help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on June 23, 2005, doi:10.1164/rccm.200505-699OC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200505-699OCv1
172/8/1047    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Eckert, D. J.
Right arrow Articles by McEvoy, R. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eckert, D. J.
Right arrow Articles by McEvoy, R. D.
American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 1047-1054, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200505-699OC

Sustained Hypoxia Depresses Sensory Processing of Respiratory Resistive Loads

Danny J. Eckert, Peter G. Catcheside, Rachel McDonald, Amanda M. Adams, Kate E. Webster, Michael C. Hlavac and R. Doug McEvoy

Adelaide Institute for Sleep Health, Repatriation General Hospital, Daw Park, South Australia; School of Molecular and Biomedical Science, Discipline of Physiology, University of Adelaide, South Australia; Department of Medicine, Flinders University, Bedford Park, South Australia; and Musculoskeletal Research Centre, La Trobe University, Bundoora, Victoria, Australia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: The combination of acute hypoxia and increased respiratory load is encountered in several respiratory diseases including acute life-threatening asthma and sleep apnea. Hypoxia has been shown to inhibit respiratory load perception in healthy and asthmatic subjects, and could contribute to treatment delays and impaired function of protective reflexes.

Objectives: Using respiratory-related evoked potentials (RREPs) this study aimed to determine the sensory processes mediating hypoxia-induced suppression of respiratory load sensation.

Methods: EEG was measured over the central and parietal cortical regions in 14 healthy subjects. RREPs were elicited by 500-ms midinspiratory resistive load stimuli during and after isocapnic normoxia or hypoxia (blood arterial O2 saturation ~ 80%). On a separate occasion, subjects rated the perceived magnitude of five externally applied inspiratory resistive loads (range, 8.6–43.7 cm H2O · L–1 · s) under similar experimental conditions. In both experiments subjects voluntarily ventilated approximately 90% above baseline to match ventilatory output between gas conditions.

Results: RREP stimulus was matched between gas conditions in 11 subjects (minimum mask pressure –9.7 ± 0.6 versus –9.2 ± 0.4 cm H2O). P1 and P2 amplitudes were reduced during isocapnic hypoxia compared with normoxia (maximal at Cz: P1, 2.5 ± 1.1 versus 3.9 ± 1.2 µv, p = 0.03; P2, 10.0 ± 2.2 versus 12.4 ± 2.1 µv, p < 0.01, respectively). Perceived magnitude of externally applied resistive loads was also reduced during hypoxia compared with normoxia (17.1 ± 1.1 versus 19.0 ± 1.1 au, p < 0.01).

Conclusions: These data confirm that isocapnic hypoxia suppresses respiratory load sensation. Decreased amplitude of the earlier (P1) RREP component suggests that this is mediated, at least in part, by suppression of respiratory afferent information before its arrival at the primary sensory cortex.

Key Words: afferent pathways • dyspnea • event-related potentials • sensation

Acute hypoxia coupled with increased respiratory load is a feature of life-threatening asthma, acute exacerbations of chronic obstructive lung disease, and sleep-disordered breathing. Dyspnea, a manifestation of load sensory processing, is a common feature of breathing impairment during wakefulness (1). There is also somatosensory cortical activation (K-complexes, evoked potentials, and arousal) to increased respiratory load during sleep (2–4). Transient exposure to brief episodes of hypoxia may produce specific sensations of dyspnea such as "air hunger" (5). However, hypoxia has also been shown to inhibit neurocognitive functioning and sensory processing in non–respiratory-related tasks (6–8). Furthermore, moderate isocapnic hypoxia (arterial blood O2 saturation [SpO2] 80%) lasting greater than 5 min, reduces the perception of externally applied inspiratory resistive loads in healthy individuals and in individuals with stable asthma (9, 10). After hypoxia, subjects with asthma reported 25 to 30% reductions in symptoms of dyspnea to methacholine bronchoconstriction (10). Thus, hypoxia has the potential to suppress respiratory sensory processing and respiratory reflexes, and to increase disease severity in a range of hypoxic respiratory disorders. The underlying mechanisms mediating suppression of respiratory load sensation with hypoxia have yet to be elucidated.

Respiratory-related evoked potentials (RREP) provide insight into the sensory processes underlying respiratory load perception (11–14). RREPs are characterized by positive (P) and negative (N) waveform components within time-locked windows relative to stimulus onset. Respiratory load perception research has primarily focused on the first (P1) and third (P3) positive peaks. P1 occurs 40 to 110 ms after stimulus onset depending on the specific stimulus characteristics (12, 14–16) and is believed to reflect the arrival of ascending respiratory signals at the somatosensory cortex (14). P1 amplitude increases with increasing stimulus magnitude (13, 17, 18). The P3 component, occurring after 250 ms, is thought to reflect cognitive and perceptual sensory processing, and unlike P1 is attention dependent (11). The amplitudes of both these RREP components strongly correlate with subjects' perception of the magnitude of respiratory resistive load (11, 13). RREP techniques have revealed perceptual processing deficits in patients with asthma and obstructive sleep apnea (15, 19–22).

