Repeated experiences of air hunger and ventilatory behavior in response to hypercapnia in the standardized rebreathing test: Effects of anxiety
Introduction
Dyspnea or breathlessness is a subjective experience of respiratory discomfort, which occurs as a result of a mismatch between actual ventilation and ventilation required to satisfy the metabolic needs. It is a common symptom, not only in cardiopulmonary and neuromuscular diseases but also in anxiety, panic, and psychosomatic disorders. It occurs in healthy subjects as well during intense emotional states and heavy labor or exercise (American Thoracic Society, 1999). One particular aspect of dyspnea, air hunger (AH), feels like an “unpleasant urge to breathe”. It is similar to the perception at the end of a long breath hold (Banzett et al., 1996) and it is particularly sensitive to increased levels of PCO2 in the blood. AH arises from both the projection of afferent information from the central and peripheral chemoreceptors and from corollary discharge of the brain stem respiratory motor drive to the cortical areas involved in interoception (Manning et al., 1992, Moosavi et al., 2004). In addition, AH may be shaped by past experience, expectations and emotional states (American Thoracic Society, 1999).
Evidence suggests an intricate relationship between anxiety, breathing and dyspnea. Dyspnea is more likely in psychiatric disorders and in persons with a high level of anxiety or negative affectivity (NA) without identifiable physical pathology (Howell, 1990, Papp et al., 1993, Han et al., 1998). For example, AH is often experienced during panic attacks in panic disorder patients without cardiopulmonary diseases (American Thoracic Society, 1999), although some respiratory abnormalities have been documented in panic disorder patients (Abelson et al., 2001). Conversely, the prevalence of anxiety disorders is elevated in pulmonary diseases (Van Peski-Oosterbaan et al., 1996) and asthma has been shown to be a predictor for the development of panic in a longitudinal study (Carr, 1998). The relationship between anxiety, breathing and dyspnea is poorly understood. In addition, in most cases such as in asthma and panic, episodes of dyspnea occur repeatedly, but the effects of repeated experiences upon subsequent perceived dyspnea, breathing behavior and their relationship have not been systematically investigated. In the present study, we aim to investigate the effects of repeated episodes of on subsequent perceived dyspnea, breathing behavior and their association in high and low trait anxious persons.
When stimuli are administered repeatedly, habituation or sensitization is often observed in various response systems. Habituation refers to a decrease in response amplitude across repeated experiences that cannot be attributed to sensory adaptation, whereas sensitization refers to an increase in the response amplitude across trials. Habituation has been shown in CO2 chemosensitivity after repeated exercise trainings (McMahon et al., 2002, Tomita et al., 2003). Exercise training also reduced dyspnea and anxiety in patients with chronic obstructive pulmonary disease (Carrieri-Kohlman et al., 1996, Gigliotti et al., 2003). Sensitization is more likely to occur when the stimulus is unpredictable, aversive and in high trait anxious persons (Bradley et al., 1996, Figueiredo et al., 2003). However, only a few studies have addressed this issue. Sensitization of fear has not been systematically found during repeated episodes of dyspnea (Beck and Shipherd, 1997, Beck et al., 1999, Forsyth et al., 2000), but neither dyspnea itself, nor breathing behavior and their association was extensively measured. Because respiratory behavior is sensitive to anticipation and feedforward regulation (Somjen et al., 1992, Van den Bergh et al., 1995, Gallego et al., 1996, Gallego et al., 2001), it is not clear whether habituation or sensitization in perceived dyspnea across repeated episodes depends on changes in breathing responses.
In a previous study (Wan et al., 2006), we applied the modified rebreathing test (MRT) three times (15-min intertrial interval, ITI) in a group of low and high trait anxious participants and we assessed both respiratory behavior and perceived AH continuously. In the MRT, participants first hyperventilated to lower the carbon dioxide stores in the body. Next, they rebreathed into a large bag filled with 95% O2 and 5% CO2 until the fractional end-tidal concentration of CO2 (FetCO2) reached 7.9% or perceived AH was rated intolerable. Across trials, the CO2 threshold (the level at which the response to increasing CO2 starts) for both perceived AH and the respiratory response increased. However, once past the threshold, the sensitivity of the AH response (the rate of increase with increasing CO2) habituated in low anxious persons and tended to sensitize in high anxious ones. This means that a dissociation between the sensitivity of subjective and respiratory responses occurred: anxiety moderated perceived AH sensitivity, but not sensitivity of respiratory behavior. These findings were the first to show the effects of repetition on the thresholds for subjective and respiratory responses to CO2. Also another intriguing finding emerged: the CO2 threshold for perceived AH was consistently lower than for respiratory behavior.
These findings may have particular relevance for both physiological studies on chemosensitivity and for studies investigating respiration in panic disorder. In this patient group, CO2 hypersensitivity of the brain stem areas has been assumed to trigger a “suffocation alarm” (Gorman et al., 1989, Klein, 1993). Carr et al. (1987) and Lousberg et al. (1988) reported higher CO2 sensitivity in panic patients than controls in Read's rebreathing test. However, no difference in CO2 sensitivity in panic disorder patients compared to healthy controls was found in other studies (Papp et al., 1995, Katzman et al., 2002, Rassovsky et al., 2006). In contrast, sensitization of the sensitivity to perceived AH in high anxious persons may help to explain respiratory abnormalities in panic disorder.
