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Journal of Abnormal Psychology
2007, Vol. 116, No. 3, 612– 617
Copyright 2007 by the American Psychological Association
0021-843X/07/$12.00 DOI: 10.1037/0021-843X.116.3.612
Fear Conditioning in Panic Disorder: Enhanced Resistance to Extinction
Tanja Michael, Jens Blechert, Noortje Vriends, Jürgen Margraf, and Frank H. Wilhelm
University of Basel
Enhanced conditionability has been proposed as a crucial factor in the etiology and maintenance of panic
disorder (PD). To test this assumption, the authors of the current study examined the acquisition and
extinction of conditioned responses to aversive stimuli in PD. Thirty-nine PD patients and 33 healthy
control participants took part in a differential aversive conditioning experiment. A highly annoying but
not painful electrical stimulus served as the unconditioned stimulus (US), and two neutral pictures were
used as either the paired conditioned stimulus (CS!) or the unpaired conditioned stimulus (CS").
Results indicate that PD patients do not show larger conditioned responses during acquisition than control
participants. However, in contrast to control participants, PD patients exhibited larger skin conductance
responses to CS! stimuli during extinction and maintained a more negative evaluation of them, as
indicated by valence ratings obtained several times throughout the experiment. This suggests that PD
patients show enhanced conditionability with respect to extinction.
Keywords: anxiety disorders, panic attacks, classical conditioning, electrodermal activity, emotion
conditioned responding during extinction among anxiety patients.
Thus, it has been proposed that AD patients are characterized by
enhanced conditionability and that this is one of the reasons why,
upon exposure to fearsome incidents, only some individuals develop pathological fears, whereas others show an adaptive fear
response (Orr et al., 2000).
It has further been suggested that ADs are associated with
elevated stimulus generalization (Mineka & Zinbarg, 1996) or
insufficient inhibition of the fear response in the presence of safety
signals (Davis, Falls, & Gewirtz, 2000). These proposals cannot be
tested within the simple FC procedures that have been employed in
most studies (a single CS is paired with a US) but require a
differential FC procedure whereby one stimulus (the CS!) is
paired with the US, and another stimulus (the CS") is not. Recent
studies in posttraumatic stress disorder (PTSD) found enhanced
responding to the CS" (Blechert, Michael, Vriends, Margraf, &
Wilhelm, 2007; Grillon & Morgan, 1999; Orr et al., 2000; Peri,
Ben-Shakhar, Orr, & Shalev, 2000) and thus provide preliminary
evidence for these proposals, at least with respect to PTSD.
Both traditional (Goldstein & Chambless, 1978) and contemporary (Bouton, Mineka, & Barlow, 2001) models of panic disorder
(PD) assign a prominent role to conditioning mechanisms. In short,
Bouton et al. (2001) have argued that panic attacks are strong
conditioning episodes during which feelings of anxiety and panic
become associated with exteroceptive (e.g., escalators) and interoceptive (e.g., dizziness) cues present during the attacks. Subsequent encountering of these cues can thus trigger feelings of
anticipatory anxiety, which may serve to exacerbate or potentiate
the next panic attack, or panic itself. If people have certain genetic,
temperamental, or experiential vulnerabilities, they will show
stronger conditioning during the initial and subsequent attacks,
thereby explaining why only some people who experience panic
attacks develop PD.
In accordance with these theoretical considerations, a number of
laboratory analogue studies in healthy populations (Forsyth &
Eifert, 1998; Godemann et al., 2001) have confirmed that condi-
Fear learning is considered to be a highly adaptive response to
aversive events that ensures survival in changing and novel environments (LeDoux, 1995). One form of fear learning is fear
conditioning (FC), which involves the pairing of a neutral (conditioned) stimulus (CS) with an aversive (unconditioned) stimulus
(US). The CS becomes a signal for imminent US onset and thus
provokes a conditioned response (CR). This serves to prepare the
organism for the US and the associated unconditioned response
(UR). Extinction refers to the decrement in response to subsequent
CS–alone trials, which is now recognized as additional learning
(that the CS has a different meaning) rather than erasure of the
original CS–US association (Bouton, 2002).
