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The current article, taking a cognitive neuroscience ... conditioning, emotion regulation, generalized anxiety disorder, social phobia, social threat processing.
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A Cognitive Neuroscience Approach to Generalized Anxiety Disorder and Social Phobia

Emotion Review Vol. 4, No. 2 (April 2012) 133­–138 © The Author(s) 2012 ISSN 1754-0739 DOI: 10.1177/1754073911430251 er.sagepub.com

Karina S. Blair R. J. R. Blair

Mood & Anxiety Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA

Abstract Generalized anxiety disorder (GAD) and social phobia (SP) are major anxiety disorders identified by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). They are comorbid, overlap in symptoms, yet present with distinct features (worry in GAD and fear of embarrassment in SP). Both have also been explained in terms of conditioning-based models. However, there is little reasoning currently to believe that GAD in adulthood reflects heightened conditionability or heightened threat processing—though patients with SP may show heightened processing of social threat stimuli. Moreover, the computational architectures that maintain these disorders in adulthood are different. For GAD this may reflect the development of an inefficient “worrying” strategy of emotional regulation. For SP this appears to reflect the atypical processing of self-referential information.

Keywords conditioning, emotion regulation, generalized anxiety disorder, social phobia, social threat processing

Generalized anxiety disorder (GAD) and social phobia (SP) are two highly prevalent, chronic, and disabling anxiety disorders that are sometimes comorbid. They show some indications of symptom overlap; for example, increased tension and thoughts of future threat (Craske et al., 2009). However, GAD is specifically characterized by persistent and excessive worry about life or the welfare of loved ones that is difficult to control and causes significant distress. SP is marked by acute anxiety to social or performance situations, related to the concern of scrutiny, or humiliation, by others. There have been claims that a similar neural, and presumably computational, architecture mediates all anxiety disorders (e.g., Martin, Ressler, Binder, & Nemeroff, 2010). The current article, taking a cognitive neuroscience perspective, suggests that this view requires modification.

GAD from a Cognitive Neuroscience Perspective Conditioning-based accounts have been proposed for the pathogenesis of anxiety disorders for most of the last century (Watson & Rayner, 1920). The suggestion is that pathological anxiety develops through classical conditioning; the individual experiences

an aversive unconditioned stimulus (US) that is associated with an event/experience that becomes the focus of the individual’s anxiety. GAD might therefore reflect a heightened propensity for aversive conditioning and the development of anxiety towards a variety of stimuli. In line with this, and on the basis of a meta-analysis of the literature, Lissek et al. concluded that anxiety-disordered adults showed atypical conditioning (2005). But only two studies have examined conditioning in patients with GAD (Pitman & Orr, 1986; Thayer, Friedman, Borkovec, Johnsen, & Molina, 2000). The first did indicate increased responsiveness to the conditioned stimulus (CS+) in the patients with GAD (Pitman & Orr, 1986). However, over 50% of the patients with GAD also presented with panic disorder and it is thus unclear whether the enhanced conditionability reflects GAD or panic disorder. The second involved dot cues anticipating either threat or neutral words and conditioned heart rate deceleration as the indexed conditioned response (Thayer et al., 2000). However, this study is difficult to interpret as this conditioned response was not shown by the healthy comparison individuals. Moreover, the results of a third study are relevant. This study examined the impact on startle reflex of cues which were either: (a) predictive of aversive stimuli; (b) associated with aversive

Corresponding author: Karina S. Blair, Mood & Anxiety Program, National Institute of Mental Health, 15K North Drive, MSC 2670, Bethesda, MD 20892, USA. Email: [email protected]

