Fearful responding to repeated CO2 inhalation: A preliminary investigation

Pergamon S0005-7967(96)00039-3

Behav. Res. Ther. Vol. 34, No. 8, pp. 609-620, 1996 Copyright © 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0005-7967/96 $15.00 + 0.00

FEARFUL RESPONDING TO REPEATED CO2 INHALATION: A PRELIMINARY INVESTIGATION J. GAYLE BECK, JILLIAN C. SHIPHERD and BARBARA J. ZEBB* Department of Psychology, State University of New York at Buffalo, 230 Park Hall, Buffalo, NY 14260, U.S.A. (Received I May 1996)

Summary--ln an effort to explore factors which maintain fear of physical sensations, repeated administration of 35% CO, was used with college students scoring high and low on the Anxiety Sensitivity Index. Half of each group was administered 12 CO2 trials, while the other half received 9 CO, trials, followed by a dishabituation trial (Trial 10) and 2 more CO2 administrations (Trials 11 and 12). Measures included subjective anxiety, heart rate, skin conductance, and number of panic symptoms reported. Results indicated a nonsignificant trend for the High AS1 group to show increased pre-inhalation anxiety across trials, while the Low ASI group showed a rapid reduction in pre-inhalation anxiety. Post-inhalation skin conductance mirrored this pattern, although rapid reduction in post-inhalation heart rate was observed. Overall, the High ASI participants showed a notable lack of fear reduction across trials. Results are discussed in light of sensitization as a factor contributing to anticipatory anxiety, with implications for understanding the etiology and maintenance of Panic Disorder. Copyright © 1996 Elsevier Science Ltd

INTRODUCTION The use of biological challenge procedures to examine the psychopathology of Panic Disorder (PD) is well-established (e.g. Nutt & Lawson, 1992; McNally, 1994; Shear, 1986). Across a variety of paradigms including infusions of sodium lactate, hyperventilation, and inhalation of 35% CO2 (e.g. Cowley & Arana, 1990; Papp, Klein, Martinez, Schneier, Cole, Liebowtz, Hollander, Fyer, Jordan & Gorman, 1993; Rapee, Brown, Antony & Barlow, 1992), PD patients have been shown to respond to challenge with more intense physical symptoms, heightened physiological response, and increased anxiety and panic, relative to patients with other anxiety disorders and normal control participants. At present, a variety of theoretical explanations exist to explain panicogenic response to challenge. These include biological accounts which emphasize physiological dysregulation (e.g. Klein, 1993), psychological theories which highlight the role of emotional hypersensitivity to bodily sensations (e.g. Clark, 1986), and models which postulate an interaction of these factors (e.g. Barlow, 1988). Although numerous challenge studies have been reported, clarity is lacking concerning the origins of anxious responding to biological challenge in PD patients. In an effort to more clearly delineate psychological factors in response to biological challenge, investigators have studied normal participants who endorse beliefs that anxiety symptoms have harmful consequences. The logic behind these studies is that individuals who report fear of anxiety symptoms (termed high anxiety sensitivity; Reiss & McNally, 1985) will respond in an emotionally hypersensitive fashion to biological challenge, much as PD patients do. Although not without controversy (Lilienfeld, Turner & Jacob, 1993), anxiety sensitivity has been extensively studied, with suggestion that this dispositional variable may be a critical predictor of response to challenge (for a review of this literature, see McNally, 1994, pp. 115-119). The standard paradigm involves a single-trial challenge, such as a brief interval of hyperventilation or one inhalation of 35% CO2 (e.g. Rapee & Medoro, 1994; Donnell & McNally, 1989; Holloway & McNally, 1987) delivered to individuals scoring high and low on the Anxiety Sensitivity Index (ASI: Reiss, Peterson, Gursky & McNally, 1986), a measure of anxiety sensitivity. Across studies, results indicate that individuals scoring high on the ASI respond more anxiously to challenge than low ASI participants. These *Now at Department of Behavioral Medicine and Psychiatry, West Virginia University.

