Association between Amygdala Hyperactivity to Harsh Faces and Severity of Social Anxiety in Generalized Social Phobia

Cannabinoid Modulation of Amygdala Reactivity to Social Signals of Threat in Humans

“…Activation in the amygdala increases with exposure to faces that convey threat, such as fearful and angry faces, but diminished with faces that convey acceptance, such as happy faces (Morris et al, 1996;Whalen et al, 1998). Consistent with this, individuals with social phobias exhibit exaggerated amygdala reactivity to threatening faces (Stein et al, 2002;Phan et al, 2006), whereas those who eagerly engage in social interactions (social fearlessness) show diminished amygdala reactivity to the same types of faces . Amygdala hyperactivity to threatening faces has also consistently been observed in patients with anxiety disorders (Etkin and Wager, 2007).…”

“…On perception of threat, the lateral nucleus of the amygdala is thought to integrate inputs and excite the central nucleus to evoke fear responses (LeDoux, 2000). In humans, detection of social signals of threat (e.g., fearful/angry faces) enhances amygdala reactivity (Morris et al, 1996;Whalen et al, 1998), and individuals with pathological anxiety exhibit exaggerated amygdala reactivity to threatening faces (Rauch et al, 2000;Phan et al, 2006). In both monkeys and humans, discrete lesions to the amygdala lead to altered fear responses and perception (Kalin et al, 2001;Adolphs et al, 2005).…”

Behavioral Inhibition and Risk for Developing Social Anxiety Disorder: A Meta-Analytic Study

“…Both BI and SAD are characterized by high and stable heart rate 29,50,51 and amygdala hyperresponsivity. 26,27,30-32 Prevalence rates of SAD in adolescence (~11%) are very similar to the 15% estimate of extreme BI in the population and within samples, and the degree of BI and social anxiety symptom severity are highly correlated. 18,52 However, not all BI children develop SAD.…”

“…Temperament-based differences in brain profiles have been reported, including differences in electroencephalography (EEG) asymmetry, 21 functional differences in amygdala response to faces, 22-27 and structural differences in the ventral prefrontal cortex. 28 Interestingly, SAD is also characterized by high and stable heart rate 29 and amygdala hyperresponsivity, 30-32 pointing to possible shared biological underpinnings.…”

Individual differences in the Behavioral Inhibition System are associated with orbitofrontal cortex and precuneus gray matter volume

“…Previous studies have shown connectivity between the OFC and the amygdala (Holland & Gallagher, 2004;Zald & Kim, 1996;Hahn et al, 2011), and also between the precuneus and the amygdala (Hahn et al, 2011). These results suggest a modulatory role for both OFC and the precuneus over amygdala activity, which could be related to individual differences in the Anxiety trait since amygdala activity has been shown to be related to anxiety in patients with anxiety disorders (Hahn et al, 2011;Phan, Fitzgerald, Nathan, & Tancer, 2006) and in healthy subjects (Haas, Omura, Constable, & Canli, 2007).…”

“…In the study by Iidaka et al (2006), only the female group presented an association between harm avoidance and amygdala volume, which contrasts with the present and previous (Barrós- Loscertales et al 2006a) studies, performed with a male sample. Therefore, although the amygdala and hippocampus have been consistently associated with anxiety at the functional level (Frings, Schulze-Bonhage, Spreer, & Wagner, 2009;Hahn et al, 2011;Haas et al, 2007;Kim & Whalen, 2009;Phan et al, 2006;Rauch, Shin, & Wright, 2003), structural studies offer mixed results, which might be partly expected from the use of different samples and questionnaires as we discuss below. On the other hand, differences relating to the VBM procedures could partly explain the lack of association between the BIS scores and amygdalar and hippocampal volumes because the image preprocessing used in VBM8 differs from the optimized VBM proposed by Good et al (2001), which was used in previous studies (Barrós-Loscertales et al, 2006a).…”

Selective aberrant functional connectivity of resting state networks in social anxiety disorder

“…It further had an important role in cognitive control related to switching between the DMN and task-related networks (Sridharan et al, 2008). Most of the previous studies highlighted a hyperactivity of the insula of anxiety patients during the processing of negative emotion (Etkin and Wager, 2007;Etkin et al, 2009;Gentili et al, 2008;Phan et al, 2006;Tillfors et al, 2001). We found decreased functional connectivity in insula.…”