The purpose of this study was to investigate which components of the RREP elicited by brief resistive loads are influenced by acute isocapnic hypoxia. To avoid the confounding influence of greater resistive load stimulus magnitude during hypoxia (increased respiratory drive) compared with normoxia (baseline respiratory drive), experiments were conducted during matched targeted hyperventilation. Measurements were also made in the recovery period immediately after gas inhalation during normal tidal breathing. It was hypothesized that hypoxia would blunt resistive load sensation and reduce the amplitude of the early and late RREP components. Some of the results of this study have been reported previously in abstract form (23–25).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subject Selection
Fourteen healthy nonsmokers with normal lung function gave informed written consent. Three subjects exhibited substantial variability in breath volume and timing during targeted ventilation such that stimulus magnitude matching was not achieved (difference in minimum mask pressure between gas conditions exceeded ± 20%). Therefore, 11 subjects successfully completed all study requirements. The study was approved by the Daw Park Repatriation General Hospital and Adelaide University Human Research and Ethics Committees.

Preliminary Visit
Subjects attended a preliminary visit for familiarization with the respiratory equipment and protocols and to practice the method for matching a predetermined target level of ventilation (I) (see online supplement for further detail). Briefly, after measurement of the hypoxic ventilatory response (SpO2 80%), the target I to be used in the main experiments was determined for each subject as follows:

Target I = 10% x (peak hypoxic I – average of baseline I) + peak hypoxic I.

Subjects performed the targeted I task by breathing, mouth closed, through a nasal mask and unidirectional valve attached to a 2-L collapsible bag filled at the target flow rate with compressed air (Figure 1). Subjects were required to maintain a constant end-inspiratory bag volume by increasing tidal volume without changing breathing frequency. A manual inspiratory bleed of CO2 maintained isocapnia.



View larger version (20K):
[in this window]
[in a new window]
  		Figure 1. Schematic of the breathing circuit.

 
Study Design, Common Techniques, and Measurements
The effects of hypoxia on respiratory load perception and RREP were examined in two separate experiments approximately 1 wk apart, in random order. Before both experiments, subjects abstained from alcohol, caffeine, and other drugs for at least 24 h. On each day, isocapnic hypoxia and isocapnic normoxia were administered, in random order, while subjects maintained voluntary hyperventilation at the target level. One hour separated each gas condition. Subjects were studied seated upright in a comfortable chair.

During hypoxia trials the inspired O2 fraction (9% O2 in N2) was adjusted as necessary by bleeding small amounts of medical air or N2 into the inspirate to maintain SpO2 at approximately 80%. To test for residual effects after hypoxia, measurements were repeated during room air breathing commencing 2 min after terminating each experimental gas. The electroencephalogram (EEG) at C3 and electrooculograms were monitored throughout to ensure wakefulness. The electrocardiogram and heart rate were monitored continuously.

Magnitude Perception of Externally Applied Inspiratory Resistive Loads ({psi})
After 5 min of room air breathing, subjects were switched to the target I arm of the circuit (Figure 1), through which the experimental gas (hypoxic mixture or medical air) was introduced at the required target I for 30 min. Five resistive loads (8.6 ± 0.1, 13.4 ± 0.2, 22.3 ± 0.4, 30.4 ± 0.6, and 43.7 ± 1.1 cm H2O · L–1 · s), were presented for a single breath, 12 times each in random order as described previously (9). Subjects rated their perception of load intensity using open magnitude scaling (9, 26). After this, subjects resumed room air tidal breathing and measurements continued over 30 min (Figure 2A). After a 1-h break, these procedures were repeated for the remaining test gas condition.



View larger version (27K):
[in this window]
[in a new window]
  		Figure 2. Minute ventilation during the load perception (A) and evoked potential protocols (B). Data are expressed as 30-s averages plotted at alternate intervals between isocapnic normoxia and isocapnic hypoxia. Values are means ± SEM, n = 11.

 
RREPs
RREPs were measured from EEG recordings overlying the central somatosensory (C3, Cz, and C4) and parietal secondary sensory association (P3, Pz, and P4) areas of the cortex. Electrodes were reapplied as necessary until impedance at each site was less than 5 Kohms. Subjects listened to music through earphones throughout the protocol. After 5 min of room air breathing, subjects were switched to the target I arm of the circuit (Figure 1). One of the experimental gases was introduced at the required target I for three 20-min periods, each separated by 15 min of room air tidal breathing (Figure 2B). This design was chosen to maximize the likelihood of detecting posthypoxia effects that previous studies have shown to persist for at least 10 to 15 min after returning to room air breathing (10, 27).

RREPs were elicited by mid-inspiratory, 500-ms external resistive load stimuli presented in random order every two to six breaths via fast-actuating computer-controlled solenoid (SXE9575-A70–00; Iso star, Norgren, Switzerland). To minimize noise, the solenoid and the breathing circuit were located in a room adjacent to the subject separated by a thick masonry wall (Figure 1). Load sequence and midinspiratory delivery was controlled by custom written software (see Figure E3 in the online supplement). To facilitate P3 responses, subjects were asked to mentally count (i.e., attend to the stimulus) and later report the number of loads presented. This procedure was repeated for the remaining test gas condition.

Statistical Procedures
Mixed model analyses were used to compare perception scores between gas treatments (SPSS version 12.1; SPSS, Inc., Chicago, IL). ANOVA for repeated measures were used to examine central (C3, Cz, and C4) and parietal (P3, Pz, and P4) gas and site effects on RREP component amplitudes and latencies. ANOVA for repeated measures was also used to examine gas effects on ventilatory parameters across study periods (baseline, target I, recovery). Where main ANOVA effects were observed, post hoc comparisons were performed using Dunn-Sidak adjusted Student's paired t tests (28). Statistical significance was inferred when p < 0.05. All data are reported as means ± SEM (see online supplement for further detail regarding data analysis).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Anthropometric Data
The 11 subjects who completed the study (6 males) were young (24.9 ± 1.1 yr) and had normal body mass index (22.2 ± 0.6 kg · m–2) and lung function (forced expiratory volume in 1 s and total lung capacity 109.3 ± 3.6 and 104.8 ± 9.2% predicted, respectively).