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results are obtained even when participants have never had a panic attack (Asmundson, Norton, Wilson & Sandler, 1994; Donnell & McNally, 1989). Taken together, these studies suggest that anxiety sensitivity may be an important mediator of panicogenic response to biological challenge, at least in normal participants. Although most challenge studies have used single-trial administration procedures, these paradigms have been expanded to examine related facets of anxious responding to physical sensations. For example, Forsyth, Eifert and Thompson (1995) used 20% CO2 administration in a study of selective fear conditioning in college students. In this context, CO2-produced sensations were conceptualized as the UCS in fear conditioning, reflecting the alarm response which has been hypothesized to play a key role in phobia acquisition (Barlow, 1988). Similarly, repeated challenge administration can assist in understanding processes which maintain or reduce fear by permitting study of fear over time. Thus, repeated presentation of CO2 can serve as a laboratory analogue for the repeated occurrence of panic sensations. Given that PD patients show persistent fear of panic sensations, this type of paradigm allows investigation of those factors which explain continued fear. Additionally, repeated administration of challenge can illuminate factors which are relevant in the etiology of PD, specifically those factors which contribute to the sensitization of fear of physical sensations in individuals at risk for PD. In many respects, repeated challenge presentation mirrors the experimental paradigms which are used to examine habituation and sensitization effects in animals and human participants (e.g. Fantino & Logan, 1979; Mackintosh, 1987). As such, this literature can provide both conceptual and methodological guidance in designing studies involving repeated challenge presentation, as will be discussed. To date, there have been only two studies examining the course of fear during repeated biological challenge in PD patients (van den Hout, van der Molen, Griez, Lousberg & Nansen, 1987; Griez & van den Hout, 1986). These paradigms exposed PD patients to 6-9 sessions of multiple 35% CO2 inhalations, resulting in significant reductions in anxiety and panic both within- and between-sessions. These reports focused on the efficacy of repeated exposure to CO2 as a treatment intervention, leaving unanswered questions concerning the natural course of fear during exposure to panic-related sensations. In a similar vein, a current cognitive-behavioral treatment for PD [termed Panic Control Treatment (PCT)] incorporates deliberate exposure to physical sensations (interoceptive exposure) as an intervention (e.g. Barlow, Craske, Cerny & Klosko, 1989; Telch, Lucas, Schmidt, Hanna, Jaimez & Lucas, 1993). Across efficacy studies, interoceptive exposure appears important to treatment success (Beck & Zebb, 1994), with reduced effectiveness when this component is deliberately omitted (Beck, Stanley, Baldwin, Deagle & Averill, 1994; Barlow et al., 1989).* Thus, repeated exposure to panic-related physical sensations appears important for reducing fear in PD patients when administered in a treatment context. In contrast, repeated exposure to panic in the natural environment does not appear to impact fear in PD patients (McNally, 1994). Thus, this investigation set out to examine the effects of presentation of 12 trials of 35% CO2, using panic-naive participants who scored high and low on the ASI. Three foci are presented in this study. The first issue involved examination of habituation of fear and physiological responding across trials. Presumably, if repeated CO2 presentation can serve as a laboratory analogue to examine the development and maintenance of PD, it must first be determined if a reduction occurs in responding across CO2 trials under controlled conditions. The second issue involved inclusion of a dishabituation trial, specifically a 'surprise' novel stimulus presented in an identical context in the midst of repeated CO2 presentation. This feature permits examination of whether habituation is indeed relevant in fear reduction under controlled circumstances. As is well-documented in the experimental literature (e.g. Fantino & Logan, 1979), presentation of a novel distractor stimulus following initial response decrement will result in increased responding to the 'habituation' stimulus on subsequent trials. If another process such as fatigue is responsible for response decrement over trials, a rebound following the dishabituation stimulus would not be expected. Thus, in the context of the present experiment, half of the participants received 12 trials of 35% CO2, while the other half received 9 trials of CO2, followed *It is noteworthy that this issue represents a current focus of PD treatment research. In particular, Brown, Antony and Barlow (1995) reported that the addition of interoceptive exposure did not improve treatment outcome above and beyond cognitive restructuring.