“…Epidemiological studies conducted on general population have pointed out that the lifetime prevalence of SAD ranges between 4.0% and 16% (Ohayon and Schatzberg, 2010). Findings from neurophysiological and brain-imaging studies (Damsa et al, 2009;Engel et al, 2009) have showed that patients with SAD exhibit greater activity than healthy subjects in several areas related to emotional process as the amygdala and insula during social fear and anxiety conditioning (Etkin and Wager, 2007;Phan et al, 2006;Stein et al, 2002;Tillfors et al, 2001), suggesting the presence in SAD of impaired cortico-limbic circuit that mainly involves medial prefrontal cortex and limbic regions (Phan et al, 2006;Stein et al, 2002;Tillfors et al, 2001). Moreover, abnormal activation in the fusiform gyrus, striatal regions, superior temporal gyrus, orbital prefrontal cortex, and inferior frontal gyrus (Gentili et al, 2008;Sareen et al, 2007;Tillfors et al, 2002) were also observed in this disease.…”

Startle response potentiation to chemosensory anxiety signals in socially anxious individuals

“…As indicated by several brain imaging studies, this processing bias seems to be related to a deviant activation pattern of emotion processing brain structures. Consistently, socially anxious individuals respond to angry, disgusted or fearful faces with increased amygdala activation (Phan et al, 2006;Stein et al, 2002;Straube et al, 2004). A hyperactivation of the amygdala during social threat perception could also account for the increased startle response in socially anxious subjects in the present study, because the central nucleus of the amygdala is considered to be the main relay during startle potentiation, responsible for the activation of the N. reticularis pontis caudalis (Lang and Davis, 2006).…”

Callousness and affective face processing in adults: Behavioral and brain-potential indicators.

“…That is, the correlations for neutral-face response were no longer significant when responses to faces of both types were examined together as predictors of callousness, whereas associations for fear-face response remained significant in the case of the P200 response and near-significant in the case of the N170 response. This finding is interesting in light of fMRI studies reporting heightened amygdala reactivity to neutral as well as negatively valenced (fearful, angry) face stimuli in individuals with high levels of social anxiety (Phan, Fitzgerald, Nathan, & Tancer, 2006). The interpretation has been that high socially anxious individuals are more apt to interpret nonexpressive faces as critical or otherwise threatening.…”

The Neurobiology of Individual Differences in Complex Behavioral Traits

“…In one study, Stein et al (2007) report that high trait anxiety is associated with greater amygdala reactivity not only to angry and fearful but also to happy facial expressions. Consistent with this pattern of normal variability, various mood and anxiety disorders (e.g., unipolar and bipolar depression, generalized anxiety disorder, social phobia) have been linked with greater amygdala responses to facial expressions depicting fear and anger, as well as sadness and disgust, and, more variably, to emotionally neutral facial expressions (Cooney et al 2006, Evans et al 2008, Phan et al 2006, Phillips et al 2003, Stein et al 2002, Whalen et al 2002). Such findings demonstrate that anxiety-related psychopathology is associated with a heightened amygdala response to diverse affective stimuli.…”

A Cognitive-Neuropsychological Account of Treatment Action in Anxiety: Can We Augment Clinical Efficacy?

“…In line with these assumptions, imaging studies suggest that threat processing in anxiety disorders is associated with increased activity in the amygdala and hippocampus (Ball et al, 2012;Blair et al, 2011;Etkin & Wager, 2007;Geuze et al, 2007;Larson et al, 2006;Monk et al, 2008;Rauch et al, 2000;Simon, Kaufmann, Musch, Kischkel, & Kathmann, 2010;Stein, Goldin, Sareen, Zorrilla, & Brown, 2002;Straube, Glauer, Dilger, Mentzel, & Miltner, 2006;Straube, Mentzel, & Miltner, 2005;van den Heuvel et al, 2005), insula (Ball et al, 2012;Etkin & Wager, 2007;Kilts et al, 2006;Klumpp, Angstadt, & Phan, 2012;Klumpp, Fitzgerald, & Phan, 2013;Sakamoto et al, 2005;Stern et al, 2011;Straube, Glauer, et al, 2006;Straube et al, 2005), and occipital cortex (Daniels et al, 2011;Goldin, Manber, Hakimi, Canli, & Gross, 2009;Lanius et al, 2002;Schneier, Pomplun, Sy, & Hirsch, 2011;Straube et al, 2005). Preliminary findings also suggest increased response in dorsal ACC and mPFC in response to threat stimuli in anxiety disorders (Amir et al, 2005;Bystritsky et al, 2001;Goossens, Sunaert, Peeters, Griez, & Schruers, 2007;Paulesu et al, 2010;Phan, Fitzgerald, Nathan, & Tancer, 2006;Shin et al, 2007;van den Heuvel et al, 2005), areas that have previously been implicated in selective attention (Botvinick, Nystrom, Fissell, Carter, & Cohen, 1999;…”

