Amygdala and insula response to emotional images in patients with generalized social anxiety disorder

Background

Functional brain imaging studies have demonstrated amygdala and insula hyper-reactivity to probes of social threat in participants with generalized social anxiety disorder (gSAD). The amygdala and insula are known to serve broad functions in emotional processing, including integration of affective information. However, few studies have examined brain responses in socially anxious participants during general emotional processing. We examined brain response to emotionally evocative images in patients with gSAD and matched healthy controls.

Methods

Eleven patients with gSAD who were not taking psychotropic medications and did not have psychiatric comorbidities and 11 matched healthy controls underwent functional magnetic resonance imaging while viewing blocks of emotionally salient (positive, negative, neutral) pictures.

Results

Participants with gSAD exhibited enhanced bilateral amygdala and insula reactivity to negative (v. neutral) images compared with healthy controls who did not exhibit enhanced reactivity. Within the gSAD group, the extent of amygdala activation was correlated with social anxiety severity, whereas the extent of insula activation was correlated with trait anxiety.

Limitations

The small sample size may have limited our ability to detect group differences in other relevant brain regions and in behavioural measures.

Conclusion

In addition to prior findings of probes of social information processing, our findings suggest that the amygdala and insula responses are hyper-reactive to general emotional images with negative emotional content and that these brain regions may play divergent roles in their representation of different phenotypes.     

Mismatch negativity (MMN) stands at the crossroads between explicit and implicit emotional processing

The amygdala is known as a key brain region involved in the explicit and implicit processing of emotional faces, and plays a crucial role in salience detection. Not until recently was the mismatch negativity (MMN), a component of the event‐related potentials to an odd stimulus in a sequence of stimuli, utilized as an index of preattentive salience detection of emotional voice processing. However, their relationship remains to be delineated. This study combined the fMRI scanning and event‐related potential recording by examining amygdala reactivity in response to explicit and implicit (backward masked) perception of fearful and angry faces, along with recording MMN in response to the fearfully and angrily spoken syllables dada in healthy subjects who varied in trait anxiety (STAI‐T). Results indicated that the amplitudes of fearful MMN were positively correlated with left amygdala reactivity to explicit perception of fear, but negatively correlated with right amygdala reactivity to implicit perception of fear. The fearful MMN predicted STAI‐T along with left amygdala reactivity to explicit fear, whereas the association between fearful MMN and STAI‐T was mediated by right amygdala reactivity to implicit fear. These findings suggest that amygdala reactivity in response to explicit and implicit threatening faces exhibits opposite associations with emotional MMN. In terms of emotional processing, MMN not only reflects preattentive saliency detection but also stands at the crossroads of explicit and implicit perception. Hum Brain Mapp 38:140–150, 2017. © 2016 Wiley Periodicals, Inc.     

Amygdala responsiveness to emotional words is modulated by subclinical anxiety and depression

Several neuroimaging studies underlined the importance of the amygdala and prefrontal brain structures (e.g. dorsolateral prefrontal cortex [DLPFC]) for the processing of emotional stimuli and for emotion regulation. Many studies used visual scenes or faces as emotion-inducing material, and there is evidence that negative or positive words activate emotion-processing brain regions in the same way. However, no study so far focused on the influence of subclinical measures of anxiety or depression on the neural processing of emotional words. In this fMRI-study, we therefore investigated brain activation to emotional words in relation to subclinical measures of trait anxiety and depression in a sample of 21 healthy subjects. We also assessed effects of subclinical anxiety and depression on amygdala-prefrontal coupling during negative (versus neutral) word reading. Both negative and positive words activated the amygdala, and negative-word processing revealed a positive correlation between amygdala activity and scores of trait anxiety and subclinical depression. During negative versus neutral word reading, subjects with high trait anxiety also showed a stronger functional coupling between left amygdala and left DLPFC. These results suggest a modulation of negative-word processing by subclinical depression and anxiety, as well as possible prefrontal compensatory processes during unintentional emotion regulation in subjects with higher trait anxiety.     

The role of the amygdala in emotional processing: a quantitative meta-analysis of functional neuroimaging studies

Functional neuroimaging studies have provided strong support for a critical role of the amygdala in emotional processing. However, several controversies remain in terms of whether different factors—such as sex, valence and stimulus type—have an effect on the magnitude and lateralization of amygdala responses. To address these issues, we conducted a meta-analysis of functional neuroimaging studies of visual emotional perception that reported amygdala activation. Critically, unlike previous neuroimaging meta-analyses, we took into account the magnitude (effect size) and reliability (variance) associated with each of the activations. Our results confirm that the amygdala responds to both positive and negative stimuli, with a preference for faces depicting emotional expressions. We did not find evidence for amygdala lateralization as a function of sex or valence. Instead, our findings provide strong support for a functional dissociation between left and right amygdala in terms of temporal dynamics. Taken together, results from this meta-analysis shed new light on several of the models proposed in the literature regarding the neural basis of emotional processing.     