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by administration of room air on Trial 10 (the dishabituation trial). CO2 was again presented to this group on Trials 11 and 12, in order to examine if increased responding occurred. Although it is recognized that a number of authors have provided cognitive accounts of habituation processes (e.g. Wagner, 1978, 1979), the present study was designed to examine whether reduction in emotional and physiological responding occurred across repeated presentation of 35% CO2 and if so, if this effect was due to habituation. Future investigations are needed to explore the influence of cognitive interpretation in the process of repeated panic experiences. The third focus of this investigation involved examination of differences between High ASI and Low ASI participants during the course of repeated CO2 presentation. Presumably, individuals who perceive anxiety sensations as potentially harmful (High ASI) should show slower reduction of responding to repeated CO2-induced sensations, relative to individuals who do not fear these sensations (Low ASI), based on greater levels of fearful responding to physical sensations (as reviewed by McNally, 1994). If this hypothesis is accurate, it has implications for understanding the etiology of PD, specifically by providing empirical direction for examination of factors which maintain fear in High ASI individuals and may influence the later development of PD (e.g. Mailer & Reiss, 1992). Although examination of cognitive variables would seem relevant in this process (see for example Rachman & Levitt, 1988), the present study is intended to explore whether differences are present in the emotional and physiological responding to repeated CO2 presentation in High and Low ASI participants, as a first step in this process. Thus, this study used a 2 (High vs Low ASI) by 2 (Habituation vs Dishabituation) by 12 (Trials) design to explore these three foci. Measures included anxiety ratings, heart rate, skin conductance, and number of panic symptoms. The hypotheses are as follows: 1. Low ASI participants would show less anxiety overall and faster reductions in anxiety over the course of repeated CO2 trials relative to High ASI participants. This effect was hypothesized on both pre-inhalation and post-inhalation anxiety. 2. On measures of heart rate and skin conductance, a lack of between-group differences was expected, based on the observation of minimal differences in physiological response to challenge between PD patients and control participants (Rapee, 1995). Similarly, the number of panic symptoms endorsed was not expected to differ, given that this variable reflects inhaled CO2 volume (e.g. van den Hout, 1988; van den Hout & Griez, 1985). Note that this prediction involved number of panic symptoms, not intensity of symptoms, where consistent differences have been observed in studies contrasting PD patients with normal control (Rapee, 1995) and High and Low ASI participants (McNally, 1994). However, based on the extensive habituation literature, a decrease across trials was anticipated on physiological measures for both ASI groups. 3. For participants in the Dishabituation condition, it was anticipated that anxiety would be reduced on the dishabituation trial (Trial 10) for both High and Low ASI groups. High ASI participants were expected to show a larger rebound of anxiety following dishabituation (on the 11th and 12th trials) than Low ASI participants, given their greater emotional sensitivity to physical sensations. On the physiological measures, only heart rate was expected to increase on the dishabituation trial, given the 'surprise' produced by this manipulation (Jennings, 1986). METHOD Participants Participants included 40 university students (27 women and 13 men, mean age = 21.4 yr, SD = 5.63), selected based on their ASI scores. Participants in the High ASI group included 13 women scoring 30 or above and 7 men scoring 23 or above (mean ASI score = 31.6, SD = 4.6). Participants in the Low ASI group included 14 women scoring 10 or below and 6 men scoring 7 or below (mean ASI score = 5.65, SD --- 2.91). ASI cut-offs were based on college norms, as used in related research (e.g. Holloway & McNally, 1987; Reiss et al., 1986). A total of 1384 students were screened, across two consecutive semesters. Racial distribution of the sample was as follows: 72.5% Caucasian (n = 29), 5% African-American (n = 2), 15% Asian-American (n = 6), 2.5% Hispanic (n = 1), and 5% unknown (n = 2). The study's focus was concealed while recruiting participants to reduce expectancy effects. Thus, students who met the ASI cut-offs were invited to

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participate in a study of 'respiratory control'. Exclusionary criteria included a prior history of panic attacks, depression, heart conditions, seizure disorders, lung disorders (other than mild exercise-induced asthma), use of any psychotropic medication, and pregnancy.* Participants provided written consent and received $10 for their involvement.