Although FC is generally an adaptive process, it may turn into
clinically relevant fear when reactivity to the CS persists in the
absence of a CS–US contingency. While FC accounts of anxiety
disorders (ADs) have been widely criticized since the 1970s
(Rachman, 1990), more recently a resurgence of interest has occurred. FC is an integral part of modern learning accounts of ADs
that incorporate some complexities of contemporary learning theory and provide a compelling explanation for the development and
persistence of ADs (e.g., Mineka & Zinbarg, 1996, 2006). Lissek
et al. (2005) recently conducted a meta-analysis of FC studies of
ADs that shows a modest elevation in both acquisition of fear and
Tanja Michael, Jens Blechert, Noortje Vriends, Jürgen Margraf, and
Frank H. Wilhelm, Department of Clinical Psychology and Psychotherapy,
Institute for Psychology, University of Basel, Basel, Switzerland.
This research was supported by Swiss National Science Foundation
Grants 105311-104038 and 105311-105850, and by a grant from the
Academic Society of Basel (Freiwillige Akademische Gesellschaft Basel).
We would like to thank Andrea Meyer for helpful suggestions with the
statistical analysis, as well as Nathalie Erpelding, Rebecca Frey, and Tanja
Meier for their help with the data collection.
Correspondence concerning this article should be addressed to Tanja
Michael, University of Basel, Institute for Psychology, Missionsstrasse
60/62, CH-4055, Basel, Switzerland. E-mail: [email protected]
612
613
BRIEF REPORTS
Table 1
Demographic and Psychometric Measures for the PD Group (n # 39) and the Control Group
(n # 33)
Variable
PD
Control
Statistic
Female sex, %
Male sex, %
Education, low/middle/high, %
Age (years), M (SD)
MI, M (SD)
ASI, M (SD)
STAI–State, M (SD)
STAI–Trait, M (SD)
BDI, M (SD)
71.8
28.2
46.2/28.2/25.6
40.3 (10.6)
2.37 (0.93)
32.6 (12.3)
48.9 (12.1)
51.0 (11.0)
14.7 (10.1)
69.7
30.3
21.2/30.3/48.5
42.6 (8.96)
1.24 (0.44)
7.12 (4.50)
36.1 (8.30)
33.2 (8.92)
4.58 (4.59)
$2(1, N # 72) # 0.38, p # .84
$2(2, N # 72) # 5.8, p # .06
t(70) # 0.98, p # .33
t(70) # 6.35, p % .001
t(70) # 11.27, p % .001
t(70) # 5.12, p % .001
t(70) # 7.45, p % .001
t(70) # 5.26, p % .001
Note. PD # panic disorder; MI # Mobility Inventory; ASI # Anxiety Sensitivity Index; STAI–State/Trait #
Spielberger State–Trait Anxiety Inventory; BDI # Beck Depression Inventory.
tioning experiences may serve as a “minimodel” for PD (Marks &
Tobena, 1990). Despite this interest in conditioning in PD and a
considerable number of FC studies in other ADs, so far only one
previous study has assessed whether PD patients differ from
healthy controls in their CRs (Grillon, Ameli, Goddard, Woods, &
Davis, 1994). No group differences were found during acquisition,
and extinction learning was not assessed. Therefore, we conducted
a differential FC study with PD patients and healthy controls to test
the assumption that PD is characterized by abnormal FC during
acquisition or extinction. Most important, we examined the hypothesis of enhanced conditionability, since this assumption can be
directly derived from the conditioning model of PD. Additionally,
we explored whether PD patients show larger CRs to the CS".
The main dependent variable was skin conductance response
(SCR), since this is the most established outcome measure in
human FC studies. We further assessed the subjective valence of
the CSs, as it has recently been suggested that this is an important
dimension in human FC (Hermans, Vansteenwegen, Crombez,
Baeyens, & Eelen, 2002). CSs were two neutral inkblot pictures
with which the participants had no prior experience, because we
wished to study conditioning for de novo stimuli. An electrical
aversive stimulus served as US.
