Enhanced discrimination between threatening and safe contexts in high-anxious individuals

Abstract

Trait anxiety, a stable personality trait associated with increased fear responses to threat, is regarded as a risk factor for the development and maintenance of anxiety disorders. Although the effect of trait anxiety has been examined with regard to explicit threat cues, little is known about the effect of trait anxiety on contextual threat learning. To assess this issue, extreme groups of low and high trait anxiety underwent a contextual fear conditioning protocol using virtual reality. Two virtual office rooms served as the conditioned contexts. One virtual office room (CXT+) was paired with unpredictable electrical stimuli. In the other virtual office room, no electrical stimuli were delivered (CXT−). High-anxious participants tended to show faster acquisition of startle potentiation in the CXT+ versus the CXT− than low-anxious participants. This enhanced contextual fear learning might function as a risk factor for anxiety disorders that are characterized by sustained anxiety.

Introduction

Identifying signals that indicate threat is vitally important for the survival of an organism. Fear and anxiety are important emotional reactions that help to mobilize appropriate behavioral responses in dangerous situations (Mineka and Öhman, 2002). Fear is a phasic reaction toward an explicit threatening stimulus, whereas anxiety is defined as a diffuse and longer-lasting state related to more unspecific and unpredictable threats (Davis et al., 2010, Marks, 1987). Moreover, fear and anxiety also vary in their neurobiological bases. Phasic responses to a threat cue have been related to the amygdala (Alvarez et al., 2008, Knight et al., 2005, LeDoux, 2000, Phelps, 2006), whereas sustained responses to unpredictable stressors have been found to be additionally mediated by the bed nucleus of the stria terminalis (BNST; Alvarez et al., 2011, Luyten et al., 2011, Zimmerman and Maren, 2011) and the hippocampus (Alvarez et al., 2008, Hasler et al., 2007, Lang et al., 2009, Marschner et al., 2008).

Cue conditioning, where a discrete cue (conditioned stimulus, CS) is predictably paired with an aversive event (unconditioned stimulus, US), is regarded as a model for phasic fear learning (Grillon, 2002a). However, in the case of an unpredictable US, the individual experiences a chronic state of anxiety because of an inability to identify periods of safety (Seligman, 1968, Seligman and Binik, 1977). Studies on contextual fear conditioning frequently combine the presentation of predictable and unpredictable aversive events in one experiment. In these studies, the US is predictably paired with a discrete cue (CS/US are paired) in one condition, whereas in another condition, the US is presented without being associated with a cue (context conditioning; CS/US are unpaired) (Grillon et al., 2004, Grillon et al., 2006, Vansteenwegen et al., 2008). In the latter condition, the context becomes associated with the unpredictable US because the context is the best predictor of it. Thus, contextual fear conditioning induces a state of chronic anticipatory anxiety as the occurrence of the US is not time-bound and experienced as unpredictable (Grillon, 2008). Therefore, contextual fear conditioning may be relevant for anxiety disorders characterized by sustained and longer lasting anxiety states (Grillon, 2002a, Lang et al., 2000, Marks, 1987). As a matter of fact, there is evidence that in patients with anxiety disorders, the processing of unpredictable threats is altered. Panic disorder patients, but not healthy controls, have been found to show increased anxiety in a context in which unpredictable aversive events occurred, compared to a safe context where no aversive event appeared (Grillon et al., 2008). Thus, we conclude that increased contextual anxiety elicited by unpredictable aversive events may be an important pathogenic marker for anxiety disorders characterized by diffuse and sustained anxiety states.

Inter-individual differences in trait anxiety are thought to have an impact on the acquisition and extinction of conditioned fear responses and are regarded as a risk factor for anxiety disorders (Chambers et al., 2004, Mineka and Oehlberg, 2008). Trait anxiety refers to the State-Trait-Anxiety Model and indicates relatively firm inter-individual differences in the tendency to rate situations as threatening. Thus, the individual reacts with increased state anxiety (Spielberger et al., 1970). Consequently, high-anxious individuals tend to feel threatened and respond with fear more often than low-anxious subjects. Interestingly, an animal study investigating the influence of a trait-like measure of anxiety on cued fear conditioning (Duvarci et al., 2009) revealed that high-anxious rats were characterized by an impaired discrimination of cues in a conditioning protocol, but displayed high freezing in the context. By contrast, low-anxious rats exhibited enhanced discrimination during cue conditioning, but showed lower contextual freezing. In the face of a predictable threat, high trait anxiety might lead to diminished discrimination between fear and safety cues and might therefore result in increased contextual anxiety. Additionally, the combination of cued and contextual fear conditioning in one paradigm was used in an fMRI study investigating the influence of trait anxiety in humans (Indovina et al., 2011). On the one hand, high trait-anxious participants showed an increased amygdala response to cues that predicted the US, suggesting vulnerability for anxiety disorders characterized by phasic fear. On the other hand, these individuals displayed decreased activity of the ventral prefrontal cortex (vPFC) to cues and contexts, indicating reduced control mechanisms to downregulate both phasic fear and sustained anxiety during acquisition, which may account for inhibitory deficits or the maintenance of anxiety disorders. Supporting this idea and in analogy to clinical samples, a cue (Sehlmeyer et al., 2011) and a contextual fear conditioning study (Barrett and Armony, 2009) employing fMRI have identified resistance to extinction as indexed by an elevated amygdala response in extinction in individuals with high trait anxiety. Other studies have reported heightened amygdala responses to unattended or unconscious fearful faces in high trait-anxious individuals (Dickie and Armony, 2008, Etkin et al., 2004). In sum, high trait anxiety seems to be a vulnerability factor for the development and maintenance of different anxiety disorders as it is associated with an increased amygdala response to fearful stimuli, resistance to extinction, and altered control mechanisms. However, studies that have investigated the influence of trait anxiety on the acquisition of contextual anxiety are lacking.

In humans, contextual fear conditioning can be conducted using virtual reality (VR). With the help of VR, it is possible to change location in spatial contexts while being physically stationary. This increases the controllability of the experiment considerably and makes it possible to register behavioral characteristics of anxiety, like avoidance or approach behavior (Glotzbach et al., 2012, Grillon et al., 2006) and physiological variables simultaneously (Baas et al., 2004, Baas et al., 2008, Mühlberger et al., 2008, Tröger et al., 2012).

To assess the influence of trait anxiety on contextual anxiety, participants scoring high versus low on the trait version of the State-Trait-Anxiety-Inventory (STAI; Spielberger et al., 1970) underwent contextual fear conditioning in a VR paradigm with two contexts and no cues. One context (the anxiety context) was paired with unpredictable slightly painful electric stimuli, whereas the other context (the safety context) was never paired with any aversive stimulus. Based on fear conditioning studies on highly trait-anxious individuals and clinical samples, we first hypothesized that high-anxious individuals would show greater physiological arousal overall (higher baseline SCL and startle magnitudes) compared to low-anxious individuals (Blechert et al., 2007, Glover et al., 2011, Orr et al., 2000). Second, we hypothesized that the high-anxious group would exhibit enhanced context conditioning (greater differences between the CXT+ and CXT− in startle, SCL, and ratings measurements) compared to the low-anxious group (Grillon et al., 2008).