Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia.

BACKGROUND: Previous functional brain imaging studies of social anxiety have implicated amygdala hyperactivity in response to social threat, though its relationship to quantitative measures of clinical symptomatology remains unknown. The primary aim of this study was to examine the association between response to emotionally harsh faces in the amygdala, a region implicated in social and threat-related processing, and severity of social anxiety symptoms in patients with generalized social phobia (GSP). METHODS: Ten subjects with GSP naive to psychotropic medications and without psychiatric comorbidity and ten healthy comparison subjects matched on age, gender, ethnicity, and education completed the Liebowitz Social Anxiety Scale and underwent high-field (4Tesla) functional magnetic resonance imaging while viewing blocks of emotionally salient faces. RESULTS: Relative to happy faces, activation of the amygdala in response to harsh (angry, disgusted, fearful) faces was greater in GSP patients than in controls, and the extent of amygdala activation was positively correlated with severity of social anxiety symptoms, but not general state or trait anxiety levels. CONCLUSIONS: Our findings suggest that amygdala activation to interpersonal threat can be specifically linked to the severity of social anxiety symptoms of individual GSP patients, and thus, may serve as a useful functional marker of disease severity.     

Striatal function in generalized social phobia: a functional magnetic resonance imaging study.

BACKGROUND: Although evidence suggests the involvement of the amygdala in generalized social phobia (GSP), few studies have examined other neural regions. Clinical, preclinical, and dopamine receptor imaging studies demonstrating altered dopaminergic functioning in GSP suggest an association with striatal dysfunction. This is the first functional magnetic resonance imaging (fMRI) study to use a cognitive task known to involve the striatum to examine the neural correlates of GSP. We examined whether subjects with GSP had differential activation in striatal regions compared with healthy control subjects while engaged in a cognitive task that has been shown to activate striatal regions reliably. METHODS: Ten adult, unmedicated subjects with a primary DSM-IV diagnosis of GSP and 10 age-, gender-, and education-matched healthy comparison subjects underwent fMRI while performing the implicit sequence learning task. RESULTS: The GSP and healthy comparison subjects did not differ significantly on the behavioral performance of the task. Subjects with GSP, however, had significantly reduced neural activation related to implicit learning compared with healthy comparison subjects in the left caudate head, left inferior parietal lobe, and bilateral insula. CONCLUSIONS: These findings support the hypothesis that GSP is associated with striatal dysfunction and further the neurobiological understanding of this complex anxiety disorder.     

Oxytocin attenuates amygdala responses to emotional faces regardless of valence.

BACKGROUND: Oxytocin is known to reduce anxiety and stress in social interactions as well as to modulate approach behavior. Recent studies suggest that the amygdala might be the primary neuronal basis for these effects. METHODS: In a functional magnetic resonance imaging study using a double-blind, placebo-controlled within-subject design, we measured neural responses to fearful, angry, and happy facial expressions after intranasal application of 24 IU oxytocin compared with placebo. RESULTS: Oxytocin reduced right-sided amygdala responses to all three face categories even when the emotional content of the presented face was not evaluated explicitly. Exploratory whole brain analysis revealed modulatory effects in prefrontal and temporal areas as well as in the brainstem. CONCLUSIONS: Results suggest a modulatory role of oxytocin on amygdala responses to facial expressions irrespective of their valence. Reduction of amygdala activity to positive and negative stimuli might reflect reduced uncertainty about the predictive value of a social stimulus and thereby facilitates social approach behavior.     

An amygdala response to fearful faces with covered eyes

Findings of amygdala responsiveness to the eye region of fearful faces raise the question of whether eye widening is the only facial cue involved. We used fMRI to investigate the differential amygdala response to fearful versus neutral stimuli for faces, eyes, and for faces in which the eye region was masked. For maximum sensitivity, a block design was used, with a region of interest (ROI) centred on the amygdala which included peri-amygdalar areas. Evidence of amygdala responsiveness to fear compared to neutral stimuli was found for whole faces, eye region only, and for faces with masked eyes. The amygdala can therefore use information from facial regions other than the eyes, allowing it to respond differentially to fearful compared to neutral faces even when the eye region is hidden.     