Method
Participants
Participants were referred by mental health institutions or answered advertisements in the local press. Exclusion criteria were as
follows: age below 18 or above 65 years; medical history of
conditions affecting the physiological systems under examination
(e.g., myocardial infarction) or regular use of medications with
strong autonomic side effects (e.g., sympathomimetic drugs);1
fulfillment of diagnostic criteria for schizophrenia, bipolar disorder, any other psychotic disorder, or alcohol or other substance
abuse in the past year; current use of recreational drugs; and
consumption of more than 20 units of alcohol per week. In addition, to be included in the analyses we required that participants
had been aware of the contingency between CS and US in the
conditioning task (e.g., Lovibond & Shanks, 2002).2
We assessed diagnostic status using the Diagnostic Interview for
Mental Disorders—Research Revision (Margraf, Schneider, Soe-
der, Neumer, & Becker, 1996), a well-validated structured interview for diagnosing disorders according to the Diagnostic and
Statistical Manual of Mental Disorders (4th ed.; DSM–IV; American Psychiatric Association, 1994).
The final sample consisted of 33 participants who had never
qualified for a diagnosis of any psychiatric disorder (control
group) and 39 participants who qualified for a primary DSM–IV
diagnosis of PD with or without agoraphobia (PD group). Twelve
PD patients (30.8%) had one or more secondary disorders: social
phobia (6), major depression (5), generalized AD (5), PTSD (3),
hypochondriasis (3), obsessive compulsive disorder (2), specific
phobia (1), and dysthymic disorder (1).
Anxiety and depressive symptoms were assessed with the German versions of the State–Trait Anxiety Inventory (Laux, Glanzmann, Schaffner, & Spielberger, 1981), the Anxiety Sensitivity
Index (Ehlers & Margraf, 1993), the Mobility Inventory (Ehlers,
Clark, & Chambless, 2001), and the Beck Depression Inventory
(Hautzinger, Bailer, Worall, & Keller, 1994). Consistent with their
diagnosis, the PD group scored higher than the control group on
these symptom measures. Groups did not differ in age, sex, and
educational background (see Table 1).
The study was approved by the local ethics committee for
medical research and participants gave written consent before
participating. Each participant received a payment of 90 Swiss
francs (approximately $70).
Procedure
When participants arrived at the laboratory, electrodes were
attached to them; then, together with the experimenter, they adjusted the intensity of the electric stimulation to a level that they
described as being “unpleasant and demanding some effort to
tolerate.” Approximately 3– 6 electric stimuli were applied to
arrive at the final intensity. After a 5-min adaptation period, a
1
Psychoactive drugs like benzodiazepines or antidepressants were allowed, but inclusion required that participants had been on a constant
regimen for at least 2 weeks before testing to avoid possible side effects or
withdrawal symptoms due to dose alternations.
2
Four participants with PD and 3 controls were excluded for this reason.
An analysis including these participants showed the same pattern of results.
614
BRIEF REPORTS
rating dial was introduced. The rating dial was a linear slider on
which a visual analog scale was affixed; the lower anchor label
was –100 and the upper label was !100. Participants then gave a
retrospective rating of US aversiveness (anchor labels: "100 #
very slightly unpleasant to !100 # extremely unpleasant/painful;
no anchor for 0).
The conditioning task commenced with the instructions that two
pictures would be presented repeatedly, and one of them would
occasionally be accompanied by the electric stimulus. Two colored
Rorschach inkblot pictures (12 in. [30.48 cm] & 12 in. [30.48 cm])
were presented on a 19-in. (48.26-cm) monitor and served as CS!
and CS" (counterbalanced across participants). The conditioning
task consisted of a habituation, an acquisition, and an extinction
phase. In each phase, both the CS! and CS" were presented six
times. CS duration was 8 s, and the intertrial interval was 18 ' 2 s
(determined at random). During acquisition, each CS! was immediately followed at stimulus offset by a 500-ms US. Otherwise,
all stimuli were presented alone.
