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.Many etiological accounts of panic disorder implicate classical conditioning as a central pathogen (1-4). According to these accounts, neutral conditioned stimuli that are present during an aversive panic attack acquire the capacity to trigger anticipatory anxiety for, or an actual occurrence of, panic attacks through classical conditioning (1,2,5). Conditioned stimuli contributing to the onset and maintenance of panic disorder are thought to extend to exteroceptive and interoceptive stimulus events resembling those co-occurring with panic (1, 2,6) via stimulus generalization-a learning mechanism whereby fear responses extend to a range of stimuli resembling the original conditioned stimuli (7). For example, conditioned fear to the environment where a panic attack occurs (e.g., a specific shopping mall) might transfer, Address correspondence and reprint requests to Dr. Lissek, NIMH, 15K North Dr., Rm. 200, Bethesda, MD 20892-2670; lisseks@mail.nih.gov. Presented in part at the 161st annual meeting of the American Psychiatric Association, Washington, D.C., May 3-8, 2008; and the 47...

Though generalization of conditioned fear has been implicated as a central feature of pathological anxiety, surprisingly little is known about the psychobiology of this learning phenomenon in humans. Whereas animal work has frequently applied methods to examine generalization gradients to study the gradual weakening of the conditioned-fear response as the test stimulus increasingly differs from the conditioned stimulus (CS), to our knowledge no psychobiological studies of such gradients have been conducted in humans over the last 40 years. The current effort validates an updated generalization paradigm incorporating more recent methods for the objective measurement of anxiety (fear-potentiated startle). The paradigm employs 10, quasi-randomly presented, rings of graduallyincreasing size with extremes serving as CS+ and CS-. The eight rings of intermediary size serve as generalization stimuli (GS's) and create a continuum-of-similarity from CS+ to CS-. Both startle data and online self-report ratings demonstrate continuous decreases in generalization as the presented stimulus becomes less similar to the CS+. The current paradigm represents an updated and efficacious tool with which to study fear generalization-a central, yet understudied conditioningcorrelate of pathologic anxiety.

Background Meta-analytic results of fear-conditioning studies in the anxiety disorders implicate generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of anxiety pathology. Due to the absence of conditioning studies assessing generalization in generalized anxiety disorder (GAD), results of this meta-analysis do not reveal whether such generalization abnormalities also apply to GAD. The current study fills this gap by behaviorally and psychophysiologically assessing levels of conditioned fear-generalization across adults with and without GAD. Methods Twenty-two patients with a DSM-IV-TR diagnosis of GAD and 26 healthy comparisons were recruited and tested. The employed generalization paradigm consists of quasi-randomly presented rings of gradually increasing size, with extreme sizes serving as conditioned danger cues (CS+) and conditioned safety-cues (CS−). The rings of intermediary size serve as generalization stimuli, creating a continuum-of-similarity between CS+ and CS− across which to assess response slopes, referred to as generalization gradients. Primary outcome variables included slopes for fear-potentiated startle (EMG) and self-reported risk ratings. Results Behavioral and psychophysiological findings demonstrate overgeneralization of conditioned fear among patients with GAD. Specifically, generalization gradients were abnormally shallow among GAD patients, reflecting less degradation of the conditioned fear response as the presented stimulus differentiated from the CS+. Conclusions Overgeneralization of conditioned fear, to safe encounters resembling feared situations, may contribute importantly to the psychopathology of GAD by proliferating anxiety cues in the individual’s environment that are then capable of evoking and maintaining anxiety and worry associated with GAD.

Objective-Predictability is a fundamental modulator of anxiety in that the ability to predict aversive events mitigates anxious responses. In panic disorder, persistent symptoms of anxiety are caused by anticipation of the next uncued (unpredictable) panic attack. The authors tested the hypothesis that elevated anxious reactivity, specifically toward unpredictable aversive events, is a psychophysiological correlate of panic disorder.Method-Participants were exposed to one condition in which predictable aversive stimuli were signaled by a cue, a second condition in which aversive stimuli were administered unpredictably, and a third condition in which no aversive stimuli were anticipated. Startle was used to assess anxious responses to cues and contexts.Results-Relative to healthy comparison subjects, patients with panic disorder displayed equivalent levels of fear-potentiated startle to the threat cue but elevated startle potentiation in the context of the unpredictable condition.Conclusions-Patients with panic disorder are overly sensitive to unpredictable aversive events. This vulnerability could be either a premorbid trait marker of the disorder or an acquired condition caused by the experience of uncued panic attacks. As a premorbid trait, vulnerability to unpredictability could be etiologically related to panic disorder by sensitizing an individual to danger, ultimately leading to intense fear/alarm responses to mild threats. As an acquired characteristic, such vulnerability could contribute to the maintenance and worsening of panic disorder symptoms by increasing anticipatory anxiety.Panic disorder involves two cardinal features: panic attacks, defined as acute surges of fear (1), and anticipatory anxiety (2), defined as persistent apprehension about future panic attacks (3). Only a subset of the many individuals who experience panic attacks develop panic disorder. The transition from panic attacks to panic disorder is thought to involve a process whereby anxiety in anticipation of subsequent panic attacks (4) increases the likelihood of additional attacks (5) and leads to full-blown panic disorder (3). According to this assessment, marked anticipatory anxiety about the uncertain recurrence of panic attacks leads to chronic anxiety (2).Interestingly, most research on the physiology of panic disorder focuses specifically on panic attacks as opposed to anticipatory anxiety in panic disorder. Understanding the correlates of Address correspondence and reprint requests to Dr. Grillon, NIMH/MAP, 15K North Dr., Bldg. 15K, Rm. 113, MSC 2670, Bethesda, MD 20892-2670 E-mail: Christian.grillon@nih.gov (e-mail anticipatory anxiety in the disorder may be very important. Because panic attacks typically are irregular and uncertain (2) and are perceived as arising 'out of the blue,' heightened sensitivity to unpredictable aversive events among individuals who experience spontaneous panic attacks may, over time, lead to persistent anticipatory anxiety, facilitating the transition from panic attacks to full-blown pa...