Increased Anxiety During Anticipation of Unpredictable But Not Predictable Aversive Stimuli as a Psychophysiologic Marker of Panic Disorder

Abstract

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...

Using the Threat Probability Task to Assess Anxiety and Fear During Uncertain and Certain Threat

“…The NPU task manipulates uncertainty regarding both IF (shock probability) and WHEN (shock timing) shocks will occur. The NPU task has been used to examine drug administration and deprivation effects on negative affective response 4,34 and etiological mechanisms in mood and anxiety disorders [22][23][24][41][42][43] . In other research, Curtin and colleagues have also developed variants of these cued threat tasks that precisely manipulate threat uncertainty about WHEN (shock timing) 5,29,44 ; WHERE (administration location on body for shock) 25 ; and HOW BAD (shock intensity) 7 .…”

“…In the Unpredictable condition of the NPU task, shocks are fully unpredictable. Patients with posttraumatic stress and panic disorders exhibit selectively increased startle potentiation during unpredictable but not predictable shock in the NPU task 22,23 . In other work, medications prescribed to treat anxiety have a greater effect on startle potentiation during unpredictable shock than during predictable shock in the NPU task 24 .…”

Phasic and Sustained Fear are Pharmacologically Dissociable in Rats

“…In this regard, other findings by Grillon et al (2009b) are also relevant. In particular, they observed that startle potentiation to short-duration stimuli that have been paired with shock are no greater in post-traumatic stress (Grillon et al, 2009b) and panic disorder patients (Grillon et al, 2008) than in healthy controls, but that the startle responses that occur between stimulus presentations, which as noted earlier may reflect a more sustained type of anxiety to the less-predictive threat context, are greater (cf, Davis et al, 2010). These very interesting results lend support to the view that drugs that reduce sustained startle increases may be more clinically efficacious than those that preferentially reduce phasic startle increases.…”

Contextual conditioning in rats as an animal model for generalized anxiety disorder

“…Moreover, evidence from developmental, neurobiological, and pharmacological preclinical studies suggests that contextual conditioning and explicit cue conditioning constitute distinct processes mediated by separate brain systems (Ameli et al, 2001;Luyten, Casteels, Vansteenwegen, van Kuyck, Koole, Van Laere et al, 2011). For comprehensive reviews, see Anagnostaras, Gale, and Fanselow (2001); Davis (1998) ;Gewirtz, McNish, and Davis (2000); Grillon (2002);and Grillon, Lissek, Rabin, McDowell, Dvir and Pine (2008).…”