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stimuli that were administered unpredictably; or (c) predictive of the absence of aversive stimuli (Grillon et al., 2009). Across conditions, patients with GAD (and unlike patients with posttraumatic stress disorder [PTSD]) showed no differences from control participants in the impact of these cues on startle reflex. If heightened conditionability was associated with GAD, patients with GAD should have shown an increased startle reflex following cues predictive of aversive stimuli. Yet this was not seen. Relatedly, studies have examined the physiological response of patients with GAD to aversive stimuli. These studies have shown either reduced, or not significantly increased, physiological arousal in patients with GAD (Grillon et al., 2009; Hoehn-Saric, McLeod, & Zimmerli, 1989). Similarly, studies have examined the response of the amygdala to emotional stimuli in patients with GAD using fMRI. Studies with pediatric patients have indicated hyperactivity to negative emotional expression faces in GAD (McClure et al., 2007; Monk et al., 2008); however, in contrast, three out of four studies with adult patients have not (Blair, Shaywitz et al., 2008; Palm, Elliott, McKie, Deakin, & Anderson, 2011; Whalen et al., 2008). The fourth, which did find increased amygdala response to fearful expressions in patients with GAD, also reported increased amygdala responses to happy expressions—suggestive of generally increased emotional responsiveness rather than a threat-specific hyper-responsiveness (Etkin, Prater, Hoeft, Menon, & Schatzberg, 2010). A fifth study also found no significant increased amygdala response to the anticipation/receipt of threatening images (though the patients with GAD did show heightened amygdala responses to the anticipation/receipt of neutral images; Nitschke et al., 2009). In short, currently, the literature does not support the suggestion of heightened threat conditioning or threat sensitivity in at least adults with GAD. The hallmark feature of GAD is an increased propensity to worry. It has been argued that patients with GAD resort to worry because of an underlying abnormality in emotional regulation (Mennin, Holaway, Fresco, Moore, & Heimberg, 2007). Imaging studies implicate a network of brain regions in both explicit emotional regulation, where subjects are told to reduce their emotional response (Ochsner et al., 2004), and implicit emotional regulation, where subjects must perform attentiondemanding tasks that lead to reductions in the emotional response (Blair et al., 2007; Pessoa, McKenna, Gutierrez, & Ungerleider, 2002). These include lateral frontal, dorsal anterior cingulate (dACC), and parietal cortices (Ochsner et al., 2004). These regions are implicated in top–down attention which is thought to facilitate attention allocation to nonemotional stimulus features in both explicit and implicit tasks. In both types of tasks, following attention theory (Desimone & Duncan, 1995), increased attention allocation to nonemotional stimulus features should reduce representation of emotional stimulus features and consequently reduce the emotional response. Only two studies have investigated emotional regulation in patients with GAD (Blair et al., under review; Etkin et al., 2010). Etkin et al. (2010) found reduced implicit emotional

regulation and reduced regulatory activity within pregenual anterior cingulate in patients with GAD. Blair et al. (under review) observed reduced recruitment of dACC and parietal cortices in the patients with GAD during both implicit and explicit emotional-regulation tasks. These data suggest that a reduced capacity for emotional regulation might be a risk factor for the emergence of GAD. However, it should be noted that Blair found that this reduced recruitment of dACC and partietal cortices was also seen in patients with SP. Moreover, other work has also reported reduced recruitment of these regions in explicit emotional-regulation tasks in patients with SP (Goldin, Manber, Hakimi, Canli, & Gross, 2009; Goldin, Manber-Ball, Werner, Heimberg, & Gross, 2009). As such, dysfunctional emotional regulation does not appear to be a specific risk factor for GAD, but rather a more general risk factor for the development of (at least these forms of) anxiety disorders. Attention-based models of anxiety have also been suggested. It has been argued that anxious individuals initially show rapid orienting of attention toward and engagement in/ difficulty disengaging from threat stimuli. This is then followed by the eventual direction of attention away from the threat in an effort to reduce subjective distress (Mogg & Bradley, 2002). It is hypothesized that this “vigilance–avoidance” pattern of cognitive bias is maladaptive because it enhances sensitization and interferes with habituation, thereby maintaining anxiety (Mogg & Bradley, 2002). In line with this view, both pediatric and adult patients with GAD have been found to show attentional bias towards threat words and angry faces (Bradley, Mogg, White, Groom, & de Bono, 1999; Waters, Mogg, Bradley, & Pine, 2008), though attentional biases away from angry faces have also been reported in pediatric patients with GAD (e.g., Waters et al., 2008, in less anxious patients with GAD). A complication should be considered, however. How is this heightened attention to threat being mediated? Emotional attention is generally considered to reflect the interaction of the amygdala and cortical regions (Blair et al., 2007; Pessoa & Ungerleider, 2004). As the connections between temporal cortex and the amygdala are reciprocal (Amaral, Price, Pitkanen, & Carmichael, 1992), the activity of neurons representing emotional stimuli in temporal cortex is further augmented by reciprocal feedback from the amygdala. By this account, emotional stimuli are more likely to be attended to because they are more likely to “win” the competition for representation (Desimone & Duncan, 1995), because of the feedback from the amygdala. Functional magnetic resonance imaging studies have indicated amygdala hyperactivity related to negative emotional expression faces in pediatric GAD (McClure et al., 2007; Monk et al., 2008); however, four studies with adult GAD, consistent with the physiological literature (Grillon et al., 2009; HoehnSaric et al., 1989), have not (Blair, Shaywitz et al., 2008; Nitschke et al., 2009; Palm et al., 2011; Whalen et al., 2008). The inconsistency between the pediatric and adult literature regarding responsiveness to threatening stimuli in patients with GAD could reflect that GAD in adulthood reflects an accommodation