Ventilatory Parameters during Main Experimental Visits
Figure 2 displays I during RREP and load perception protocols. I was well matched between gas conditions during target I and not different during recovery periods. Table 1 shows other ventilatory characteristics during load perception and RREP experiments (see online supplement for preliminary visit data). By design SpO2 was lower during hypoxia target I trials compared with normoxia, baseline, and recovery periods. SpO2 was marginally lower during the normoxic recovery period compared with baseline during the RREP protocol. As instructed, subjects achieved target I by increasing peak inspiratory flow and tidal volume without changing breathing frequency. These ventilatory parameters were not different between normoxia and hypoxia. End tidal carbon dioxide levels were not different between gas conditions or between baseline, target I, and recovery periods.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Group average ventilatory characteristics during main experimental visits

 
Magnitude Perception of Externally Applied Inspiratory Resistive Loads
Target ventilation.
Inspiratory resistive load magnitude perception ({psi}) increased nearly linearly with peak inspiratory pressure (PIP) (Figure 3A), and a linear model tended to provide a better fit compared with Stevens' power function ({psi} = aPIP + b overall r2 = 0.97 ± 0.01, sum of squares = 5.9 ± 2.1 versus {psi} = kPIPn r2 = 0.96 ± 0.01, sum of squares = 9.2 ± 3.4, p = 0.06). This accords with several recently published studies that have compared linear versus power function models of respiratory load perception (9, 10, 29) and recent reviews supporting neural coding phenomena may behave linearly (30, 31). Mixed model analyses showed a main gas effect with lower {psi} during hypoxia compared with normoxia (Figure 3A). In addition, there was a trend for a lower slope of the PIP versus {psi} relationship during hypoxia compared with normoxia (1.71 ± 0.29 versus 2.06 ± 0.36 {psi} · cm H2O–1, p = 0.07).



View larger version (18K):
[in this window]
[in a new window]
  		Figure 3. Peak inspiratory pressure (PIP) versus the perceived magnitude of externally applied resistive loads ({psi}) during 30 min of targeted ventilation with isocapnic normoxia and isocapnic hypoxia (A) and recovery periods (B). Resistance versus the perceived magnitude of externally applied resistive loads ({psi}) during 30 min of targeted ventilation with isocapnic normoxia and isocapnic hypoxia (C) and recovery periods (D). * Significant decrease in {psi} during hypoxia compared with normoxia (p < 0.01). Values are means ± SEM, n = 11.

 
In contrast, {psi} tended to increase in a curvi-linear manner with resistance (R) (Figure 3C). Stevens' power function provided a superior fit compared with a linear model ({psi} = kRn overall r2 = 0.94 ± 0.02, sum of squares 18.0 ± 6.3 versus {psi} = aPIP + b r2 = 0.90 ± 0.02, sum of squares = 20.4 ± 6.1, p = 0.02), although this was poorer than the fit of a linear model of PIP ({psi} = kRn versus {psi} = aPIP + b, p = 0.03). Mixed model analyses of the log-transformed data also revealed a main gas effect with lower {psi} for a given R during hypoxia than normoxia (Figure 3C). There were no differences in the slope of logR versus log{psi} relationships between hypoxia and normoxia (0.57 ± 0.07 versus 0.59 ± 0.08 {psi} · cm H2O · L–1 · s, p = 0.47).

Recovery.
{psi} for a given level of PIP tended to be lower during the posthypoxia compared with postnormoxia period using mixed model analyses, although this was not statistically significant (Figure 3B, p = 0.12). In addition, there was a trend for the slope of the PIP versus {psi} relationship to be lower posthypoxia than postnormoxia (2.06 ± 0.31 versus 2.42 ± 0.40 {psi} · cm H2O–1, p = 0.06). There was no mixed model analyses main effect (Figure 3D, p = 0.51) or difference in the slope of Steven's power function of R versus {psi} posthypoxia compared with postnormoxia (0.79 ± 0.12 versus 0.91 ± 0.14 {psi} · cm H2O · l–1 · s, p = 0.18).

RREPs
Target ventilation.
119.7 ± 12.9 brief resistive loads per subject during hypoxia and 131.2 ± 10.5 during normoxia (p = 0.15) were averaged to construct group average RREP waveform and stimulus characteristics. RREP stimulus magnitude was well matched between hypoxia and normoxia (minimum mask pressure –9.7 ± 0.6 versus –9.2 ± 0.4 cm H2O, p = 0.18, Figure 4A).



View larger version (17K):
[in this window]
[in a new window]
  		Figure 4. Group mean average respiratory-related evoked potential (RREP) waveforms during target ventilation periods (3 x 20-min periods combined) during isocapnic normoxia and isocapnic hypoxia (A) and during recovery periods (3 x 15-min periods combined) (B). Positive and negative peaks are highlighted at the maximal sites of activation. Differences between normoxia and hypoxia; *p < 0.05, {dagger}p < 0.01 (n = 11).