During the conditioning procedure several online ratings of
stimulus valence ("100 # pleasant to 100 # unpleasant) were
collected. A previous study established that these ratings do not
influence the SCR measurement (Blechert, Michael, Williams,
Purkis, & Wilhelm, in press). Participants rated stimulus valence in
the middle and at the end of each conditioning phase. Following
extinction, contingency awareness was assessed by presenting the
CS! and the CS" along with a control stimulus and asking which
of the three pictures was paired with the US. Finally, all participants were orally debriefed, and the PD patients were given
information about PD and treatment options.
the average SCL within 2 s preceding the US from the maximum
increase in SCL during the 7.5 s following the US. SCRs below
0.025 (S were scored as zero. We normalized SCR data using the
natural logarithm of 1 ! SCR.
Statistical analyses. Separate analyses were conducted for
each outcome measure and each conditioning phase. Responses to
each stimulus type (CS!, CS") were averaged for each experimental phase (6 SCRs, 2 ratings). For habituation, we tested
differences in responses using analysis of variance with stimulus
Type (CS!, CS") as within-subjects factors and diagnostic Group
(PD, control) as between-subjects factors. Since acquisition and
extinction effects depend on the response level of the respective
previous phase, the analyses of these phases contained an additional within-subjects factor, Time (Time1, Time 2). Analyses of
variance were followed by analyses of interaction contrasts between diagnostic Group and Time within each stimulus type. F
values derived from contrasts were based on the full model error
term (pooled over both stimulus types) to preserve adequate
power. Effect sizes ()p2, in percentages) were calculated. If the
sphericity assumption was not met, a Greenhouse–Geisser correction was computed, with nominal degree of freedom values being
reported. An alpha level of .05 determined statistical significance.
Results
Control Variables
Groups did not differ on important control variables, such as
SCL baseline, US current level, perceived aversiveness of US,
strength of UR, sigh count, and skin temperature, ps * .42.4
Apparatus and Physiological Recordings
The experiment took place in a temperature-controlled, fully lit,
sound-attenuated room electrically connected to an adjacent control room in which the experimental apparatus was located. An
electrical stimulator (constant current unit, Biopac Systems, Inc.,
Goleta, CA) was used to deliver the US via Ag/AgCl electrodes at
the right lower arm. Stimulus delivery and physiological data
acquisition were controlled by two computers that used E-Prime
(Psychology Software Tools, Inc., Pittsburgh, PA) and AcqKnowlege software (Biopac Systems, Inc., Goleta, CA).
We recorded physiological channels and rating dial information
using the Biopac MP150 system at a sample rate of 1000 Hz. We
obtained skin conductance (SC) using 11-mm inner diameter Ag/
AgCl electrodes filled with isotonic electrode paste. Electrodes
were placed on the middle phalanx of the index and middle fingers
of the left hand. Respiration and movement were measured to
enable detection and exclusion of spurious SCRs.
Data Reduction and Statistical Analysis
SCR. An SCR was calculated by subtracting the average SC
level (SCL) for the 2 s immediately before CS onset from the
maximum SCL recorded between 4 s after CS onset and CS offset
(4 s duration, second interval response). Conditioning effects were
based on the second interval response,3 as it is relatively unaffected by nonassociative processes like dishabituation of the orienting response and is considered to represent the signal value of
the CS (Lovibond, 1992). The UR was computed by subtracting
SCR
Means for each experimental phase are presented in Figure 1.
The statistical analysis for habituation found no main effects for
the factors Type and Group or their interaction, thus demonstrating
that there was no difference in responding to the CS! and the
CS" when the stimuli were presented alone, and no difference
between the diagnostic groups. Regarding acquisition, a significant
interaction between the factors Time and Type, F(1, 70) # 30.11,
p % .01, )p2 # 30.1%, revealed that the acquisition phase yielded
successful conditioning with participants differentiating between
CS! and CS" during acquisition but not during habituation.
