Overgeneralization of Conditioned Fear as a Pathogenic Marker of Panic Disorder

Nineteen patients with a current DSM-IV-TR diagnosis of panic disorder and 19 healthy comparison subjects were recruited for the study. The demographic and clinical characteristics of the two groups are provided in Table 1. There were no between-group differences in gender or age.

Diagnostic exclusion criteria for patients with panic disorder included current major depressive disorder; history of alcohol or substance abuse or dependence (other than nicotine) within 6 months of study start; and current or past history of bipolar depression, psychosis, or delusional disorders. Comparison subjects had to be free of any current or past axis I psychopathology as assessed by the Structured Clinical Interview for DSM-IV-TR, Patient Edition (SCID; 16). Additionally, exclusion criteria that applied to all participants were use of psychopharmacological medication or other drugs that alter CNS function within 2 weeks of testing or use of fluoxetine within 6 weeks of testing; current use of illicit drugs, as determined by the SCID and confirmed with a urine test; pregnancy; or medical conditions or treatment for conditions that would interfere with the objectives of the study as determined by a staff physician.

anic diagnoses were determined by the SCID, administered by one of four staff psychologists (interrater reliability, kappa=0.76). All patients were also independently assessed by a senior psychiatrist (D.S.P.) to confirm the SCID diagnosis. Finally, the Panic Disorder Severity Scale (17) was completed for patients with panic disorder to provide a continuous measure of symptom severity. At study outset, participants received a description of the experimental procedures and gave written informed consent, as approved by the National Institute of Mental Health institutional review board.

Stimulation and recording were controlled by a commercial system (Contact Precision Instruments, Boston). Startle blink was measured electromyographically through two 6-mm tin-cup electrodes placed under the left eye (sampling rate=1000 Hz; bandwidth=30–500 Hz). Startle was probed with a burst of white noise (40 msec, 102 dBA) with a near instantaneous rise time presented binaurally through headphones.

The paradigm used in this study was identical to the one we described in detail elsewhere (9), in which 10 rings of gradually increasing size (Figure 1) presented on a computer monitor serve as conditioned stimuli and generalization stimuli. The largest and smallest rings serve as the conditioned danger cue (CS+) and conditioned safety cue (CS–), the former paired and the latter unpaired with an aversive unconditioned stimulus; the eight intermediately sized rings serve as generalization stimuli that form a continuum of similarity between the conditioned danger and conditioned safety cues. All conditioned and generalization stimuli are presented for 8 seconds on a computer monitor. The unconditioned stimulus is a 100-msec electric shock delivered to the left wrist (3–5 mA) that was rated by participants as being "highly uncomfortable but not painful."

The paradigm consists of three phases: preacquisition, acquisition, and generalization test. Table 2 lists the trial types and frequencies included in each phase, including the number of conditioned danger cues coterminating with the unconditioned stimulus. Half of the trials for each phase were followed by startle probes 4 or 5 seconds after onset of the conditioned or generalization stimulus and were intermixed with a balanced number of startle probes presented during intertrial intervals. Nine startle probes were presented prior to study start, and time intervals between startle probes ranged from 18 to 25 seconds throughout the study.

During the remaining unprobed stimulus trials and intertrial intervals, behavioral ratings of perceived risk for shock, as well as the associated response times, were assessed. Specifically, the question "Level of risk?" appeared on the computer monitor above the presented stimulus 1 or 2 seconds after trial onset and cued participants to enter a risk rating on a 3-point scale (1=no risk, 2=moderate risk, and 3=high risk). Participants were instructed to answer according to their "gut feeling" of risk and to respond as quickly as possible using a computer keyboard. Finally, after the acquisition and generalization phases, participants reported levels of anxiety evoked by conditioned danger and conditioned safety cues using 10-point Likert scales (1=none, 5=some, 10=a lot).

Startle electromyography (EMG) was rectified and smoothed (20-msec moving window average). The onset latency window for the blink reflex was 20–100 msec, and the peak magnitude was determined within 120 msec of response onset. The average baseline EMG level for the 50 msec preceding the startle stimulus was subtracted from peak levels. EMG magnitudes across all phases were standardized using within-subject T score conversions. The size of the conditioned danger cue was not found to interact with the effects of stimulus type across groups for any dependent measure, so this factor was not entered in the final analyses. Acquisition of conditioning was analyzed with a 2×2 (group [patients and comparison subjects] by stimulus [danger cue and safety cue]) analysis of variance (ANOVA) with repeated measures. Additionally, generalization effects were analyzed using a 2×6 (group by stimulus type [safety cue, class 1, class 2, class 3, class 4, danger cue]) ANOVA with repeated measures. ANOVAs were computed using Wilks's lambda and were followed, when necessary, by either trend analyses or paired-samples t tests. Quadratic trend analyses were particularly important for testing the shape of generalization gradients, with the a priori hypothesis that patient but not comparison subject gradients would depart from the quadratic function found in healthy humans and intact animals (9–12). Alpha was set at 0.05 and was corrected using Hochberg's adjustment for multiple tests where appropriate (18). Finally, effect sizes were estimated using the unbiased estimator d (19).

Analyses of startle EMG and online risk ratings revealed neither main effects of stimulus type nor stimulus type-by-group interactions.