 
ANOVA revealed a significant main gas effect for P1 and P2 amplitudes at scalp electrode sites overlying the central primary somatosensory (C3, Cz, and C4) and the parietal secondary sensory association (P3, Pz, and P4) areas of the cortex. Compared with normoxia, overall P1 amplitude at central and parietal sites was lower during hypoxia (2.1 ± 1.0 µv versus 3.1 ± 1.0 µv, p = 0.02; and 2.8 ± 0.6 µv versus 3.9 ± 0.7 µv, p = 0.02, respectively). Similarly, overall P2 amplitude at the central and parietal sites was lower during hypoxia compared with normoxia (7.1 ± 1.7 µv versus 8.9 ± 1.6 µv, p < 0.01; and 4.6 ± 1.1 µv versus 5.7 ± 1.1 µv, p = 0.02, respectively). An example of one individual's evoked potential response across each of the measured scalp electrode sites is displayed in Figure E4.

ANOVA site effects for each RREP component consistently revealed maximal activation at the central electrode site (Cz for Nf, P1, N1, P2 peaks and Pz for the P3 peak). Group grand mean RREP waveforms at Cz and Pz are presented in Figure 4A. The grand mean amplitudes and latencies at the site where each component was maximal are presented in Table 2. P1 and P2 amplitudes were significantly reduced during hypoxia compared with normoxia. Although N1 amplitude appeared to be greater during hypoxia compared with normoxia, this difference was not statistically significant (Table 2, p = 0.12). When P2 was expressed as an N1–P2 difference at the maximal Cz site there were no differences between hypoxia and normoxia (17.4 ± 3.6 versus 17.5 ± 2.3 µv, p = 0.94). There were no further between-gas differences in RREP amplitude or latency.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Respiratory related evoked potential mean amplitude and latency data at maximal sites of activation during target ventilation and recovery periods

 
Recovery.
To construct group average RREP waveforms, 90.0 ± 7.6 brief resistive loads per subject posthypoxia and 90.5 ± 7.5 postnormoxia (p = 0.91) were averaged. RREP stimulus magnitude was not different between recovery periods (minimum mask pressure –6.3 ± 0.4 versus –6.0 ± 0.2 cm H2O following hypoxia versus normoxia, p = 0.45, Figure 4B). Similar to the target I periods, P1 and P2 amplitudes at the central sites tended to be lower posthypoxia compared with postnormoxia, although these differences were not statistically significant (P1, hypoxia 2.4 ± 1.0 µv versus normoxia 3.4 ± 0.9 µv, p = 0.19; P2, hypoxia 7.2 ± 2.0 µv versus normoxia 8.7 ± 1.5 µv, p = 0.17). There were no amplitude or latency differences in any other RREP components between recovery periods at the maximal sites of activation (Table 2 and Figure 4B).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main finding of this study was that in healthy subjects hypoxia resulted in decreased amplitudes of the early P1 and P2 components of the RREP to resistive load stimuli during conditions confirmed to produce a reduction in the perceived magnitude of respiratory resistive loads. These comparisons during hypoxia and normoxia were obtained during carefully matched conditions of ventilatory output and consequently respiratory stimulus magnitude. The findings provide further evidence that sustained hypoxia leads to impaired sensations of respiratory load, and importantly, show that these effects are not mediated solely by higher center cortical cognitive depression. The suppression of the early P1 component of the RREP suggests that acute hypoxia likely depresses respiratory afferent neural transmission lower in the neuraxis.

These data extend earlier observations during free breathing trials in healthy individuals and subjects with asthma (9, 10). The decrements in respiratory load perception in the current study were comparable to those observed in previous experiments, providing strong support that the background pattern of ventilation per se is not responsible for hypoxia-induced sensory impairment. While this agrees with other reports of suppressed respiratory sensation to a variety of sensory stimuli during acute sustained hypoxia (32–34), it contrasts with the recent work of Moosavi and colleagues (5). These investigators demonstrated sensations of "air hunger" during 20 min of isocapnic hypoxia in healthy individuals when ventilation was constrained using a mechanical ventilator (5). Visual analog scores of air hunger assessed at 30-s intervals were found to remain proportional to ventilatory drive (measured on another occasion during unrestrained breathing) throughout hypoxic ventilatory rolloff. Thus, although sustained hypoxia caused ventilatory depression, presumably due to hypoxia-induced central nervous system inhibitory effects (35), this was not reflected in a disproportionate depression of "air hunger." While the reasons for these seemingly disparate results are unclear, we speculate that it may relate to different susceptibilities of various respiratory afferent pathways to hypoxia. Sensations of "air hunger" are likely mediated by a mismatch between respiratory afferent and efferent signals, perhaps reflecting corollary discharge from the respiratory pattern generator itself (36, 37). Corollary discharge neural pathways may remain relatively intact during hypoxia, potentially serving as a last line of defense during asphyxial insults. Other respiratory sensations, such as load perception mediated by different afferent pathways (e.g., airway, lung, or chest wall receptors), may be more vulnerable to suppression by hypoxia.

Respiratory Afferent Neural Transmission and Respiratory Load Perception
Dyspnea and the perception of increased respiratory load are highly integrated neural responses arising from the stimulation of a variety of respiratory sensory receptors. Upon presentation of an external resistive load to breathing, as in this study, breathing effort is reflexively augmented to compensate, respiratory muscle tension increases, and more negative inspiratory pressures are generated in the pleural space and airways. Together these changes have the potential to stimulate upper airway mechanoreceptors and a variety of respiratory pump receptors (1, 38). Activated respiratory sensory receptors relay electrical impulses via various myelinated and unmyelinated afferents (including the vagus, phrenic, hypoglossal, and laryngeal nerves) to the central nervous system. While direct cortical projections may exist, numerous brain stem structures likely receive impulses from many of these primary sensory afferents, including structures such as the nucleus tractus solitarius (NTS). Activated brainstem structures project to the primary somotosensory cortex, either directly or via the thalamus (39). The higher center processing of summated afferent information relative to motor output and previous experience is believed to underlie what subjects cognitively perceive as "increased load."