However, no main or interaction effects emerged that involved
diagnostic group. With respect to the extinction phase, a significant interaction between Time and Type, F(1, 70) # 20.22, p %
.01, )p2 # 22.4%, revealed a general extinction effect. In line with
the assumption, this effect was modulated by diagnostic group. A
close to significant interaction, F(1, 70) # 3.95, p # .051, )p2 #
5.3%, between Type, Time, and Group indicated that PD patients
exhibited a reduced extinction response to the CS! trials. Planned
interaction contrasts between the groups for each stimulus type
showed that the PD group had less reduction in its response to the
CS! than the control group, F(1, 140) # 4.98, p # .027, )p2 #
3
The pattern of results was, however, the same when the first interval
response or the maximum response during CS presentation was analyzed.
4
Details available on request.
BRIEF REPORTS
615
Figure 1. Means and standard errors of skin conductance responses (SCRs, left panel) and negative valence
ratings (right panel) in response to the paired conditioned stimulus (CS plus) and the unpaired conditioned
stimulus (CS minus) across the habituation (Hab), acquisition (Acq), and extinction (Ext) phases for the panic
disorder (PD) and control groups.
7.1%, whereas the groups did not differ regarding the CS", F(1,
140) # 0.05, p # .823, )p2 # 0.1%.
Negative Valence Rating
For habituation none of the main effects or the interaction effect
was statistically significant. A significant interaction between
Type and Time, F(1, 70) # 53.89, p % .01, )p2 # 43.5%, showed
that the acquisition phase resulted in successful conditioning, but
acquisition was not influenced by diagnostic Group. There was a
general extinction effect, as indicated by a significant interaction
between Time and Type, F(1, 70) # 10.22, p % .01, )p2 # 12.7%.
A significant interaction, F(1, 70) # 4.28, p # .042, )p2 # 5.8%,
between Time, Type, and Group revealed that PD patients exhibited a reduced extinction response to the CS! trials. Interaction
contrasts between groups for each stimulus type showed that the
PD group reduced its negative evaluation of the CS! less strongly
than the control group, F(1, 140) # 5.5, p # .020, )p2 # 7.9%, but
that the groups did not differ with respect to the CS", F(1, 140) #
0.28, p # .598, )p2 # 0.4% (see Figure 1).
Discussion
In this study, we investigated whether PD patients differ from
healthy control participants in their CRs to both paired and unpaired stimuli during an FC procedure. We examined several
variables that might bias conditioning results but found no group
difference on any of these control variables, so results can be
interpreted straightforwardly. With respect to the reinforced stimulus (CS!), we found no difference between the groups at acquisition. However, the PD patients showed a reduced extinction
response, which was evidenced both by the primary conditioning
outcome measure SCR and by the negative valence ratings. Thus,
the CS! was a stronger danger signal and continued to be appraised more negatively in the PD group than in the control group.
Groups did not differ regarding their CRs to the CS".
The current finding of reduced extinction in a differential FC
paradigm is in line with previous research that employed similar
procedures in other ADs and mainly found group differences with
respect to extinction (Hermann, Ziegler, Birbaumer, & Flor, 2002;
Orr et al., 2000; Peri et al., 2000; Pitman & Orr, 1986). In contrast
to a recent meta-analysis (Lissek et al., 2005), we found no
differences during acquisition. However, most of the studies included in the meta-analysis used a single CS design that cannot
control for nonassociative processes like sensitization. Sensitization, an increase of responding due to the introduction of the US,
is confounded with conditioning effects in single CS designs
during the acquisition phase. Moreover, given that fear acquisition
is an important survival mechanism, whereas fear extinction is a
flexible response to a changing environment, it is unsurprising that
pathological fear seems to be more strongly characterized by
deficits in extinction. Extinction is a fragile learning process that
can be attenuated by the passage of time or shift of context (e.g.,
Bouton, 2002). Extinction learning is characterized by ambiguity,
induced by the rivalry of the acquisition and the extinction contingency. Interestingly, research in cognitive biases has repeatedly
shown that patient– control differences are most frequently observed under conditions of conflict or ambiguity (e.g., Michael,
Ehlers, & Halligan, 2005).
The reduced-extinction result also agrees with the general assumption of the conditioning model of PD (Bouton et al., 2001),
which asserts that conditioned anxiety partly explains why only a
subgroup of people who have panic attacks develops persistent PD.