Association between amygdala response to emotional faces and social anxiety in autism spectrum disorders

Difficulty interpreting facial expressions has been reported in autism spectrum disorders (ASD) and is thought to be associated with amygdala abnormalities. To further explore the neural basis of abnormal emotional face processing in ASD, we conducted an fMRI study of emotional face matching in high-functioning adults with ASD and age, IQ, and gender matched controls. In addition, we investigated whether there was a relationship between self-reported social anxiety and fMRI activation. During fMRI scanning, study participants were instructed to match facial expressions depicting fear or anger. The control condition was a comparable shape-matching task. The control group evidenced significantly increased left prefrontal activation and decreased activation in the occipital lobes compared to the ASD group during emotional face matching. Further, within the ASD group, greater social anxiety was associated with increased activation in right amygdala and left middle temporal gyrus, and decreased activation in the fusiform face area. These results indicate that level of social anxiety mediates the neural response to emotional face perception in ASD.     

Atypical modulation of medial prefrontal cortex to self-referential comments in generalized social phobia

Generalized social phobia (GSP) involves the fear of being negatively evaluated. Previous work suggests that self-referentiality, mediated by the medial prefrontal cortex (MFPC), plays an important role in the disorder. However, it is not clear whether this anomalous MPFC response to self-related information in patients with GSP concerns an increased representation of their own or others' opinions. In this article, we examine whether GSP is associated with increased response to own (1st person) or other individuals' (2nd person) opinions relative to healthy individuals. Unmedicated individuals with GSP (n = 15) and age-, IQ-, and gender-matched comparison individuals (n = 15) read 1st (e.g., I'm ugly), and 2nd (e.g., You're ugly) person viewpoint comments during functional magnetic resonance imaging. We observed significant group-by-viewpoint interactions within the ventral MPFC. Whereas the healthy comparison individuals showed significantly increased (or less decreased) BOLD responses to 1st relative to 2nd person viewpoints, the patients showed significantly increased responses to 2nd relative to 1st person viewpoints. The reduced BOLD responses to 1st person viewpoint comments shown by the patients correlated significantly with severity of social anxiety symptom severity. These results underscore the importance of dysfunctional self-referential processing and MPFC in GSP. We believe that these data reflect a reorganization of self-referential reasoning in the disorder with a self-concept perhaps atypically related to the view of others.     

Increased activation of the anterior cingulate cortex during processing of disgust faces in individuals with social phobia.

BACKGROUND: Researchers have examined the role of differential activation of various brain regions involved in processing emotional information in subjects with social phobia. These studies have focused mostly on the activation of the amygdala. The anterior cingulate cortex (ACC) also has been implicated in processing emotional information, but its role in social phobia has not been examined. METHODS: We recruited subjects with social phobia and matched them with non-anxious control subjects. Participants viewed facial expressions of disgust ("disgust faces") and neutral facial expressions ("neutral faces"). We measured brain activation, focusing on the ACC, using functional magnetic resonance imaging. We also recorded participants' ratings of emotional valence of faces, as well as response latencies to make these valence judgments. We repeated this procedure using three different sets of facial expressions. RESULTS: Individuals with social phobia exhibited a significant increase in ACC activity compared with non-anxious control subjects when processing disgust versus neutral faces. Additionally, compared with control subjects, subjects with social phobia were faster in their ratings of disgust faces and rated the neutral faces more negatively. CONCLUSIONS: Our findings demonstrate that the ACC might be involved in affective processing of negative information in socially phobic subjects.     

Altered fusiform connectivity during processing of fearful faces in social anxiety disorder

Social anxiety disorder (SAD) has been associated with hyper-reactivity in limbic brain regions like the amygdala, both during symptom provocation and emotional face processing tasks. In this functional magnetic resonance imaging study we sought to examine brain regions implicated in emotional face processing, and the connectivity between them, in patients with SAD (n=14) compared with healthy controls (n=12). We furthermore aimed to relate brain reactivity and connectivity to self-reported social anxiety symptom severity. SAD patients exhibited hyper-reactivity in the bilateral fusiform gyrus in response to fearful faces, as well as greater connectivity between the fusiform gyrus and amygdala, and decreased connectivity between the fusiform gyrus and ventromedial prefrontal cortex. Within the SAD group, social anxiety severity correlated positively with amygdala reactivity to emotional faces, amygdala-fusiform connectivity and connectivity between the amygdala and superior temporal sulcus (STS). These findings point to a pivotal role for the fusiform gyrus in SAD neuropathology, and further suggest that altered amygdala-fusiform and amygdala-STS connectivity could underlie previous findings of aberrant socio-emotional information processing in this anxiety disorder.     