Potential Mechanisms for Hypoxia-induced Suppression of Respiratory Afferent Transmission and Load Perception
There are two main possible explanations for our findings. In response to an acute sustained reduction in oxygen availability, there is a central accumulation of neuroinhibitory modulators including adenosine, {gamma}-aminobutyric acid (GABA), and endogenous opioids (40). The presence of these modulators may act to suppress respiratory sensory synaptic transmission and therefore decrease awareness of intensifying respiratory load. An alternate explanation is that acute hypoxia actively triggers a "central inhibitory network" within the midbrain and brain stem. This mechanism has recently been proposed to contribute to hypoxic ventilatory depression (35). In the same way that specific neuronal networks may inhibit ventilatory motor output, they could potentially inhibit respiratory sensory afferent pathways and contribute to impaired sensations of respiratory load.

A reduction in P1 amplitude during hypoxia suggests that there is a reduction in neural transmission of respiratory afferent information to the cortex. Should inhibitory neuromodulators accumulate widely throughout the nervous system in response to sustained hypoxia, respiratory sensory depression could occur at multiple levels. Primary muscle spindle function has been shown to be impaired during hypoxia in cats (41). In addition, the dorsal central column of primary afferent fibers within the spinal cord appears susceptible to the inhibitory effects of hypoxia in rats (42). Thus, sensory information processing could be impaired as low in the neurosensory axis as the level of the primary receptor.

However, the CNS is known to exhibit a rostral to caudal vulnerability to hypoxia, and rostral structures may be more prominent in mediating these effects. Neurons within the pons and thalamus, which may be actively recruited as part of a "hypoxic-induced inhibitory network," may be involved (35). Indeed, various hypoxic sensitive neurons may actively inhibit caudal sensory projections at one or at multiple levels. The NTS in the medulla also appears to be sensitive to the effects of hypoxia and may play an important role (43, 44). GABA, which appears in part to mediate hypoxic respiratory depression, is augmented within the NTS during sustained hypoxia (43). The NTS receives afferent fibers from the vagus and glossopharyngeal nerves by way of the tractus solitarius, and the caudal two-thirds of the nucleus processes afferent neural activity originating in the pharynx and larynx (39). GABA and potentially other neuroinhibitory modulators and transmitters within the NTS may not only suppress respiratory motor output but also a wide range of respiratory afferent pathways projecting to this nucleus. Axons from the NTS project to the thalamus (39), which acts as a relay station to direct sensory traffic for a variety of sensory stimuli to higher centers (primary somatosensory cortex). During sustained hypoxia, increased thalamic gating may decrease respiratory sensory projections to higher centers. In support of this hypothesis, the red nucleus within the midbrain, recently identified as an anatomic location activated during inspiratory resistive loading (45), is highly sensitive to hypoxic inhibition (35).

The functional significance and neural genesis of the second positive (P2) peak of the RREP remains poorly understood (46). The latency and preservation of the P2 peak in both stimulus attend and ignore conditions suggest that it reflects a combination of exogenous and endogenous processes. Earlier work in nonrespiratory sensory modalities incorporated the P2 as part of an N1–P2 complex. However, this approach has recently been challenged in a review on the subject by Crowley and Colrain (46). These authors suggest that P2 has an independent sensory role, and highlight the need for future studies to elucidate its genesis and functional significance. Given the current level of understanding, interpretation of the P2 findings in this study must be treated with caution. While there were no between gas differences in N1–P2 amplitude, hypoxia-induced decreases in P2 amplitude in the current study may be indicative of suppression of early perceptual processing.

It was somewhat unexpected that P3 amplitude was not also depressed in the current study. While it is possible that the later processing components of respiratory sensory information are not affected by hypoxia, several other methodologic factors may explain this finding (see below).

Methodologic Considerations
In this study subjects were required to voluntarily target their ventilation. While this was essential to match respiratory stimuli between gas conditions it unavoidably introduced differences in volitional versus chemoreceptor drive. Even though these differences were minimal, particularly after the first five minutes when hypoxic ventilatory drive declines, behavioral and attention dependent responses such as P3 may have been affected. While these differences do not likely affect earlier exogenous components (16), later components (such as P3 during the target ventilation arm of this study) should be treated with caution.

During the RREP arm of this study, subjects were asked to attend to and mentally count the number of pulses presented to facilitate P3 responses. P3 amplitude appears to be a sensory threshold–dependent phenomenon. In the current study, RREP stimuli were well in excess of sensory threshold and were easily discernable with little attention. Had subjects been presented with a range of resistive load magnitudes during the RREP protocol and been asked to differentiate load magnitude between presentations, gas-related differences in P3 may have been detected. Hypoxic-induced P3 amplitude reductions and increased P3 latency in nonrespiratory sensory modalities (hearing and vision) support this hypothesis (47, 48). These experiments did not incur the need to volitionally match stimuli between gas conditions as in this experiment.