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to the increased responsiveness that was present when the patients were children. As such, GAD should not be considered an increased responsiveness to threat stimuli (this is particularly the case since increased responsiveness to threatening facial stimuli is seen in pediatric patients with SP who do not present with GAD; see following lines). Rather GAD might reflect an accommodation to this increased responsiveness to threatening stimuli that, while pathological, is at least successful in negating the original phenomena. In short, increased responsiveness to threat might be a nonspecific risk factor that can, but need not, lead to the development of GAD. In this regard it is worth briefly returning to a consideration of worry. As noted above, an increased propensity to worry is the hallmark feature of GAD. As such, to understand GAD we probably need to understand worry. Worry has been thought to reflect an overlearned compensatory strategy for dulling emotional experience (Borkovec, Alcaine, & Behar, 2004). However, excessive worry does not solve objective and subjective difficulties; worrying people do not plan complex responses to overwhelming events but rather repeat to themselves that things will get worse (Paulesu et al., 2010). Unfortunately, very little work has been conducted on worry from a cognitive perspective and only two studies (both with very small sample sizes) have investigated worry in patients with GAD using fMRI (Hoehn-Saric, Schlund, & Wong, 2004; Paulesu et al., 2010). Both implicated prefrontal regions, but the regions implicated were not mutually consistent and no computational account of worry has yet been offered. In summary, neither heightened conditionability nor heightened threat sensitivity is likely to maintain GAD as the current literature indicates that neither is heightened in adult patients. However, heightened generalized threat sensitivity may play a role in the initial development of the disorder given the literature on youth with GAD. It is possible that this heightened generalized threat sensitivity in an individual with a reduced capacity for emotional regulation may lead to the development of worry (as noted, an overlearned compensatory strategy for dulling emotional experience [Borkovec et al., 2004]). While the computational processes involved in worry remain unspecified, part of these processes, or their consequences, likely reflect internally driven priming of representations of potential threat. Such priming may lead to greater and stronger semantic representations of these threats, increasing their capacity to win the competition for representation; that is, increasing their capacity to become the focus of attention. Of course, these speculations are very preliminary but they are currently guiding our research.