The serotonin transporter gene polymorphism and the effect of baseline on amygdala response to emotional faces

Previous research has found that a common polymorphism in the serotonin transporter gene (5-HTTLPR) is an important mediator of individual differences in brain responses associated with emotional behaviour. In particular, relative to individuals homozygous for the l-allele, carriers of the s-allele display heightened amygdala activation to emotional compared to non-emotional stimuli. However, there is some debate as to whether this difference is driven by increased activation to emotional stimuli, resting baseline differences between the groups, or decreased activation to neutral stimuli. We performed functional imaging during an implicit facial expression processing task in which participants viewed angry, sad and neutral faces. In addition to neutral faces, we included two further baseline conditions, houses and fixation. We found increased amygdala activation in s-allele carriers relative to l-homozygotes in response to angry faces compared to neutral faces, houses and fixation. When comparing neutral faces to houses or fixation, we found no significant difference in amygdala response between the two groups. In addition, there was no significant difference between the groups in response to fixation when compared with a houses baseline. Overall, these results suggest that the increased amygdala response observed in s-allele carriers to emotional faces is primarily driven by an increased response to emotional faces rather than a decreased response to neutral faces or an increased resting baseline. The results are discussed in relation to the tonic and phasic hypotheses of 5-HTTLPR-mediated modulation of amygdala activity.     

The time-course of attention to emotional faces in social phobia

This study investigated the time-course of attentional bias in socially phobic (SP) and non-phobic (NP) adults. Participants viewed angry and happy faces paired with neutral faces (i.e., face-face pairs) and angry, happy and neutral faces paired with household objects (i.e., face-object pairs) for 5000 ms. Eye movement (EM) was measured throughout to assess biases in early and sustained attention. Attentional bias occurred only for face-face pairs. SP adults were vigilant for angry faces relative to neutral faces in the first 500 ms of the 5000 ms exposure, relative to NP adults. SP adults were also vigilant for happy faces over 500 ms, although there were no group-based differences in attention to happy-neutral face pairs. There were no group differences in attention to faces throughout the remainder of the exposure. Results suggest that social phobia is characterised by early vigilance for social cues with no bias in subsequent processing.     

Amygdala and insular responses to emotionally valenced human faces in small animal specific phobia.

BACKGROUND: Contemporary neurobiological models suggest that the amygdala plays an important role in the pathophysiology of anxiety disorders. However, it is not clear to what extent this concept applies across anxiety disorders. Several studies have examined brain function in specific phobias but did not demonstrate amygdala responses or use specific probes of the amygdala. METHODS: Ten subjects with specific small animal phobia and 10 matched control subjects were studied with functional magnetic resonance imaging. Subjects viewed emotionally expressive and neutral faces, and amygdala blood oxygenation level dependent responses from each group were compared. RESULTS: There was a significant response to the fearful versus neutral faces in the amygdala across both groups but no diagnosis x condition interaction. Post hoc analysis of the whole brain revealed a significantly greater response to the fearful versus neutral faces in the right insular cortex of the specific phobia group than in the control group. CONCLUSIONS: Amygdala hyperresponsivity to emotional faces was not observed in subjects with small animal specific phobia, in contrast to findings in other anxiety disorders (e.g., posttraumatic stress disorder). This suggests a restricted role for the amygdala in specific phobia. The insular hyperresponsivity to fearful versus neutral faces in the subjects with specific phobias warrants further study.     

Fear is fast in phobic individuals: amygdala activation in response to fear-relevant stimuli.