In this study we did not observe statistically significant deficits in external load perception or reductions in RREP responses in the posthypoxia period. In contrast, in a previous study we found reductions in symptoms of bronchoconstriction in individuals with asthma in the 10-min posthypoxia period (10). There was, however, a tendency for reduced load magnitude perception and to a lesser extend P1 and P2 amplitudes to be decreased posthypoxia in the current study. Given the longer recovery time frame necessary to collect sufficient trials for meaningful RREP analysis combined with uncertainty regarding the time-course of recovery from hypoxic effects, it is possible that shorter-term posthypoxia effects were missed due to type {Pi} error combined with averaging effects over a longer recovery time.

Alternatively, while bronchoconstriction and external resistive loading may share some common mechanisms, there may be important differences in afferent stimulation with differing susceptibilities to hypoxia. Finally, individuals with asthma show respiratory sensory processing deficits (22), which may render them more susceptible to hypoxia-induced sensory impairment.

While we hypothesize that the deficits in early RREP components and load perception during hypoxia are caused by suppression of respiratory sensory pathways, it is possible that hypoxia may have altered respiratory mechanics and the nature of the respiratory stimulus during brief respiratory loads. However, we believe that this is an unlikely explanation of our findings. The level of hypoxia administered in our experiments appears unlikely to alter respiratory mechanics (i.e., airway caliber or respiratory function) (49, 50), and certainly we did not find differences in the magnitude or pattern of inspiratory mouth pressure generated during brief resistive loads.

Clinical Implications and Summary
In summary, the main findings of this study were that acute sustained hypoxia reduced P1 and P2 amplitudes of the RREP and decreased the sensation of respiratory loading. Mechanistically, in addition to a potential role for impaired cognitive processing, the reduced amplitude of P1 in the RREP suggests that primary respiratory afferent neural transmission may be impaired by hypoxia.

Should hypoxia disrupt respiratory afferent neural transmission (and/or higher cortical processing) in hypoxic respiratory disease, as the findings in this study suggest, several vital protective respiratory responses could potentially be adversely affected. These might include arousal and neuromuscular compensation to increased respiratory load during sleep and important reflexes such as cough. We recently found, for example, that hypoxia caused an increase in arousal threshold in sleep to inspiratory resistive loads (51). Hypoxia-induced depression of respiratory load sensation could lead to treatment delays and adverse outcomes in conditions such as acute exacerbations of chronic lung disease and acute life-threatening asthma.


   Acknowledgments
 
The authors are grateful to David Schembri and the Respiratory Function Laboratory staff, Repatriation General Hospital, Daw Park, South Australia for the use of their facilities for lung function measurements. They also thank Dr. Neubauer for her helpful feedback on the manuscript.


   FOOTNOTES
 
Supported by the National Health and Medical Research Council of Australia.

Correspondence and requests for reprints should be addressed to Danny Eckert, B.Sc. (Hons), Adelaide Institute for Sleep Health, Repatriation General Hospital, Daw Park South Australia, Australia, 5041. E-mail: danny.eckert{at}rgh.sa.gov.au

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form May 4, 2005; accepted in final form June 17, 2005