Predictors of amygdala activation during the processing of emotional stimuli: a meta-analysis of 385 PET and fMRI studies

Although amygdala activity has been purported to be modulated by affective and non-affective factors, considerable controversy remains on its precise functional nature. We conducted a meta-analysis of 385 functional neuroimaging studies of emotional processing, examining the effects of experimental characteristics on the probability of detecting amygdala activity. All emotional stimuli were associated with higher probability of amygdala activity than neutral stimuli. Comparable effects were observed for most negative and positive emotions, however there was a higher probability of activation for fear and disgust relative to happiness. The level of attentional processing affected amygdala activity, as passive processing was associated with a higher probability of activation than active task instructions. Gustatory-olfactory and visual stimulus modalities increased the probability of activation relative to internal stimuli. Aversive learning increased the probability of amygdala activation as well. There was some evidence of hemispheric specialization with a relative left-lateralization for stimuli containing language and a relative right-lateralization for masked stimuli. Methodological variables, such as type of analysis and magnet strength, were also independent predictors of amygdala activation.     

An experimental investigation of emotional reactivity and delayed emotional recovery in borderline personality disorder: the role of shame

Despite the emphasis on emotional reactivity and delayed emotional recovery in prominent theoretical accounts of borderline personality disorder (BPD), research in this area remains limited. This study sought to extend extant research by examining emotional reactivity (and recovery following emotional arousal) to 2 laboratory stressors (one general, and the other involving negative evaluation) and exploring the impact of these stressors on subjective responding across the specific emotions of anxiety, irritability, hostility, and shame. We hypothesized that outpatients with BPD (compared to outpatients without a personality disorder; non-PD) would demonstrate heightened subjective emotional reactivity to both stressors, as well as a delayed return to baseline levels of emotional arousal. Results provide evidence for context- and emotion-specific reactivity in BPD. Specifically, BPD participants (compared to non-PD participants) evidenced heightened reactivity to the negative evaluation but not the general stressor. Furthermore, results provide support for shame-specific reactivity in BPD, with BPD participants (vs non-PD participants) evidencing a significantly different pattern of change in shame (but not in reported anxiety, irritability, or hostility) across the course of the study. Specifically, not only did BPD participants report higher levels of shame in response to the negative evaluation, their levels of shame remained elevated following this stressor (through the post-recovery period at the end of the study). Findings suggest the importance of continuing to examine emotional reactivity in BPD within specific contexts and across distinct emotions, rather than at the general trait level.     

Amygdala reactivity to masked negative faces is associated with automatic judgmental bias in major depression: a 3 T fMRI study

OBJECTIVE: In a previous study, we demonstrated that amygdala reactivity to masked negative facial emotions predicts negative judgmental bias in healthy subjects. In the present study, we extended the paradigm to a sample of 35 inpatients suffering from depression to investigate the effect of amygdala reactivity on automatic negative judgmental bias and clinical characteristics in depression. METHODS: Amygdala activity was recorded in response to masked displays of angry, sad and happy facial expressions by means of functional magnetic resonance imaging at 3 T. In a subsequent experiment, the patients performed an affective priming task that characterizes automatic emotion processing by investigating the biasing effect of subliminally presented emotional faces on evaluative ratings to subsequently presented neutral stimuli. RESULTS: Significant associations between (right) amygdala reactivity and automatic negative judgmental bias were replicated in our patient sample (r=-0.59, p<0.001). Further, negatively biased evaluative processing was associated with severity and longer course of illness (r=-0.57, p=0.001). CONCLUSION: Amygdala hyperactivity is a neural substrate of negatively biased automatic emotion processing that could be a determinant for a more severe disease course.     