616
BRIEF REPORTS
The model of Bouton et al. (2001) is based on a complex interplay
of different conditioning processes and cannot, for reasons of
brevity, be discussed in detail. To give one example, Bouton et al.
stated that several CSs (e.g., change in respiration, being alone in
a closed space) need to be present before a CR (panic attack) is
triggered. Assuming that PD patients show reduced extinction to
all or most CSs, they would reach the critical summation value for
experiencing a panic attack more easily, with each attack reinforcing the CS/US association, thereby enhancing the likelihood of
further attacks.
Most formal classical conditioning models (e.g., Rescorla &
Wagner, 1972) assume that inhibitory conditioning, which is based
on a negative CS/US association, is responsible for the extinction
response and for low responding to a CS–. As we found no group
differences regarding responses to the CS", one can assume that
PD patients may not have a deficit in general inhibitory conditioning5— or, expressed slightly differently, a deficit in learning safety
cues (Davis et al., 2000). Elevated responding to the CS" has
repeatedly been found in PTSD (Blechert, Michael, Vriends, &
Wilhelm, in press; Grillon & Morgan, 1999; Peri et al., 2000). This
interesting difference in conditioning findings between PD and
PTSD may indicate that some learning processes are disorder
specific and may reflect the clinical features of these disorders.
While PTSD patients experience a global sense of threat (Ehlers &
Clark, 2000) and an easy triggering of anxiety by cues that bear
only a vague perceptual similarity to those that occurred during the
trauma (Michael et al., 2005), PD patients typically fear only
stimuli that are directly linked with episodes of panic and easily
feel safe in the presence of safety signals.
Though this study may be regarded as initial evidence for the
reduced extinction hypothesis in PD, the observed effect sizes
were small (which is in line with findings of FC studies in other
ADs). Besides the high variability in our measures, the relatively
mild nature of the US and the nonspecificity of both the CS and the
US for PD could be responsible for this. The use of disorder
nonspecific stimuli allowed us to use de novo stimuli as CSs and
a US that was comparable for both groups. A PD-specific US like
CO2-enriched air (e.g., Forsyth & Eifert, 1998) would have been
likely to produce stronger URs or CRs in the PD patients, but
would have entailed the risk of provoking panic attacks. Further,
the stimuli used in the current study are similar to those employed
in other FC studies and thus allow a comparison between the CRs
of patients with PD and patients with another AD (although testing
different patient groups with exactly the same paradigm would
provide the best basis for this). Yet, a conditioning procedure with
disorder-specific stimuli would probably result in stronger group
differences and would allow testing more specific hypotheses like
abnormal interoceptive conditioning in PD (Bouton et al., 2001).
A limitation of the present study is its cross-sectional design,
which can only provide circumstantial evidence within an etiological model. The conditioning model of PD (and other ADs) assumes that enhanced conditionability is a trait-like predisposition
(i.e., the current differences between the groups should reflect a
vulnerability factor for PD). Support for this assumption comes
from studies showing that conditionability demonstrates considerable heritability (Hettema, Annas, Neale, Kendler, & Fredrikson,
2003) and that children qualifying for an AD diagnosis already
show retarded FC extinction (Liberman, Lipp, Spence, & March,
2005). First evidence from longitudinal research supports the idea
of FC as a vulnerability factor (Guthrie & Bryant, 2006), and
genetic association studies are starting to explore its genetic basis
(Garpenstrand, Annas, Ekblom, Oreland, & Fredrikson, 2001).
Clearly, research has to surpass the stage of cross-sectional designs
in patient populations and move on to prospective designs, possibly in high-risk populations. On a more general note, given that
ADs in general, and not only PD specifically, are characterized by
reduced extinction, it might be best considered as a nonspecific
biological marker for PD that has to interact with more specific
biological processes (e.g., to easily experience symptoms of panic)
to result in PD (Barlow, 2002).
5
Inhibitory conditioning is formally assessed in designs that use compound CS (e.g., Chan & Lovibond, 1996). Thus, responding to the CS" in
differential FC designs can only provide indirect evidence for inhibitory
conditioning.
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Received March 28, 2006
Revision received March 5, 2007
Accepted March 6, 2007 !