Corticolimbic Brain Reactivity to Social Signals of Threat Before and After Sertraline Treatment in Generalized Social Phobia

“…This task was designed to isolate brain (e.g., amygdala, insula) response to signals of threat (angry and fearful faces) against those that do not convey any perceived threat (happy faces); the contrast of angry/fearful expression against happy expressions (herein referred to as ‘AvH’ and ‘FvH’) allows specificity for the threat signal while matching the non-emotional face element. Also, prior evidence in our laboratory (12, 13) has specifically shown that gSP subjects would differ in their limbic-frontal reactivity to threat (angry/fearful) but not non-threat (happy) signals, and that this ‘activation’ difference is less evident in healthy controls (33); in other words, in order to maximize the activation ‘signal’ for the SSRI treatment to target, we chose to contrast threatening against happy faces which yields the most robust and consistent finding of exaggerated amygdala reactivity in gSP based on our (12, 13) and others’ previous work (6) and given that contrasts between threat against neutral faces or against fixation/shapes were less powered to detect gSP versus HC differences (12, 13). Moreover, prior work had also suggested that different face expressions may convey different messages about the ‘source’ of threat (e.g., direct threat from angry faces, indirect threat from fearful faces) and may differentially engage amygdala, insula, ACC and mPFC (34).…”

Neural predictors and mechanisms of cognitive behavioral therapy on threat processing in social anxiety disorder

“…Prior evidence from our laboratory (Phan et al, 2006, 2013) and others (Stein et al, 2002) has shown that patients with gSAD differ significantly in their fronto-limbic reactivity to threatening (angry/fearful) but not non-threat (happy) signals, whereas this differential response is less evident in healthy volunteers (Fitzgerald et al, 2006). To maximize the activation ‘signal’ for CBT effects, we contrasted threatening against happy faces, rather than neutral faces, fixation crosses or shapes, as this contrast results in more robust and consistent findings of exaggerated limbic reactivity in gSAD based on our (Phan et al, 2006, 2013) and others’ previous work (Etkin and Wager, 2007; Freitas-Ferrari et al, 2010). Moreover, we contrasted angry versus happy faces (AvH) and fearful against happy faces (FvH) allowing us to examine potential separate effects for the type of threat signal based on evidence that angry and fear differentially perturb emotion processing circuitry (Fusar-Poli et al, 2009; Whalen et al, 2001), which may influence treatment-related brain changes.…”

“…The null amygdala result here is somewhat surprising. One possibility is our use of happy faces as a contrast to angry/fearful faces, which we based on fronto-limbic findings that the contrast differentiates gSAD from healthy volunteers (Phan et al, 2006, 2013; Stein et al, 2002). Though not a consistent finding, happy faces can elicit amygdala reactivity in social anxiety (Evans et al, 2008; Straube et al, 2005), potentially due to negative interpretations of the expression (unapproachable, mocking; Campbell et al, 2009; Coles and Heimberg, 2005).…”

“…Exaggerated cortical response has also been observed in gSAD both to, and in anticipation of, threat (Etkin and Wager, 2007; Freitas-Ferrari et al, 2010). While not as consistently demonstrated as subcortical hyperactivity, exaggerated activity has also been shown in the anterior cingulate cortex (ACC) in gSAD (Amir et al, 2005; Blair et al, 2008; Goldin et al, 2009; Phan et al, 2006) a component of the anterior attention system involved in the detection of salient cues (Posner and Petersen, 1990). Other prefrontal cortex (PFC) regions serving executive functions (Bush et al, 2000; Etkin et al, 2011) have been implicated in gSAD such as dorsomedial, dorsolateral, and medial orbitofrontal cortex (Goldin et al, 2009; Stein et al, 2002; Tillfors et al, 2002) as well as higher-level visual regions (inferior occipital, fusiform gyrus, superior temporal sulcus; Evans et al, 2008; Goldin et al, 2009; Straube et al, 2004) engaged in social cognition (Adolphs 1999; Fusar-Poli et al, 2009).…”