Measures Anxiety Sensitivity Index. The ASI is a 16-item questionnaire which assesses fear of anxiety-related symptoms. Items reflect concern about the negative meaning of symptoms or perceptions that symptoms will result in negative consequences (e.g. "It scares me when I feel faint") and are rated on a 0--4 Likert-type scale. Reliability of the ASI appears high (e.g. test-retest reliability over a 2-week interval: r = 0.75; Reiss et al., 1986; split-half reliability: r -- 0.85; Peterson & Heilbronner, 1987). Considerable support exists for the construct validity of the ASI (e.g. McNally, 1994), which appears distinct from measures of trait anxiety (e.g. Taylor, Koch & Crockett, 1991). Psychophysiological measures. Heart rate and skin conductance were assessed throughout the procedure. Heart rate was included as an index of cardiovascular arousal and has been used extensively in biological challenge studies (e.g. Shear, 1986). HR was assessed with two Ag-AgC1 electrodes placed bilaterally on the chest, 5 cm below the midpoint of each clavicle, using a Coulbourn $75-01 amplifier and $77-26 tachograph. Skin conductance (SC) was included to index generalized autonomic arousal. Elevations in resting SC has been shown to differentiate anxiety-disordered patients from normal controls (e.g. Lader & Wing, 1966) and is a common measure in habituation studies (e.g, Roth, Ehlers, Taylor & Margraf, 1990). SC was assessed from the medial phalanx of the palmar surface of the first two fingers of the nondominant hand with Ag-AgCI electrodes, using a Coulbourn $71-23 isolated coupler (0.5 constant voltage). Participants washed their hands with non-alkaline soap prior to electrode placement, to control for seasonal variation. SC was scored as micromhos. K-Y jelly was used as the conducting medium. Both H R and SC were sampled online and transformed into meaningful units via A-D conversion. Values then were averaged into 1-min epochs for the intervals preceding and following each inhalation. Subjective anxiety. A measure of subjective anxiety was used involving a potentiometer attached to a mechanical dial, calibrated on a 0-100 scale. Participants were instructed to use the dial to rate their level of anxiety with 0 indicating no anxiety and 100 indicating extreme anxiety and panic. Ratings were taken preceding and following each inhalation, at the experimenter's prompt. An advantage of this methodology is the assessment of subjective anxiety simultaneous with psychophysiological assessment. This device was sampled online, in conjunction with the psychophysiological measures. Panic symptoms. After each inhalation, participants were instructed to rate each of 13 DSM-III-R panic symptoms on a 0-3 scale, with 0 indicating that the symptom was not experienced, 1 indicating mild severity, 2 indicating moderate severity, and 3 indicating extreme severity and panic. The number of panic symptoms reported (rated > 1) was derived, owing to skewness in panic severity ratings. Panic symptom ratings were modeled after the Acute Panic Inventory (Fyer, Uy, Martinez, Goetz, Klein, Fyer, Liebowitz & Gorman, 1987), which is used extensively in biological challenge studies. Apparatus H R and SC were recorded on a Coulbourn system, interfaced to a 486 computer using a Coulbourn videograph A-D converter. Procedure Following completion of the ASI and initial phone screening, each potential participant attended a laboratory session, which began with a screening interview to ensure the absence of exclusionary criteria. Participants were assessed individually, following random assignment to habituation or *These exclusionary criteria were used to ensure the physical and emotional safety of participants, as CO: could have negative consequences if these conditions are present.

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dishabituation conditions. The participant was introduced to the laboratory, a sound- and light-controlled chamber with intercom communication. H R and SC electrodes were attached by a trained technician, followed by a 10-min adaptation phase. The CO2 procedure then was explained, using the following instructions: The purpose of this study is to examine the effectsof specificrespiratory factors on you. You will be asked to take a single breath of a mixture of 35% CO: and 65% 02, using a breathing mask that covers your mouth and nose. We will ask you to take a total of 12 gas breaths throughout the procedure. You can expect to experience some physical reactions after each gas breath, which will go away when you exhale. Each breath will be separated by a brief interval. Following explanation of the procedure, the participant was taught vital capacity breathing. Pre-inhalation measures of anxiety, H R , and SC were taken and the participant was instructed to deeply inhale a mixture of 35% CO2 / 65% 02 through a face mask (Hans Rudolph) using vital capacity breathing. The gas mixture was delivered using a 270 1 meterological balloon, filled at about 30% capacity, which allowed for controlled administration. Outflow from the balloon led to a two-way valve in the mask, via a 1-inch diameter tube. The dishabituation trial involved the same instructions and procedure, except that the outflow valve from the balloon was not opened to release CO2. Thus, on the dishabituation trial, the balloon was filled and the identical procedure followed, with delivery of room air. These steps were taken so that the participant was not informed that the dishabituation trial differed in any way from the preceding CO2 inhalations. Measures of anxiety, H R , SC, and panic symptoms were taken immediately following gas administration. Inhalations were separated by a 5-min intertrial interval. To reduce experimenter bias, laboratory personnel were unaware of the participant's ASI score until the procedure was completed.