SP from a Cognitive Neuroscience Perspective Conditioning-based theories have also been offered for SP. Phobias have been thought to potentially reflect hypersensitivity in the pathways that mediate innate fear. This argument has also been made for SP (cf. Milad & Rauch, 2007), though it rests on the assumption that social stimuli are innately fear inducing. Three studies have examined aversive conditioning in patients with SP (Hermann, Ziegler, Birbaumer, & Flor, 2002;

Schneider et al., 1999; Veit et al., 2002). All reported heightened conditioning in the disorder. Moreover, patients with SP show greater amygdala responses whilst associating neutral facial expressions with aversive stimuli (Schneider et al., 1999). However, some caveats should be considered. First, these data indicate that SP is associated with a greater preparedness to associate aversive outcomes with social stimuli rather than necessarily an increased innate fear of social threat. To conclude the latter, we have to assume that neutral facial expressions are innate social threats. Perhaps they are. There are reports that neutral expressions activate the amygdala and we could assume that the amygdala is a component of the innate response to social threat (Murphy, Nimmo-Smith, & Lawrence, 2003). But if neutral expressions were innate social threats and patients with SP show an increased innate fear of social threat, we should predict that patients with SP will show enhanced amygdala responses to neutral expressions. However, children and adults with SP typically do not (Blair, Shaywitz et al., 2008; Phan, Fitzgerald, Nathan, & Tancer, 2006; Stein, Goldin, Sareen, Zorrilla, & Brown, 2002; Straube, Mentzel, & Miltner, 2005; but see Birbaumer et al., 1998; Cooney, Atlas, Joormann, Eugene, & Gotlib, 2006). Second, all three studies used face stimuli as the conditioned stimulus (CS). As such, the literature cannot disentangle whether the effects represent a general propensity for increased condition-ability or a specific propensity to condition towards social stimuli. In this regard, however, it is worth considering the literature on threat responsiveness in SP. Thus, fMRI work has indicated heightened amygdala and temporal cortical activity to angry (Evans et al., 2008; Phan et al., 2006; Stein et al., 2002; Straube, Kolassa, Glauer, Mentzel, & Miltner, 2004; Straube et al., 2005) and fearful expressions in SP (Blair, Geraci, Korelitz et al., 2011; Blair, Shaywitz et al., 2008; but see Stein et al., 2002). In contrast, patients with SP do not appear to show an increased amygdala (Goldin, Manber-Ball, et al., 2009) or physiological response (McTeague et al., 2009) to physical threat. As such, we assume that SP does reflect a specific propensity to condition towards social stimuli. In this regard, it is worth noting that there are significant disadvantages with respect to using facial expression stimuli to understanding SP. Thus, while facial expression stimuli serve as reinforcers (happy expressions increase the probability of the repetition of actions that elicited them while fearful/ sad expressions decrease this probability; see Blair, 2003), they may be either primary, innately specified unconditioned stimuli or learnt, secondary reinforcers/conditioned stimuli or both. In other words, the heightened amygdala responses to angry expressions in SP may reflect: (a) an innately specified hyper-sensitivity to this expression; (b) heightened learning of an association between aversive experiences and this expression; or (c) both. It is thus important to determine whether patients with SP show heightened amygdala responses to socially aversive experiences that are unlikely to be innately specified aversive social unconditioned stimuli. In this regard, several studies have investigated the response of patients with SP to anticipated public speaking. Of these, two have reported

