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...

Classical fear-conditioning is central to many etiologic accounts of panic disorder (PD), but few lab-based conditioning studies in PD have been conducted. One conditioning perspective proposes associative-learning deficits characterized by deficient safety learning among PD patients. The current study of PD assesses acquisition and retention of discriminative aversive conditioning using a fear-potentiated startle paradigm. This paradigm was chosen for its specific capacity to independently assess safety- and danger-learning in the service of characterizing putative anomalies in each type of learning among those with PD. Though no group difference in fear-potentiated startle was found at retention, acquisition results demonstrate impaired discrimination learning among PD patients as indexed by measures of conditioned startle-potentiation to learned safety and danger cues. Importantly, this discrimination deficit was driven by enhanced startle potentiation to the learned safety-cue rather than aberrant reactivity to the danger cue. Consistent with this finding, PD patients relative to healthy individuals reported higher expectancies of dangerous outcomes in the presence of the safety cue, but equal danger expectancies during exposure to the danger cue. Such results link PD to impaired discrimination learning, reflecting elevated fear responding to learned safety-cues.

Past studies beginning with Jackson and colleagues (2000) document increases and decreases in emotionally-potentiated startle by way of instructing participants to enhance or suppress their emotional responses to symbolic sources of threat (unpleasant pictures). The present study extends this line of work to a threat-of-shock paradigm to assess whether startle potentiation elicited by threat of actual danger or pain is subject to emotion regulation. Results point to successful volitional modulation for both Affective-Picture and Threat-of-Shock experiments with startle magnitudes from largest to smallest occurring in the enhance, maintain, and suppress conditions. Successful regulation of startle potentiation to the threat of shock found by the current study supports the external validity of the Jackson paradigm for assessment of regulation processes akin to those occurring in the day-to-day context in response to real elicitors of emotion.