BACKGROUND: Two core characteristics of pathologic fear are its rapid onset and resistance to cognitive regulation. We hypothesized that activation of the amygdala early in the presentation of fear-relevant visual stimuli would distinguish phobics from nonphobics. METHODS: Chronometry of amygdala activation to phobia-relevant pictures was assessed in 13 spider phobics and 14 nonphobics using functional magnetic resonance imaging (fMRI). RESULTS: Blood oxygen level-dependent (BOLD) responses in the amygdala early in picture processing consistently differentiated between phobic and nonphobic subjects, as well as between phobogenic and nonphobogenic stimuli among phobics. Furthermore, amygdalar BOLD responses associated with timing but not magnitude of activation predicted affective responses to phobogenic stimuli. Computational modeling procedures were used to identify patterns of neural activation in the amygdala that could yield the observed BOLD data. These data suggest that phobic responses were characterized by strong but brief amygdala responses, whereas nonphobic responses were weaker and more sustained. CONCLUSIONS: Results are discussed in the context of the amygdala's role in rapid threat detection and the vigilance-avoidance hypothesis of anxiety. These data highlight the importance of examining the neural substrates of the immediate impact of phobogenic stimuli for understanding pathological fear.     

Amygdala response to faces parallels social behavior in Williams syndrome

Individuals with Williams syndrome (WS), a genetically determined disorder, show relatively strong face-processing abilities despite poor visuospatial skills and depressed intellectual function. Interestingly, beginning early in childhood they also show an unusually high level of interest in face-to-face social interaction. We employed functional magnetic resonance imaging (fMRI) to investigate physiological responses in face-sensitive brain regions, including ventral occipito-temporal cortex and the amygdala, in this unique genetic disorder. Participants included 17 individuals with WS, 17 age- and gender-matched healthy adults (chronological age-matched controls, CA) and 17 typically developing 8- to 9-year-old children (developmental age controls, DA). While engaged in a face discrimination task, WS participants failed to recruit the amygdala, unlike both CA and DA controls. WS fMRI responses in ventral occipito-temporal cortex, however, were comparable to those of DA controls. Given the integral role of the amygdala in social behavior, the failure of WS participants to recruit this region during face processing may be a neural correlate of the abnormally high sociability that characterizes this disorder.     

Vigilant and avoidant attention biases as predictors of response to cognitive behavioral therapy for social phobia

Background: Attention bias for socially threatening information, an empirically supported phenomenon, figures prominently in models of social phobia. However, all published studies examining this topic to date have relied on group means to describe attention bias patterns; research has yet to examine potential subgroups of attention bias among individuals with social phobia (e.g., vigilant or avoidant). Furthermore, almost no research has examined how attention biases in either direction may predict change in symptoms as a result of treatment. Methods: This study (N = 24) compared responses to cognitive behavioral therapy (CBT) for social phobia between individuals with avoidant and vigilant biases for threatening faces at pretreatment. Results: Participants with avoidant biases reported significantly and clinically higher symptom levels at posttreatment than did those with vigilant biases. Conclusions: These findings suggest that an avoidant attention bias may be associated with reduced response to CBT for social phobia. Depression and Anxiety, 2011. © 2011 Wiley‐Liss, Inc.     

Amygdala hyperreactivity in borderline personality disorder: implications for emotional dysregulation.

BACKGROUND: Disturbed interpersonal relations and emotional dysregulation are fundamental aspects of borderline personality disorder (BPD). The amygdala plays important roles in modulating vigilance and generating negative emotional states and is often abnormally reactive in disorders of mood and emotion. The aim of this study was to assess amygdala reactivity in BPD patients relative to normal control subjects. We hypothesized that amygdala hyperreactivity contributes to hypervigilance, emotional dysregulation, and disturbed interpersonal relations in BPD. METHODS: Using functional magnetic resonance imaging, we examined neural responses to 20-sec blocks of neutral, happy, sad, and fearful facial expression (or a fixation point) in 15 BPD and 15 normal control subjects. The DSM IV-diagnosed BPD patients and the normal control subjects were assessed by a clinical research team in a medical school psychiatry department. RESULTS: Borderline patients showed significantly greater left amygdala activation to the facial expressions of emotion (vs. a fixation point) compared with normal control subjects. Post-scan debriefing revealed that some borderline patients had difficulty disambiguating neutral faces or found them threatening. CONCLUSIONS: Pictures of human emotional expressions elicit robust differences in amygdala activation levels in borderline patients, compared with normal control subjects, and can be used as probes to study the neuropathophysiologic basis of borderline personality disorder.     

Differential sex-independent amygdala response to infant crying and laughing in parents versus nonparents.