Statistical approaches All data initially were screened for univariate and multivariate outliers.* Pre-inhalation measures (anxiety, H R , SC) were examined using a 2 (High/Low AS1) × 9 (Trials) M A N O V A , with repeated measures on the second factor; significant effects were followed using Tukey's procedure with comparison-specific error terms for the Trials factor. These analyses were conceptualized as examining anticipatory responding prior to CO2. Given inclusion of the dishabituation trial (Trial 10), pre-inhalation analyses only focused on the first 9 trials. Post-inhalation measures (anxiety, HR, SC, and number of panic symptoms) were examined with a 2 (High/Low ASI) x 2 (Habituation/Dishabituation) x 12 (Trials) M A N O V A , using similar procedures to follow significant effects.t These analyses examined responding following CO2 provocation. Following the recommendations of Rosenthal (1995), effect sizes (ES) were computed (using partial rl: which reflects % of variance explained by a given effect) and evaluated using Cohen's (1988) classification system, wherein small effects range from 2 to 12% of variance, raedium effects from 13 to 44%, and large effects > 45% of variance.~

RESULTS

Pre-inhalation responding Examination of the anxiety data revealed a ASI by Trial trend [F(8,29)= 2.07, P < 0.07, ES = 36% variance]. Although nonsignificant, this trend was examined further given the effect size. *One outlier was noted on the subjectiveanxiety measure, with deletion of these data in subsequent analysesof this measure. tln the case of post-inhalation panic symptom data, singularity of variance-covariancewas noted. FollowingTabachnick and Fidell (1989), BMDP4V was used for this analysis. Additionally, some participants had missing HR data, owing to movement during the post-inhalation interval. Thus, post-inhalation HR was examined using BMDP5V, which conducts the MANOVA using the method of maximum likelihood to estimate regression and covariance parameters, allowing inclusion of participants with partial data. :~At the suggestion of a reviewer, these analyses were repeated, using trait anxiety scores from the State-Trait Anxiety Inventory (Spielberger,Gorsuch & Lushene, 1970) as a covariate. The purpose of these covarianceanalyseswas to clarify if obtained effectsinvolving AS1 differenceswere due to anxiety sensitivity or to a more general anxiety factor. In each case, the pattern of results was unchanged. In order to clarify data presentation, the covariance analyses are not reported here.

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Follow-up testing indicated that the High ASI group showed increasing pre-inhalation anxiety beginning at Trial 3, relative to Trial 1, while the Low ASI group reported a decrease in anxiety on Trials 2-5, relative to Trial 1 (P < 0.05; see Fig. 1). Additionally, a significant ASI main effect was noted [F(1,36) = 4.93, P < 0.03, ES = 12% variance], indicating that the High ASI group had overall higher levels of pre-inhalation anxiety (,~ = 21.8, SD = 2.66) relative to the Low ASI group (~ = 0.7, SD = 1.06). Examination of pre-inhalation H R indicated a significant ASI main effect [F(I,18)= 4.71, P < 0.05, ES = 21% variance] and a nonsignificant Trial trend [F(2,11) = 2.53, P < 0.07, ES = 65% variance]. The High ASI group had significantly higher pre-inhalation heart rates (~ = 83.9 beats/rain, SD = 1.67), relative to the Low ASI group (~ = 72.3, SD = 1.37). Follow-up of the Trial trend indicated that pre-inhalation H R decreased steadily across Trials 1-9. Examination of pre-inhalation SC revealed no significant effects. Post-inhalation responding

Examination of post-inhalation anxiety data revealed a significant ASI by Habituation/Dishabituation interaction [F(1,34) = 5.53, P < 0.05, ES = 14% variance]. Follow-up testing indicated that the High ASI-Habituation group reported greater overall levels of anxiety than the Low ASI-Habituation and High ASI-Dishabituation groups (P < 0. 05). Additionally, a significant Trial effect was noted [F(11,24) = 2.46, P < 0.03, ES = 53% variance], which was interpreted in light of a Habituation/Dishabituation by Trial trend [F(11,24)= 1.96, P < 0.08, ES = 47% variance]. Due to the effect size, this trend was followed, with results plotted in Fig. 2. Within-group analyses revealed that the Habituation group showed increased anxiety on Trial 4, relative to Trial 1. The Dishabituation group showed increased anxiety on Trials 6-9 and 11-12, relative to Trial 1, with reduced anxiety on Trial 10 as hypothesized (see Fig. 2). Between-group analyses indicated that the Dishabituation condition showed lower levels of anxiety on Trials 1-5, relative to the Habituation group. As hypothesized, the Dishabituation group reported significantly lower anxiety on Trial 10, with a significant rebound noted on Trial 12, relative to the Habituation condition. Owing to differences in pre-inhalation anxiety between the High and Low ASI groups, these analyses were repeated using pre-inhalation anxiety ratings on Trial 1 as the covariate, with the same results noted for the Trial factor. This indicates that the pattern of post-inhalation anxiety could not be accounted for by ASI group differences.