Whereas patients displayed weaker differentiation of conditioned danger and conditioned safety cues as indicated by online risk ratings and reported anxiety during the first half of the study (acquisition phase; p values ≤0.01), levels of differentiation were comparable across groups during the latter half of the study (generalization phase). This observation was confirmed by a time (acquisition versus generalization)-by-group-by-stimulus type interaction for both risk ratings (F=4.24, df=1, 36, p<0.05; d=0.65) and reported anxiety (F=10.95, df=1, 36, p=0.002; d=1.05) and suggests retarded acquisition of conditioning among panic patients.

Notably, patients relative to comparison subjects displayed higher risk ratings (p=0.001) as well as a nonsignificant trend for stronger startle reactions (p=0.09) during intertrial intervals, suggesting stronger perceived threat among patients during intervals separating ring presentations when the computer monitor was blank.

The overgeneralization in panic patients observed in this study may contribute importantly to the psychopathology of the disorder. Although conditioned stimuli themselves are restricted to actual stimuli present at the time of panic, fear generalization may result in proliferation of environmental cues capable of eliciting panic-related apprehension. Thus, a proclivity toward overgeneralization may result in an increased likelihood of encountering "panic reminders" in the weeks and months following the attack—conferring greater risk for additional attacks and eventual panic disorder. That said, because this study did not use prospective methods but rather tested individuals with existing panic disorder, longitudinal work is needed to determine whether abnormalities in generalization predate the onset of panic disorder and contribute toward its development or reflect ongoing disease processes of the disorder.

Fear of fear, referring to the tendency to respond fearfully to somatic arousal associated with fear, is an emotional process centrally implicated in explanatory models of panic disorder (1, 3, 22). Through this process, minor increases in anxious arousal occurring in the everyday context are escalated by secondary fear of such arousal. Whereas healthy individuals may be more able to regulate these minor increases in anxiety by way of top-down cognitive control, those with panic disorder may be unable to regulate because of the secondary fear of this arousal that escalates minor anxious reactivity to a more major form. In the current context, the danger information contained in the danger cue approximation (i.e., generalization stimulus) likely evokes a degree of initial fear reactivity. Subsequently, higher-level sensory processing of the approximation, revealing more subtle sensory distinctions between the actual danger cue and its approximation, is likely to result in a nonthreatening appraisal of the approximation—leading to a dampening of the initial fear response. According to this perspective, the fear-of-fear process associated with panic disorder escalates the initial fear response to the approximation that in turn overwhelms the panic patient's capacity to down-regulate this reactivity by way of higher-order sensory discrimination, resulting in the expression of fear in the presence of the approximation. Additionally, our finding of retarded acquisition of discriminative conditioning (as indicated in risk ratings and reported anxiety) suggests that discrimination abnormalities in panic disorder may be reversed given a sufficient number of learning trials—an observation consistent with past conditioning findings in the disorder (21). That is, with enough training, the unreinforced generalization stimulus may come to elicit little initial fear with which to form secondary fear of fear, resulting in the relative absence of a fear response to the generalization stimulus among panic patients.

The results of this study suggest hypotheses on novel treatments for panic disorder. Our data suggest that panic disorder involves perturbed discrimination of risk for aversive outcomes, as opposed to another form of pathology: oversensitivity to overt danger, as modeled by the conditioned danger cue. Data in animal models demonstrate that administration of d-cycloserine, a partial agonist of the N-methyl-d-aspartate receptor, enhances an organism's ability to discriminate conditioned danger cues from conditioned safety cues (22, 23). Given animal findings that d-cycloserine strengthens acquisition of aversive conditioning (see references 24 and 25, for example), d-cycloserine may enhance conditioned discrimination by strengthening the accuracy of learning—with a resulting decrease in generalization errors.

Another pharmacological prediction may be drawn from work in gerbils implicating conditioning-dependent retuning of sensory representations of the conditioned danger cue toward resembling stimuli (see reference 26, for example) that may lead to overgeneralization by rendering perceptual discrimination of the danger cue from its approximations more difficult. This perceptual blurring of the conditioned danger cue and its approximations has been tightly linked to the cholinergic system, with increased acetylcholine activity (in primary sensory cortex) associated with increases in this type of conditioning-dependent plasticity (27). Consequently, medications with anticholinergic properties (e.g., scopolamine) may facilitate improved sensory discrimination of the conditioned danger cue and its approximations and may thereby treat overgeneralization of the kind associated with panic disorder.

One final treatment implication stems from retarded acquisition of discriminative conditioning in panic disorder evidenced by deficient levels of learning in panic patients during the first but not the second half of the study. This conditioning deficit is related to the speed of—rather than the capacity for—discriminative conditioning. That is, after a sufficiently large number of learning trials, panic patients are able to discriminate the hedonic value of danger signals from those of safety at a level comparable to healthy comparison subjects. This finding suggests that overgeneralization in panic disorder might be reduced through psychotherapeutic interventions with a sufficient number of sessions aimed at imparting discriminative learning between genuine panic cues and resembling cues that may trigger false alarms but are themselves associated with no negative outcome. The pharmacological interventions described above, in tandem with this type of psychotherapy, may facilitate the strength and speed of discriminative learning in panic patients, with a resulting decrease in fear generalization.