BACKGROUND: Animal and human studies implicate forebrain neural circuits in maternal behavior. Here, we hypothesized that human brain response to emotional stimuli relevant for social interactions between infants and adults are modulated by sex- and experience-dependent factors. METHODS: We used functional magnetic resonance imaging and examined brain response to infant crying and laughing in mothers and fathers of young children and in women and men without children. RESULTS: Women but not men, independent of their parental status, showed neural deactivation in the anterior cingulate cortex, as indexed by decreased blood oxygenation level-dependent signal, in response to both infant crying and laughing. The response pattern changed fundamentally with parental experience: in the amygdala and interconnected limbic regions, parents (independent of sex) showed stronger activation from crying, whereas nonparents showed stronger activation from laughing. CONCLUSIONS: Our data show sex- and experience-dependent modulation of brain response to infant vocalizations. Successful recognition and evaluation of infant vocalizations can be critical for bonding mechanisms and for offspring well-being and survival. Thus, the modulation of responses by experience seems to represent an adaptive mechanism that can be related to reproductive fitness.     

Altered emotion regulation capacity in social phobia as a function of comorbidity

Social phobia (SP) has been associated with amygdala hyperreactivity to fear-relevant stimuli. However, little is known about the neural basis of SP individuals’ capacity to downregulate their responses to such stimuli and how such regulation varies as a function of comorbid depression and anxiety. We completed an functional magnetic resonance imaging (fMRI) study wherein SP participants without comorbidity (n = 30), with comorbid depression (n = 18) and with comorbid anxiety (n = 19) and healthy controls (n = 15) were scanned while completing an affect labeling emotion regulation task. Individuals with SP as a whole exhibited a reversal of the pattern observed in healthy controls in that they showed upregulation of amygdala activity during affect labeling. However, subsequent analyses revealed a more complex picture based on comorbidity type. Although none of the SP subgroups showed the normative pattern of amygdala downregulation, it was those with comorbid depression specifically who showed significant upregulation. Effects could not be attributed to differences in task performance, amygdala reactivity or right ventral lateral prefrontal cortex (RVLPFC) engagement, but may stem from dysfunctional communication between amygdala and RVLPFC. Furthermore, the particularly altered emotion regulation seen in those with comorbid depression could not be fully explained by symptom severity or state anxiety. Results reveal altered emotion regulation in SP, especially when comorbid with depression.     

Selective processing of social stimuli in the superficial amygdala

The human amygdala plays a pivotal role in the processing of socially significant information. Anatomical studies show that the human amygdala is not a single homogeneous structure but is composed of segregable subregions. These have recently been functionally delineated by using a combination of functional magnetic resonance imaging (fMRI) and cytoarchitectonically defined probabilistic maps. However, the response characteristics and individual contribution of these subregions to the processing of social‐emotional stimuli are little understood. Here, we used this novel technique to segregate intra‐amygdalar responses to facial expressions and nonsocial control stimuli. We localized facial expression‐evoked signal changes bilaterally in the superficial amygdala, which suggests that this subregion selectively extracts the social value of incoming sensory information. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Individual differences in alexithymia and brain response to masked emotion faces

Alexithymia is considered a dimensional personality trait that refers to a cluster of deficits in the recognition, differentiation, and verbalization of emotions. Research on the neurobiology of alexithymia has focused hitherto on impairments in the controlled processing of emotional information. In the present study automatic brain reactivity to facial emotion was investigated as a function of alexithymia (as assessed by the 20-Item Toronto Alexithymia Scale - TAS-20). During 3 T fMRI scanning, pictures of sad, happy, and neutral facial expression masked by neutral faces were presented to 33 healthy women. A priori regions of interest in the whole brain analysis were cerebral structures that are known to be crucially involved in the emotion perception from the face. Independently from trait anxiety and depression TAS-20 alexithymia was negatively correlated with activation to masked sad and happy faces in several regions of interest (in particular, insula, superior temporal gyrus, middle occipital and parahippocampal gyrus). In addition, the TAS-20 score was negatively correlated with response of the left amygdala to masked sad faces. A reduced automatic reactivity of the amygdala and visual occipito-temporal areas could implicate less automated engagement in the encoding of emotional stimuli in high alexithymia. In addition, a low spontaneous insular and amygdalar responsivity in high alexithymia individuals could be related to an attenuation of basic emotional experiences which may contribute to problems in identifying and differentiating one's feelings.