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. American Thoracic Society. Dyspnea: mechanisms, assessment, and management: a consensus statement. Am J Respir Crit Care Med 1999;159:321–340.[Free Full Text]
  2. Berry RB, Gleeson K. Respiratory arousal from sleep: mechanisms and significance. Sleep 1997;20:654–675.[Medline]
  3. Webster KE, Colrain IM. Multichannel EEG analysis of respiratory evoked-potential components during wakefulness and NREM sleep. J Appl Physiol 1998;85:1727–1735.[Abstract/Free Full Text]
  4. Wheatley JR, White DP. Influence of NREM sleep on respiratory-related cortical evoked potentials in normal humans. J Appl Physiol 1993;74:1803–1810.[Abstract/Free Full Text]
  5. Moosavi SH, Golestanian E, Binks AP, Lansing RW, Brown R, Banzett RB. Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans. J Appl Physiol 2003;94:141–154.[Abstract/Free Full Text]
  6. Berry DT, McConnell JW, Phillips BA, Carswell CM, Lamb DG, Prine BC. Isocapnic hypoxemia and neuropsychological functioning. J Clin Exp Neuropsychol 1989;11:241–251.[Medline]
  7. Fowler B, Lindeis AE. The effects of hypoxia on auditory reaction time and P300 latency. Aviat Space Environ Med 1992;63:976–981.[Medline]
  8. Fowler B, Kelso B. The effects of hypoxia on components of the human event-related potential and relationship to reaction time. Aviat Space Environ Med 1992;63:510–516.[Medline]
  9. Orr RS, Jordan AS, Catcheside P, Saunders NA, McEvoy RD. Sustained isocapnic hypoxia suppresses the perception of the magnitude of inspiratory resistive loads. J Appl Physiol 2000;89:47–55.[Abstract/Free Full Text]
  10. Eckert DJ, Catcheside PG, Smith JH, Frith PA, McEvoy RD. Hypoxia suppresses symptom perception in asthma. Am J Respir Crit Care Med 2004;169:1224–1230.[Abstract/Free Full Text]
  11. Webster KE, Colrain IM. The relationship between respiratory-related evoked potentials and the perception of inspiratory resistive loads. Psychophysiology 2000;37:831–841.[CrossRef][Medline]
  12. Daubenspeck JA, Manning HL, Baird JC. Midlatency respiratory-related somatosensory activity and perception of oral pressure pulses in normal humans. J Appl Physiol 2001;90:2048–2056.[Abstract/Free Full Text]
  13. Knafelc M, Davenport PW. Relationship between resistive loads and P1 peak of respiratory-related evoked potential. J Appl Physiol 1997;83:918–926.[Abstract/Free Full Text]
  14. Davenport PW, Friedman WA, Thompson FJ, Franzen O. Respiratory-related cortical potentials evoked by inspiratory occlusion in humans. J Appl Physiol 1986;60:1843–1848.[Abstract/Free Full Text]
  15. Gora J, Trinder J, Pierce R, Colrain IM. Evidence of a sleep-specific blunted cortical response to inspiratory occlusions in mild obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002;166:1225–1234.[Abstract/Free Full Text]
  16. Webster KE, Colrain IM. The respiratory-related evoked potential: effects of attention and occlusion duration. Psychophysiology 2000;37:310–318.[CrossRef][Medline]
  17. Bloch-Salisbury E, Harver A, Squires NK. Event-related potentials to inspiratory flow-resistive loads in young adults: stimulus magnitude effects. Biol Psychol 1998;49:165–186.[CrossRef][Medline]
  18. Knafelc M, Davenport PW. Relationship between magnitude estimation of resistive loads, inspiratory pressures, and the RREP P(1) peak. J Appl Physiol 1999;87:516–522.[Abstract/Free Full Text]
  19. Afifi L, Guilleminault C, Colrain IM. Sleep and respiratory stimulus specific dampening of cortical responsiveness in OSAS. Respir Physiol Neurobiol 2003;136:221–234.
  20. Akay M, Leiter JC, Daubenspeck JA. Reduced respiratory-related evoked activity in subjects with obstructive sleep apnea syndrome. J Appl Physiol 2003;94:429–438.[Abstract/Free Full Text]
  21. Davenport PW, Cruz M, Stecenko AA, Kifle Y. Respiratory-related evoked potentials in children with life-threatening asthma. Am J Respir Crit Care Med 2000;161:1830–1835.[Abstract/Free Full Text]
  22. Webster KE, Colrain IM. P3-specific amplitude reductions to respiratory and auditory stimuli in subjects with asthma. Am J Respir Crit Care Med 2002;166:47–52.[Abstract/Free Full Text]
  23. Eckert DJ, Catcheside PG, McDonald R, Adams AM, Hlavac MC, Webster KE, McEvoy RD. Amplitude reductions in early RREP components and blunted perception of respiratory load with hypoxia [abstract]. Proc Am Thorac Soc 2005;2:A63.
  24. Eckert DJ, Catcheside PG, McDonald R, Adams AM, Hlavac MC, Webster KE, McEvoy RD. Decreased amplitude in early respiratory related evoked potential components and impaired perception of respiratory load with hypoxia [abstract]. Respirology 2005;10:A18.
  25. Eckert DJ, Catcheside PG, McDonald R, Adams AM, Webster KE, Hlavac MC, McEvoy RD. Evoked potential differences and blunted perception to respiratory stimuli with hypoxia [abstract]. Intern Med J 2005;35:A21.[CrossRef]
  26. Killian KJ, Mahutte CK, Campbell EJ. Magnitude scaling of externally added loads to breathing. Am Rev Respir Dis 1981;123:12–15.[Medline]
  27. Easton PA, Slykerman LJ, Anthonisen NR. Recovery of the ventilatory response to hypoxia in normal adults. J Appl Physiol 1988;64:521–528.[Abstract/Free Full Text]
  28. Ludbrook J. On making multiple comparisons in clinical and experimental pharmacology and physiology. Clin Exp Pharmacol Physiol 1991;18:379–392.[Medline]
  29. Bijl-Hofland ID, Cloosterman SG, Folgering HT, Akkermans RP, van den Hoogen H, van Schayck CP. Measuring breathlessness during histamine challenge: a simple standardized procedure in asthmatic patients. Eur Respir J 1999;13:955–960.[Abstract]
  30. Johnson KO. Neural coding. Neuron 2000;26:563–566.[CrossRef][Medline]
  31. Johnson KO, Hsiao SS, Yoshioka T. Neural coding and the basic law of psychophysics. Neuroscientist 2002;8:111–121.[Abstract/Free Full Text]
  32. Masuda A, Ohyabu Y, Kobayashi T, Yoshino C, Sakakibara Y, Komatsu T, Honda Y. Lack of positive interaction between CO2 and hypoxic stimulation for P(CO2)-VAS response slope in humans. Respir Physiol 2001;126:173–181.[CrossRef][Medline]
  33. Chonan T, Okabe S, Hida W, Satoh M, Kikuchi Y, Takishima T, Shirato K. Influence of sustained hypoxia on the sensation of dyspnea. Jpn J Physiol 1998;48:291–295.[CrossRef][Medline]
  34. Lane R, Adams L, Guz A. The effects of hypoxia and hypercapnia on perceived breathlessness during exercise in humans. J Physiol 1990;428:579–593.[Abstract/Free Full Text]
  35. Neubauer JA, Sunderram J. Oxygen-sensing neurons in the central nervous system. J Appl Physiol 2004;96:367–374.[Abstract/Free Full Text]
  36. McCloskey DI. Corollary discharges: motor commands and perception. In: Brookhart JM, Mountcastle VB, editors. Section 1: the Nervous System. Vol. 2. Part 2 of Handbook of physiology. Bethesda, MD: American Physiological Society; 1981. pp. 1415–1447.
  37. Banzett RB, Lansing RW, Reid MB, Adams L, Brown R. ‘Air hunger’ arising from increased PCO2 in mechanically ventilated quadriplegics. Respir Physiol 1989;76:53–67.[CrossRef][Medline]
  38. Manning HL, Schwartzstein RM. Pathophysiology of dyspnea. N Engl J Med 1995;333:1547–1553.[Free Full Text]
  39. Nervous System. In: Williams PL, editor. Gray's Anatomy: the anatomical basis of medicine and surgery, 38th ed. New York: Churchill Livingstone; 1995. pp. 1017–1079.
  40. Neubauer JA, Melton JE, Edelman NH. Modulation of respiration during brain hypoxia. J Appl Physiol 1990;68:441–451.[Abstract/Free Full Text]
  41. Zimmerman GW, Grossie J. Sensitivity and behavior of muscle spindles to systemic arterial hypoxia. Proc Soc Exp Biol Med 1969;132:1114–1118.[CrossRef][Medline]
  42. Utzschneider DA, Kocsis JD, Waxman SG. Differential sensitivity to hypoxia of the peripheral versus central trajectory of primary afferent axons. Brain Res 1991;551:136–141.[CrossRef][Medline]
  43. Tabata M, Kurosawa H, Kikuchi Y, Hida W, Ogawa H, Okabe S, Tun Y, Hattori T, Shirato K. Role of GABA within the nucleus tractus solitarii in the hypoxic ventilatory decline of awake rats. Am J Physiol Regul Integr Comp Physiol 2001;281:R1411–R1419.[Abstract/Free Full Text]
  44. Gozal D, Simakajornboon N, Czapla MA, Xue YD, Gozal E, Vlasic V, Lasky JA, Liu JY. Brainstem activation of platelet-derived growth factor-beta receptor modulates the late phase of the hypoxic ventilatory response. J Neurochem 2000;74:310–319.[CrossRef][Medline]
  45. Isaev G, Murphy K, Guz A, Adams L. Areas of the brain concerned with ventilatory load compensation in awake man. J Physiol 2002;539:935–945.[Abstract/Free Full Text]
  46. Crowley KE, Colrain IM. A review of the evidence for P2 being an independent component process: age, sleep and modality. Clin Neurophysiol 2004;115:732–744.[CrossRef][Medline]
  47. Fowler B, Prlic H. A comparison of visual and auditory reaction time and P300 latency thresholds to acute hypoxia. Aviat Space Environ Med 1995;66:645–650.[Medline]
  48. Wesensten NJ, Crowley J, Balkin T, Kamimori G, Iwanyk E, Pearson N, Devine J, Belenky G, Cymerman A. Effects of simulated high altitude exposure on long-latency event-related brain potentials and performance. Aviat Space Environ Med 1993;64:30–36.[Medline]
  49. Saunders NA, Betts MF, Pengelly LD, Rebuck AS. Changes in lung mechanics induced by acute isocapnic hypoxia. J Appl Physiol 1977;42:413–419.[Abstract/Free Full Text]
  50. Goldstein RS, Zamel N, Rebuck AS. Absence of effects of hypoxia on small airway function in humans. J Appl Physiol 1979;47:251–256.[Abstract/Free Full Text]
  51. Hlavac MC, Catcheside PG, McDonald R, Eckert DJ, Windler S, McEvoy RD. The effects of sustained hypoxia on the arousal response to external resistive loading and airway occlusion [abstract]. Intern Med J 2005;35:A21.