Emotion effects on attention, amygdala activation, and functional connectivity in schizophrenia

Emotional abnormalities are a critical clinical feature of schizophrenia (SCZ), but complete understanding of their underlying neuropathology is lacking. Numerous studies have examined amygdala activation in response to affective stimuli in SCZ, but no consensus has emerged. However, behavioral studies examining 'in-the-moment' processing of affect have suggested intact emotional processing in SCZ. To examine which aspects of emotional processing may be impaired in SCZ, we combined behavior and neuroimaging to investigate effects of aversive stimuli during minimal cognitive engagement, at the level of behavior, amygdala recruitment, and its whole-brain task-based functional connectivity (tb-fcMRI) because impairments may manifest when examining across-region functional integration. Twenty-eight patients and 24 matched controls underwent rapid event-related fMRI at 3 T while performing a simple perceptual decision task with negative or neutral distraction. We examined perceptual decision slowing, amygdala activation, and whole-brain amygdala tb-fcMRI, while ensuring group signal-to-noise profile matching. Following scanning, subjects rated all images for experienced arousal and valence. No significant group differences emerged for negative vs neutral reaction time, emotional ratings across groups, or amygdala activation. However, even in the absence of behavioral or activation differences, SCZ subjects demonstrated significantly weaker amygdala-prefrontal cortical coupling, specifically during negative distraction. Whereas in-the-moment perception, behavioral response, and amygdala recruitment to negative stimuli during minimal cognitive load seem to be intact, there is evidence of aberrant amygdala-prefrontal integration in SCZ subjects. Such abnormalities may prove critical for understanding disturbances in patients' ability to use affective cues when guiding higher level cognitive processes needed in social interactions.     

Sex differences in brain activation to emotional stimuli: a meta-analysis of neuroimaging studies

Substantial sex differences in emotional responses and perception have been reported in previous psychological and psychophysiological studies. For example, women have been found to respond more strongly to negative emotional stimuli, a sex difference that has been linked to an increased risk of depression and anxiety disorders. The extent to which such sex differences are reflected in corresponding differences in regional brain activation remains a largely unresolved issue, however, in part because relatively few neuroimaging studies have addressed this issue. Here, by conducting a quantitative meta-analysis of neuroimaging studies, we were able to substantially increase statistical power to detect sex differences relative to prior studies, by combining emotion studies which explicitly examined sex differences with the much larger number of studies that examined only women or men. We used an activation likelihood estimation approach to characterize sex differences in the likelihood of regional brain activation elicited by emotional stimuli relative to non-emotional stimuli. We examined sex differences separately for negative and positive emotions, in addition to examining all emotions combined. Sex differences varied markedly between negative and positive emotion studies. The majority of sex differences favoring women were observed for negative emotion, whereas the majority of the sex differences favoring men were observed for positive emotion. This valence-specificity was particularly evident for the amygdala. For negative emotion, women exhibited greater activation than men in the left amygdala, as well as in other regions including the left thalamus, hypothalamus, mammillary bodies, left caudate, and medial prefrontal cortex. In contrast, for positive emotion, men exhibited greater activation than women in the left amygdala, as well as greater activation in other regions including the bilateral inferior frontal gyrus and right fusiform gyrus. These meta-analysis findings indicate that the amygdala, a key region for emotion processing, exhibits valence-dependent sex differences in activation to emotional stimuli. The greater left amygdala response to negative emotion for women accords with previous reports that women respond more strongly to negative emotional stimuli, as well as with hypothesized links between increased neurobiological reactivity to negative emotion and increased prevalence of depression and anxiety disorders in women. The finding of greater left amygdala activation for positive emotional stimuli in men suggests that greater amygdala responses reported previously for men for specific types of positive stimuli may also extend to positive stimuli more generally. In summary, this study extends efforts to characterize sex differences in brain activation during emotion processing by providing the largest and most comprehensive quantitative meta-analysis to date, and for the first time examining sex differences as a function of positive vs. negative emotional valence. The current findings highlight the importance of considering sex as a potential factor modulating emotional processing and its underlying neural mechanisms, and more broadly, the need to consider individual differences in understanding the neurobiology of emotion.     

The influence of gender and emotional valence of visual cues on FMRI activation in humans

Emotional neuroscience maps neurocircuits associated with the processing of affective stimuli. To assess gender differences in brain activation elicited by affective stimuli, we used pictures from the International Affective Picture System in a functional magnetic resonance imaging (fMRI) study. Ten male and ten female age-matched healthy volunteers were included and viewed affectively negative versus positive pictures, which were presented in an event related design. There was a significant interaction between valence of emotional stimuli and gender in the sublenticular extended amygdala (SLEA) and the rostral anterior cingulate. fMRI activation in these regions was stronger for negative compared to positive cues in women. In men fMRI activation was independent of stimulus valence. These results suggest to take gender differences into account when emotional paradigms are tested in functional brain imaging.     