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increased amygdala–hippocampal and temporal cortical activity in the patients with SP (Lorberbaum et al., 2004; Tillfors, Furmark, Marteinsdottir, & Fredrikson, 2002). Two others did not (Nakao et al., 2011; van Ameringen et al., 2004). However, both of these studies involved very small sample sizes (5/6 patients with SP) and may not have had sufficient power to detect group differences. In short, patients with SP show heightened amygdala responses to socially aversive experiences that are unlikely to be innately specified aversive social unconditioned stimuli. But is SP only a heightened propensity to condition towards social stimuli? A core concern in SP is the fear of being negatively evaluated. These data have led to the suggestion that disordered self-referential processing, relating to dysfunctional medial prefrontal cortex activity (MPFC), is a core component of this disorder. This was first suggested by Blair, Geraci et al. (2008) in an fMRI study where patients were assessed when processing self- versus other-referential criticism (e.g., “You’re ugly” vs. “He’s ugly”) and praise (e.g., “You’re beautiful” vs. “He’s beautiful”). This study revealed selectively increased blood oxygen level dependent (BOLD) responses within both the amygdala and a dorsal/lateral region of MPFC in patients with SP to self-referential criticism. Since then a series of studies have examined issues related to selfreferential processing in patients with SP. Thus, patients with SP have been found to show increased amygdala responses to self-referential statements (Blair, Geraci, Majestic, et al., 2011), in anticipation of self-referential comments (Guyer et al., 2008) and to negative self-beliefs (Goldin et al., 2009). With respect to MPFC, regions proximal to the dorsal/lateral region of MPFC noted by Blair, Geraci et al. (2008) were identified in the context of the group main effects in two further studies (Blair et al., 2010; Blair, Geraci, Majestic et al. 2011). Patients with SP showed increased activity within these regions for self-referential statements irrespective of valence and when processing intentional, unintentional (embarrassment inducing) and normative social interaction vignettes. But ventromedial prefrontal cortex (VMPFC), also implicated in self-referential processing (Northoff et al., 2006), is important. Patients with SP have shown heightened VMPFC responses in anticipation of self-referential comments (Guyer et al., 2008) and to negative self-beliefs (Goldin, Manber-Ball, et al., 2009). Recent work has potentially clarified the basis of this ­atypical VMPFC activity in patients with SP. Blair et al. (2010) involved the subjects processing intentional and unintentional (embarrassing) conventional (social disorder-based) transgressions. Previous work with this paradigm, replicated by Blair et al. (2010), demonstrated that healthy individuals show significantly greater activity to intentional relative to unintentional conventional social transgressions (Berthoz, Armony, Blair, & Dolan, 2002). This response is thought to reflect heightened representation of the protagonist’s intent to challenge the social order (Berthoz et al., 2002). However, adults with SP showed a notably different pattern; increased activity to the unintentional relative to intentional social transgressions. In a second study, Blair, Geraci, Majestic et al. (2011) examined the response of patients with SP and comparison individuals to own

(first person; e.g., “I’m ugly”) or other individuals’ (second person; e.g., “You’re ugly”) negative, positive, and neutral opinions about the self. They found that healthy comparison adults showed an increased activation to first (“I”) relative to second (“You”) viewpoints within VMPFC. In contrast, however, the patients with SP showed significantly greater activation to “You” relative to “I” comments. Taken together, these data suggest a profound reorganization of self-referential reasoning in SP. While a detailed computational account of self-referential reasoning remains to be provided, it appears to involve matching information to the individual’s “selfconcept” (Berthoz et al., 2002). For healthy individuals this appears to be particularly related to the potential status challenges indicated by intentional social transgressions and self-generated viewpoints (“am I really like this?”). In contrast, evaluations of the self in SP primarily focus on potentially embarrassing events and are particularly related to others’ viewpoints (“am I really like what this other person considers me to be?”). In summary, SP does appear to reflect a heightened propensity to condition towards social stimuli even if it is unclear, and perhaps even doubtful, that this reflects “hypersensitivity in the pathways that mediate the innate fear of social stimuli.” But SP, at least by adulthood, is not simply this. SP also appears to be associated with atypical processing of self-referential information and it is this impairment that likely leads to the patient’s crippling concerns about potential embarrassment.

Conclusion GAD and SP are two highly comorbid anxiety disorders, and similar computational architectures have been proposed for them. However, more recent data suggest that there are notable differences in the computational impairments associated with these disorders. For example, there is little reason, currently, to believe that GAD in adulthood reflects heightened conditionability or heightened threat processing. In contrast, SP may reflect such heightened threat processing, albeit only for social stimuli. Both disorders may share developmental risk factors, however. GAD may be associated with heightened conditionability/ threat processing in childhood and both are associated with a deficient capacity to engage in emotional regulation. It is the computational architectures that maintain these disorders in adulthood that are different. For GAD this may reflect the development of an inefficient “worrying” strategy of emotional regulation (though we are clearly some way from understanding this phenomenon). For SP this appears to reflect the atypical processing of self-referential information.

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