This article has been cited by other articles:


Home page
 J. Appl. Physiol.Home page
D. J. Eckert, R. D. McEvoy, K. E. George, K. J. Thomson, and P. G. Catcheside
Effects of hypoxia on genioglossus and scalene reflex responses to brief pulses of negative upper-airway pressure during wakefulness and sleep in healthy men
J Appl Physiol, May 1, 2008; 104(5): 1426 - 1435.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
M. Hallani, J. R. Wheatley, and T. C. Amis
Initiating oral breathing in response to nasal loading: asthmatics versus healthy subjects
Eur. Respir. J., April 1, 2008; 31(4): 800 - 806.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
M. C. Hlavac, P. G. Catcheside, A. Adams, D. J. Eckert, and R. D. McEvoy
The effects of hypoxia on load compensation during sustained incremental resistive loading in patients with obstructive sleep apnea
J Appl Physiol, July 1, 2007; 103(1): 234 - 239.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
D. E. O'Donnell, R. B. Banzett, V. Carrieri-Kohlman, R. Casaburi, P. W. Davenport, S. C. Gandevia, A. F. Gelb, D. A. Mahler, and K. A. Webb
Pathophysiology of Dyspnea in Chronic Obstructive Pulmonary Disease: A Roundtable
Proceedings of the ATS, May 1, 2007; 4(2): 145 - 168.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
D. J. Eckert, A. S. Jordan, P. Merchia, and A. Malhotra
Central Sleep Apnea: Pathophysiology and Treatment
Chest, February 1, 2007; 131(2): 595 - 607.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
R. L. Horner and T. D. Bradley
Update in sleep and control of ventilation 2005.
Am. J. Respir. Crit. Care Med., April 15, 2006; 173(8): 827 - 832.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. J. Eckert, P. G. Catcheside, D. L. Stadler, R. McDonald, M. C. Hlavac, and R. D. McEvoy
Acute Sustained Hypoxia Suppresses the Cough Reflex in Healthy Subjects
Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 506 - 511.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200505-699OCv1
172/8/1047    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Eckert, D. J.
Right arrow Articles by McEvoy, R. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eckert, D. J.
Right arrow Articles by McEvoy, R. D.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2005 American Thoracic Society