In order to corroborate and extend our findings, we replicated our study and added several improvements in order to make a more fine-grained analysis of the effects of repeated AH. First, we used the standardized rebreathing test (SRT) instead of the MRT, the difference being a hyperventilation (HV) phase inserted in the latter test prior to each rebreathing trial. HV is useful to lower the body stores of carbon dioxide, which may contribute to a more accurate measurement of the chemoreceptor threshold. However, HV may impact upon the perceived AH sensation differently in high and low anxious persons. In the present study, no prior HV was applied, leaving the perceived AH sensation unbiased by a preceding hypocapnic respiratory challenge. Secondly, in the previous study AH ratings were prompted by a tone every 12 s. In this study, participants were instructed to indicate the very first sensation of AH and, subsequently, to rate their AH each time they felt a change of the sensation. Studies comparing continuous and discrete (prompted) measurement of breathlessness during exercise have demonstrated that both approaches had high reliability (Mahler et al., 2001, Fierro-Carrion et al., 2004). The continuous rating was employed in the present study in order to yield a better threshold rating. Thirdly, in the previous study threshold determination of the curves representing ventilatory behavior or AH plotted against end-tidal fractional concentration of CO2 (FetCO2) was based on Piecewise Linear Regression software (Statistica 6.0), which may be more conservative than the more widely used Sigmaplot 9.0, STAT software (Duffin et al., 2000, Mateika et al., 2004). Although no study provides evidence to prefer one over the other, we opted for the more widely used method in order to allow comparisons with other studies. Fourthly, in the present study, AH ratings were plotted both against FetCO2 and time in order to compare the relative thresholds of both response channels (subjective and respiratory). Finally, we explored the association between AH perception and respiratory behavior in more detail. Other research from our group (Bogaerts et al., 2005, Van den Bergh et al., 2004) has repeatedly demonstrated more dissociation between respiratory behavior and respiratory sensations in high compared to low anxious persons, especially in a distressing context.
Across trials, we expected to (1) replicate the finding that perceived AH precedes the ventilatory response to increasing CO2; (2) replicate habituation of the threshold for both the perceived AH and the ventilatory response; (3) replicate the moderating effect of trait anxiety on the sensitivity (rate of increase) of the perceived AH across trials (i.e. habituation in low and sensitization in high anxious participants); (4) find a lower correlation between AH and respiratory behavior in high anxious than in low anxious persons.
Section snippets
Participants
Thirty-one healthy women, all undergraduate psychology students, of age 18–23 years, participated in return for course credit or 6€. The participants were selected from a large pool of students (N = 288) who had completed the STAI-T questionnaire (see further) a few weeks before the experiment. Sixteen women scored in the lower quartile of the STAI-T (the low trait anxiety group, LTA) and fifteen women scored in the upper quartile (the high trait anxiety group, HTA). Because men and women have
Maximal CO2 stimulus and AH rating
The maximal AH rating (AHmax) during the rebreathing period was recorded, together with the maximal FetCO2 (maximal CO2 stimulus). Because the maximal rating was always rated by participants at the end of each rebreathing period, FetCO2max was also the maximal CO2 stimulus participants received in each trial.
AH response
An AH rating of 5 was defined by instruction as the just noticeable level (“absolute threshold”) (Shea et al., 1995). Therefore, when a trial started the time at which participants rated 5
Statistical analysis
Four response characteristics (threshold, maximum, slope (B) and Beta coefficient) were calculated for each of the test responses (AH, VT and RR). The threshold for the test responses was determined in two ways: (1) in plots of the variable with time on the X-axis (time-based) and (2) in plots with FetCO2 on the X-axis (CO2-based). Besides state anxiety (SA) and fatigue (F) in each trial, 15 response characteristics were generated: time threshold, the relevant CO2 and slope values for AH, VT
Anxiety and fatigue
The HTA group had higher trait anxiety than the LTA group (t(29) = 11.57, p < 0.01; 45.80 ± 5.60 in the HTA vs. 28.75 ± 1.81 in the LTA group). SA was high in both groups during each trial (mean ± S.D. was, respectively for the subsequent trials, 5.27 ± 1.03, 5.93 ± 0.88, 6.00 ± 1.25 in the HTA group and 5.38 ± 0.96, 5.19 ± 1.17, 5.38 ± 1.26 in LTA group). SA increased across trials in the HTA group, but did not change in the LTA group (interaction of trial by group: F (2, 58) = 3.69, p < 0.05, є = 0.80; f2 = 0.13).
Fatigue
Discussion
In the present study, CO2-induced AH and ventilatory behavior were assessed continuously and simultaneously in three consecutive trials with the standardized rebreathing test (SRT), administered to high and low trait anxious young women. Compared to the modified rebreathing test (MRT; Wan et al., 2006), the SRT does not include a voluntary hyperventilation phase prior to a rebreathing trial. Such phase may have both influenced subsequent breathing behavior and primed interoceptive attention
Conclusion
The standardized rebreathing test was used to investigate the dynamic changes of AH and ventilatory responses to repeated hypercapnia. AH was always triggered before an increase in ventilation was observed. Furthermore, participants reported lower maximal AH while they endured higher maximal CO2 levels during repeated exposures to hypercapnia. Also the sensitivity of the AH response habituated and shifts in the dynamics of the breathing response occurred: the thresholds for AH and VT moved
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