Overgeneralization of conditioned fear as a pathogenic marker of panic disorder

Abstract

Objective: Classical conditioning features prominently in many etiological accounts of panic disorder. According to such accounts, neutral conditioned stimuli present during panic attacks acquire panicogenic properties. Conditioned stimuli triggering panic symptoms are not limited to the original conditioned stimuli but are thought to generalize to stimuli resembling those co-occurring with panic, resulting in the proliferation of panic cues. The authors conducted a laboratory-based assessment of this potential correlate of panic disorder by testing the degree to which panic patients and healthy subjects manifest generalization of conditioned fear.

Method: Nineteen patients with a DSM-IV-TR diagnosis of panic disorder and 19 healthy comparison subjects were recruited for the study. The fear-generalization paradigm consisted of 10 rings of graded size presented on a computer monitor; one extreme size was a conditioned danger cue, the other extreme a conditioned safety cue, and the eight rings of intermediary size created a continuum of similarity from one extreme to the other. Generalization was assessed by conditioned fear potentiating of the startle blink reflex as measured with electromyography (EMG).

Results: Panic patients displayed stronger conditioned generalization than comparison subjects, as reflected by startle EMG. Conditioned fear in panic patients generalized to rings with up to three units of dissimilarity to the conditioned danger cue, whereas generalization in comparison subjects was restricted to rings with only one unit of dissimilarity.

Conclusions: The findings demonstrate a marked proclivity toward fear overgeneralization in panic disorder and provide a methodology for laboratory-based investigations of this central, yet understudied, conditioning correlate of panic. Given the putative molecular basis of fear conditioning, these results may have implications for novel treatments and prevention in panic disorder.

FIGURE 1. Conditioning and Generalization Stimuli in a Study of Overgeneralization of Conditioned Fear in Panic Disorder^a

^a Participants were counterbalanced into two groups. For half of participants (group A), the largest ring was the conditioned danger cue (conditioned stimulus paired with shock, CS+) and the smallest was the conditioned safety cue (conditioned stimulus unpaired with shock, CS−), and for the other half (group B) this was reversed. The numerals below the rings label the stimuli from smallest to largest. As was done previously by Lissek et al. (9) to avoid an unduly large number of trials while maintaining a gradual continuum of size across rings, each of two intermediaries were collapsed into a single class of stimulus, leaving four classes of generalization stimuli. For both counterbalancing groups A and B, these classes of generalization stimuli are numbered such that class 4 consists of the two rings closest in size to the conditioned danger cue (rings 8 and 9 for counterbalancing group A, rings 3 and 2 for group B), and classes 3, 2, and 1 consist of rings progressively increasing in similarity to the conditioned safety cue. The diameter for the smallest ring (ring 1) was 2.00 inches, and diameters of subsequent rings increased progressively by 15%, such that ring 2 was 15% larger than ring 1 (diameter=2.30 inches), ring 3 was 30% larger than ring 1 (diameter=2.60 inches), ring 4 was 45% larger than ring 1 (diameter=2.90 inches), and so on (through 4.70 inches).

FIGURE 2. Average Standardized Startle-Blink EMG Magnitudes at Generalization Test, by Group, for Conditioned Stimuli Paired (CS+) and Unpaired (CS−) With Shock, Classes of Generalization Stimuli (Classes 1–4 [C1–C4]), and Intertrial Intervals (ITIs)^a

^a The dotted lines refect linear decreases in startle from CS+ to CS− with which to visualize the deviation of gradients from linearity. Such deviations refect a significant quadratic component in the generalization gradient of healthy comparison subjects (p=0.001) but not patients with panic disorder (p=0.62). The data points outlined in green mark stimulus classes for which startle is potentiated relative to the CS− (at the Hochberg-adjusted p value) for each group. Startle EMG was standardized using within-subject T score transformations ([([EMG_{single trial} − EMG_mean]/SD)*10]+50).

FIGURE 3. Risk Ratings and Reaction Times for Conditioned Fear Generalization in Patients With Panic Disorder and Healthy Comparison Subjects^a

^a Participants were instructed to rate their perceived risk of shock, answering according to their “gut feeling” of risk (1=no risk, 2=some risk, 3=high risk), and to respond as quickly as possible using a computer keyboard. CS+=conditioned stimulus paired with shock; CS−=conditioned stimulus unpaired with shock; C1, C2, C3, and C4=generalization stimulus classes 1, 2, 3, and 4; ITI=intertrial interval.