressures) also suggests an increase in upper airway dimensions and stiffness, and (3) upper airway dilating muscles appear to be recruited in a coordinated fashion with inspiratory muscles in normal humans during NREM sleep. The implications of these findings in patients with obstructive sleep apnea are not clear at this point.     

Upper airway imaging in relation to obstructive sleep apnea.

A variety of imaging techniques have been used to assess upper airway size and function in patients with OSA. Each technique has certain advantages and limitations. Many of the imaging techniques study awake and upright patients, whereas OSA typically occurs while the patient is asleep in the supine position. Upper airway imaging may identify specific upper airway abnormalities that cause OSA. Furthermore, the majority of patients with OSA have a narrow and more collapsible airway in the velopharynx. Upper airway occlusion during sleep usually starts in the velopharynx and extends caudally. Obesity results in both extrinsic upper airway narrowing and soft tissue enlargement. Upper airway edema may occur secondary to OSA and subsequently exacerbate the OSA by causing further upper airway narrowing. Upper airway imaging provides some insights into the mechanism of action of certain treatments and is increasingly used to help direct treatment. Weight loss reduces upper airway collapsibility. Nasal CPAP increases upper airway size and reduces upper airway edema. UPPP enlarges the oropharynx and reduces upper airway collapsibility. Patients with a narrow upper airway, particularly relative to tongue size, have a good response to UPPP.     

Effect of upper airway pressure pulses on breathing pattern

Importance of the time of application of upper airway pressure pulses on breathing pattern was investigated in 19 anesthetized, spontaneously breathing rabbits. The upper airway was functionally isolated into a closed system. A servo-respirator, triggered by the inspiratory activity of the diaphragm, was used to apply pressure pulses to the isolated upper airway. Negative pressure pulses of -5, -10, and -15 cm H2O when applied in early inspiration (within the first half) produced a reversible inhibition of inspiration in most trails (86.2%). This resulted in a prolongation of inspiratory duration (TI) and a decrease in mean inspiratory drive (P.Dia/TI) whereas peak diaphragm (P.Dia) activity and expiratory duration (TE) remained largely unaffected. In the remaining 13.8% of trials, an irreversible inhibition with short TI and reduced P.Dia activity was observed. In contrast, with late application of negative pressure pulses the only significant change was a shortening of TI. When positive pressure pulses were applied during expiration, no significant change in TE occurred with either early or late application. A significant prolongation of subsequent TI was seen irrespective of the time of positive pressure application. These results indicate that time of application during the respiratory cycle is an important variable in determining the response to upper airway pressure pulses.     

Upper airway artifact in respiratory impedance measurements

When studying respiratory impedance by forced oscillations, part of the flow measured at the mouth is lost in upper airway wall motion and does not enter the trachea. The corresponding error was studied in 10 normal subjects and 8 patients with chronic obstructive pulmonary disease (COPD) by measuring respiratory impedance with the cheeks unsupported, with the cheeks supported, and when upper airway wall motion was simultaneously measured with a head plethysmograph, and corrected for. In normal subjects, wall motion had little influence on respiratory resistance but, whether the cheeks were supported or not, increased the resonant frequency (p less than 0.05) and respiratory compliance (p less than 0.001) and decreased respiratory inertance (p less than 0.001). In patients with COPD, average resistance from 4 to 30 Hz was significantly lower when the cheeks were not supported (3.32 +/- 0.57 cm/H2O X L-1 X s; m +/- SD) than when they were (4.59 +/- 0.73, p less than 0.01) and when the data were corrected (5.41 +/- 1.14, p less than 0.001). Moreover, resistance increased with increasing frequency when wall motion was corrected for and decreased when it was not. Upper airway wall motion also tended to increase resonant frequency and decrease inertance in patients. The data show that supporting the cheeks does not prevent large errors on respiratory impedance and derived parameters, especially in obstructive patients; accurate measurements require that airway wall motion be evaluated and corrected for.     

Bench model to simulate upper airway obstruction for analyzing automatic continuous positive airway pressure devices

BACKGROUND: Automatic positive airway pressure (APAP) devices are increasingly being used in patients with obstructive sleep apnea. Some APAP devices present an unstable behavior when subjected to some events or artifacts. The aims were to develop a bench model capable of reproducing real flow, snoring, and obstructive patterns and to compare the response of APAP devices based on flow and snoring with other devices using, in addition, the forced oscillation technique (FOT). METHODS: The bench model subjected APAP devices to apneas with and without obstruction, obstructive hypopneas with and without snoring, periods of flow limitation, and artifacts such as leaks and mouth expiration. RESULTS: Almost all the devices increased the pressure when subjected to apneas with obstruction, but at different rates. The time required by each device to reach 10 cm H(2)O ranged from 2.5 to 13 min. In the presence of apneas without obstruction, all the devices based on flow and snoring increased the pressure at the same rate as during apneas with obstruction. However, the devices using FOT did not modify the pressure. Four devices did not modify the pressure in the presence of obstructive hypopneas, and all but one device increased the pressure in the presence of snoring. Mask leaks had little effect on the response of the devices, but four devices increased the pressure during mouth expiration artifacts. CONCLUSIONS: When, in addition to the flow and snoring signals, the measurement of the upper airway resistance is included, the accuracy of the event detection algorithms is improved.     

Heterogeneity within geniohyoid motor unit subpopulations in firing patterns during breathing

Respiratory motor units (MU) segregate into subpopulations, which differ in firing patterns during resting and stimulated breathing. For phrenic/diaphragm MUs, diversity also exists within subpopulations, and is greater for late than early-onset MUs. The present study characterized the extent of diversity within upper airway respiratory MU subpopulations by recording geniohyoid MUs in anesthetized cats. Inspiratory MUs (I-MU, n=21) had a wide range of firing durations (coefficient of variation (CV)=42%). In contrast, inspiratory-expiratory MUs (I/E-MU, n=19) had a narrow range of firing durations during inspiration (CV=13%), but a wide range of firing durations during expiration (CV=36%). Mean firing frequency had similar degrees of diversity among units for I-MU and I/E-MU (CV=31-40%). For I-MU firing duration correlated with mean firing frequency, whereas no such relationship was apparent for I/E-MU. Single-breath end-expiratory airway occlusion decreased heterogeneity in firing duration during inspiration and increased it during expiration, whereas end-inspiratory airway occlusion decreased heterogeneity during expiration. In conclusion, (a) there is considerable diversity within geniohyoid MU subpopulations receiving respiratory drive; (b) the degree of diversity within subpopulations differs for I-MU and I/E-MU; and (c) diversity within subpopulations in timing of activity is modulated by single-breath airway occlusion.