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Fig. 2. Anxiety following 35% CO~ inhalation (Trials 1-12) by Habituation and Dishabituation conditions.

Post-inhalation H R showed an ASI main effect [F(I,16) = 5.57, P < 0.05, ES = 26% variance], indicating that the High ASI group had higher overall heart rates (~ = 80.7 beats/min, SD = 1.53) than the low ASI group (~ = 68.6, SD = 1.45). Additionally, a Trial trend was noted IF(11,6) = 3.09, P < 0.08, ES = 85% variance], indicating that HR decreased significantly after Trial 1, with the exception of Trial 10 where it was not different from Trial I (see Fig. 3). Post-inhalation SC indicated a significant ASI by Trial interaction [F(11,23) = 2.73, P < 0.05, ES = 56% variance], contrary to prediction. Follow-up testing indicated that the High ASI group showed increased SC responding on Trials 9-12, while the Low ASI group showed increased SC on Trial 6 and decreased SC on Trials 8-11, relative to Trial 1 (see Fig. 4). The High ASI group showed significantly higher SC at each trial, relative to the Low ASI group. Examination of the number of panic symptoms endorsed indicated a Habituation/Dishabituation by Trial effect [F(12,25)= 2.32, P < 0.03, ES = 45% variance], revealing a significant reduction in the number of panic symptoms endorsed in the Dishabituation group on Trial 10, relative to Trials 1-9 and 11-12 (see Fig. 5). No between-group (ASI) effects were noted on this variable.

DISCUSSION Overall, these data provide an interesting pattern of findings. Differences emerged between pre-inhalation and post-inhalation measures, suggesting that separate factors may influence responding during these two intervals. As noted in Fig. 1, High ASI participants showed increased pre-inhalation anxiety (sensitization) beginning at Trial 3, which showed a gradual, nonsignificant decrease by Trial 8.* In contrast, the Low ASI group showed consistently low levels of

*Despite observation of increasing fear, no High ASI participants terminated the procedure or reported adverse consequences following the procedure.

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Fig. 4. Skin conductance following 35% CO2 inhalation by High and Low ASI groups. pre-inhalation anxiety throughout the first nine trials. Because these data reflect nonsignificant trends, they should be regarded as preliminary. Desynchrony was noted, as pre-inhalation heart rate showed rapid reduction following Trial 1 for both High and Low ASI groups. It thus would appear that the increases in pre-inhalation anxiety noted in the High ASI group were not facilitated by heightened physiological arousal. In contrast, post-inhalation responding illustrated a different pattern of findings. No differences were observed across trials between the ASI groups in post-inhalation anxiety, although the High ASI-Habituation participants reported overall higher levels of anxiety. Participants in the Habituation condition showed reduced anxiety by the end of the procedure, while those in the Dishabituation condition showed the anticipated rebound in anxiety after the dishabituation trial

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Fig. 5. Number of panic symptoms endorsed following 35% CO2 inhalation by Habituation and Dishabituation conditions.

