Both fear and anxiety are biologically adaptive responses to environmental threat. However, when experienced over a long period of time they can have a devastating effect, as sufferers of anxiety disorders know only too well. So why is it that some of us can overcome the discrete fears and nonspecific anxiety that we experience in our lives more easily than others? Researchers conducting experimental fear conditioning in both humans and animals have argued that dysregulation of the mechanisms underlying the development and maintenance of “conditioned” fear responses may provide an explanation. Basic neuroscience and functional neuroimaging studies have greatly advanced our understanding of these mechanisms (Maren and Quirk, 2004; Sotres-Bayon et al., 2004; Phelps and LeDoux, 2005; Bishop, 2007
). Findings from these studies implicate the amygdala in the acquisition and expression of conditioned fear, this being modulated by input from the ventromedial prefrontal cortex (vmPFC) which is thought to inhibit the expression of conditioned fear following extinction training (i.e., when the conditioned stimulus [CS] or acquisition context is repeatedly presented alone, without the aversive unconditioned stimulus [UCS]) (Phelps et al., 2004; Quirk et al., 2006
). The hippocampus is also implicated in the contextual modulation of conditioned fear, in particular its extinction (Ji and Maren, 2007
). However, it remains to be established how personality characteristics such as high trait anxiety act through these mechanisms to confer a diathesis, or increased vulnerability, for anxiety disorders (Mineka and Oehlberg, 2008
). Or to pose the question another way: what differences in neurocognitive function protect low trait anxious individuals from experiencing chronic fear and anxiety? A possibility considered here is that the mechanisms which determine whether certain individuals are more or less anxiety-prone than others might include regulatory processes that fall outside the standard conceptual framework of rodent models of fear conditioning.
Studies investigating differences in neural or cognitive function associated with vulnerability to anxiety have typically sought to distinguish high from low trait anxious individuals in a unitary manner. However, symptom variability across anxiety disorders suggests that there may be at least two dimensions of function associated with risk for these disorders (Mineka and Oehlberg, 2008
). In particular, certain anxiety disorders, such as specific phobia, are primarily characterized by cue-specific or phasic fear, while others, e.g., generalized anxiety disorder, are also characterized by diffuse or non-cue-specific anxiety. Experimental fear-conditioning studies suggest that the development of phasic fear and non-cue-specific anxiety may be modeled by cued and contextual fear conditioning, respectively (Grillon and Davis, 1997; Grillon, 2002
). In cued fear conditioning, an initially neutral CS is presented such that it temporally predicts the occurrence of an aversive UCS. This association results in “cued” or phasic fear responses upon subsequent presentation of the CS. This contrasts with “contextual” fear responses—non-cue-specific fear of the environment in which an UCS is encountered—which occur when the CS is absent or nonpredictive of UCS occurrence. While multiple mechanisms influence the acquisition and maintenance of cued and contextual fear (Phillips and LeDoux, 1994; Davis and Shi, 1999; Maren and Quirk, 2004; Sotres-Bayon et al., 2004; Phelps et al., 2004; Ji and Maren, 2007
), potentially only a subset of these vary substantially in their function across individuals and are linked to differences in trait vulnerability to anxiety. Here, we used functional neuroimaging of cued and contextual fear conditioning in humans to test a dual-route model of trait vulnerability to anxiety
, according to which two, at least partially, independent dimensions of neurocognitive function are associated with elevated trait vulnerability to anxiety.
We hypothesized that amygdala responsivity to phasic fear cues would provide the first dimension of individual variability associated with trait vulnerability to anxiety, primarily influencing phasic fear acquisition. Here, we built on findings from lesion studies in rodents and neuroimaging research in humans supporting the involvement of the amygdala in the acquisition and expression of cued fear (Maren and Quirk, 2004; Phelps and LeDoux, 2005
). This hypothesis was also informed by meta-analyses suggesting that clinically anxious patients show stronger acquisition of cued fear than healthy control participants (Lissek et al., 2005
Diverging from rodent models of fear conditioning, the second key dimension was predicted to involve the recruitment of ventral prefrontal cortical (vPFC) dependent emotion regulation mechanisms to diminish both cued and contextual fear responses before the omission of threat (i.e., of the UCS). Here, the use of information about CS-UCS contingencies to engage vPFC emotion regulation mechanisms when cued and contextual fear are at their respective peaks is hypothesized to enable individuals to decrease these fear responses prior to extinction. This hypothesis was informed, in part, by models arguing for impoverished contingency-appropriate inhibition of conditioned fear in anxiety (Davis et al., 2000; Lissek et al., 2005
) but draws especially upon recent findings indicating that, in humans, vPFC circuitry supports not only the extinction of conditioned fear but also emotion regulation (Ochsner et al., 2002; Ochsner and Gross, 2005; Delgado et al., 2008
). The vPFC circuitry underlying emotion regulation encompasses both the medial regions typically implicated in the extinction of conditioned fear and more lateral regions implicated in other forms of cognitive control—e.g., attention regulation (Wager et al., 2008
). During intentional emotion regulation, these vPFC regions are coactivated with dorsolateral PFC regions thought to support the deliberate selection of strategies for reappraising emotional stimuli (Ochsner et al., 2002; Mauss et al., 2007; Hartley and Phelps, 2010
). The strength of vPFC recruitment during emotion regulation distinguishes individuals able to successfully reduce negative responses to aversive stimuli (Wager et al., 2008
). Further, under instruction, emotion regulation can facilitate the reduction of conditioned fear (Delgado et al., 2008
). Recently, the role of uninstructed or “automatic” emotion regulation (AER) has received attention, with adaptive forms of AER being proposed to involve recruitment of these same vPFC mechanisms (Mauss et al., 2007
). Individual differences in the recruitment of vPFC mechanisms supporting AER might be a key dimension influencing risk for psychopathology. Specifically, we hypothesized that individuals who, without instruction, spontaneously engaged vPFC mechanisms to downregulate acquired fear responses would be less at risk of developing chronic levels of fear and anxiety, with this being reflected in lower trait anxiety scores.