(Trial 10). As has been noted in other studies of panic-naive participants, less anxiety was noted in responding to CO2 relative to PD patients (e.g. Rapee et al., 1992; Telch & Harrington, 1992). Heart rate showed rapid reduction across trials, as hypothesized. Visual examination of these data indicated that the observed increase in heart rate on Trial 10 was due to the Dishabituation condition alone.* This heart rate increase was expected given that the dishabituation trial was rapid onset, startling, and unexpected (Jennings, 1986). Again, because these data reflect nonsignificant trends, they should be regarded as preliminary. The only post-inhalation measure that showed ASI effects across trials was skin conductance. On this measure, the High ASI group showed significant increases in responding across trials while the Low ASI group showed a gradual reduction. Interestingly, this same ASI by Trial pattern was noted on the pre-inhalation anxiety measure as well (although as a nonsignificant trend). Skin conductance has been used in other contexts as an index of emotional responsivity (e.g. Andreassi, 1989) although it is not accurately self-monitored as with other physiological indices (e.g. Katkin, 1985). Thus, it appears that some degree of synchrony was noted between subjective anxiety and skin conductance, with generalized autonomic arousal following anxiety by a 1-2 min delay. It is important to note that this same degree of synchrony was not noted between heart rate and anxiety. This lack of synchrony has important implications for cognitive theories of panic, which postulate that heightened physiological responding (such as heart rate and ventilatory changes) follow from anxious interpretation of bodily sensations (e.g. Clark (1986). Direct assessment of cognitive interpretation of CO2-produced symptoms is necessary to examine this pattern of synchrony/desynchrony more closely. In the present investigation, anxiety increases were not accompanied by heart rate acceleration. A notable lack of fear reduction was observed in this study, particularly considering the gradual increase in pre-inhalation anxiety in the High ASI group, This finding parallels Roth et al. (1990), who observed extremely slow rates of skin conductance habituation to repeated presentation of neutral tones in PD patients. Thus, failure of the High ASI group to habituate across trials possibly represents a general feature of individuals who fear physical sensations, rather than a specific psychopathological feature of PD. Given that the participants in this study had never experienced *Low power, owing to loss of heart rate data due to subject movement, precluded statistical significance.

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a panic attack, one cannot attribute the lack of pre-inhalation anxiety reduction in the High ASI group to previously learned fear of panic. In light of the significance of anticipatory anxiety in the current diagnosis of Panic Disorder (American Psychiatric Association, 1994), this finding is particularly intriguing. Despite the absence of fear reduction in the High ASI group preceding CO2 inhalation, post-inhalation anxiety did not significantly differ in the ASI groups. However, the expected rebound in anxiety was noted following the dishabituation trial. Without reduction in responding over trials, one cannot technically term this rebound 'dishabituation'. It is possible that a greater number of C 0 2 trials are necessary in order to explore whether habituation is indeed relevant in fear reduction in panic naive participants. Maintenance of fear across repeated CO2 presentation suggests that perhaps sensitization processes are at work. Examination of related learning parameters, such as stimulus specificity effects (Fantino & Logan, 1979; Mackintosh, 1987) will assist in clarifying whether habituation is indeed relevant in fear reduction. Ideally, direct assessment of CO2 volume changes would have provided procedural validation for this study. Unfortunately, this instrumentation was not available at the time this study was conducted. However, examination of the number of panic symptoms endorsed suggests that CO2 was administered consistently across trials and participants. Secondly, the relative absence of panic symptoms during the dishabituation trials further supports the manipulation. Additionally, as suggested by McNally and Eke (1996), the ASI may not have been the most salient dimension upon which to select participants. These authors suggest that suffocation fear, assessed using the Suffocation Fear Scale (Rachman & Taylor, 1993; Taylor & Rachman, 1994) is a better predictor of anxious responding and physical sensations to challenges that increase carbon dioxide. It may be useful to replicate the current paradigm with individuals reporting elevations in suffocation fear. In sum, the present investigation sought to examine patterns of anxiety and physiological responding during repeated administration of 35% CO2 to High and Low anxiety sensitivity participants. The preliminary results indicate that individuals reporting high levels of anxiety sensitivity showed a trend towards increasing anticipatory anxiety preceding inhalation, while Low ASI reported rapid fear reduction. Heart rate was desynchronous with fear both preceding and following CO2 inhalation, although skin conductance showed a pattern of delayed synchrony with anxiety. These findings suggest that sensitization may occur as a result of repeated experience with panic sensations for individuals who are emotionally hypersensitive to physical sensations. This effect was noted on the pre-inhalation anxiety measure, highlighting the importance of anticipatory anxiety in understanding the natural course of fear over time. What factors underlie this sensitization process? Certainly, the role of cognitive processes during repeated exposure to panic sensations deserves exploration in this context. Ultimately, the answer to this question may hold the key to understanding the etiology of PD and those factors which maintain fear over time. Acknowledgements--This investigationwas supported in part by a Research DevelopmentFund Award from the Research

Foundation of the State Universityof New York. We gratefullyacknowledgethe assistance of Ken Ruggerio,Kim Hopkins, J. Noel Leon, Marc Renzoni, Andy Yartz. and Michael Zvolensky in data collection and management. Input from Drs Samuel M. Turner, Tim A. Brown, and Georg H. Eifert on an earlier draft of this manuscript is greatly appreciated.

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