Dissociable meta‐analytic brain networks contribute to coordinated emotional processing

Meta‐analytic techniques for mining the neuroimaging literature continue to exert an impact on our conceptualization of functional brain networks contributing to human emotion and cognition. Traditional theories regarding the neurobiological substrates contributing to affective processing are shifting from regional‐ towards more network‐based heuristic frameworks. To elucidate differential brain network involvement linked to distinct aspects of emotion processing, we applied an emergent meta‐analytic clustering approach to the extensive body of affective neuroimaging results archived in the BrainMap database. Specifically, we performed hierarchical clustering on the modeled activation maps from 1,747 experiments in the affective processing domain, resulting in five meta‐analytic groupings of experiments demonstrating whole‐brain recruitment. Behavioral inference analyses conducted for each of these groupings suggested dissociable networks supporting: (1) visual perception within primary and associative visual cortices, (2) auditory perception within primary auditory cortices, (3) attention to emotionally salient information within insular, anterior cingulate, and subcortical regions, (4) appraisal and prediction of emotional events within medial prefrontal and posterior cingulate cortices, and (5) induction of emotional responses within amygdala and fusiform gyri. These meta‐analytic outcomes are consistent with a contemporary psychological model of affective processing in which emotionally salient information from perceived stimuli are integrated with previous experiences to engender a subjective affective response. This study highlights the utility of using emergent meta‐analytic methods to inform and extend psychological theories and suggests that emotions are manifest as the eventual consequence of interactions between large‐scale brain networks.     

Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects.

BACKGROUND: Previous neuroimaging studies have demonstrated exaggerated amygdala responses to negative stimuli in posttraumatic stress disorder (PTSD). The time course of this amygdala response is largely unstudied and is relevant to questions of habituation and sensitization in PTSD exposure therapy. METHODS: We applied blood oxygen level dependent functional magnetic resonance imaging and statistical parametric mapping to study amygdala responses to trauma-related and nontrauma-related emotional words in sexual/physical abuse PTSD and normal control subjects. We examined the time course of this response by separate analysis of early and late epochs. RESULTS: PTSD versus normal control subjects have a relatively increased initial amygdala response to trauma-related negative, but not nontrauma-related negative, versus neutral stimuli. Patients also fail to show the normal patterns of sensitization and habituation to different categories of negative stimuli. These findings correlate with measured PTSD symptom severity. CONCLUSIONS: Our results demonstrate differential time courses and specificity of amygdala response to emotional and control stimuli in PTSD and normal control subjects. This has implications for pathophysiologic models of PTSD and treatment response. The results also extend previous neuroimaging studies demonstrating relatively increased amygdala response in PTSD and expand these results to a largely female patient population probed with emotionally valenced words.     

Amygdala reactivity predicts automatic negative evaluations for facial emotions

The amygdala is a key structure in a limbic circuit involved in the rapid and unconscious processing of facial emotions. In the present study, the role of the amygdala in automatic, involuntary appraisal processes, which are believed to be a crucial component of emotion processing, was investigated in 23 healthy subjects. Amygdala activity was recorded in response to masked displays of angry, sad, and happy facial expressions using functional magnetic resonance imaging (fMRI). In a subsequent experiment, the subjects performed a masked affective priming task that characterizes automatic emotion processing by investigating the biasing effect of subliminally presented emotional faces on evaluative ratings to subsequently presented neutral stimuli. In the affective priming task, significant valence-congruent evaluation manipulation was observed. Subjects rated neutral targets more positively if they were primed by happy faces. Significant correlations were found between amygdala responses to masked negative facial expressions and negative evaluation shifts elicited by the corresponding emotion quality in the affective priming task. Spontaneous amygdala reactivity to facial emotions appears to be a determinant of automatic negative evaluative response tendencies. This finding might shed some light on how amygdala hyperresponsivity contributes to negative cognitive biases commonly observed in affective disorders.     

Restricted emotional processing and somatic attribution in fibromyalgia.

OBJECTIVE: Medically unexplained symptoms or syndromes, such as fibromyalgia (FM), might be partly caused or sustained by a mechanism involving restricted emotional processing (REP) and the subsequent attribution of emotional arousal to somatic or syndrome-consistent causes. In this study, it was hypothesized that FM patients, compared to healthy individuals, would be higher on trait measures of REP (defensiveness and alexithymia), and would show affective-autonomic response dissociation, that is, higher standardized scores of heart rate responses than affective responses, during negative emotional stimulation. Additionally, FM patients were expected to attribute their bodily symptoms more to somatic than to psychological causes. METHOD: Emotional movie excerpts were shown to 16 female FM patients and 17 healthy women. Affective response and heart rate were monitored continuously, while symptoms and their causal attributions were measured before and after the excerpts. Repressor coping style and alexithymia were measured, along with negative affectivity and habitual attributions of somatic complaints. RESULTS: FM patients nearly all showed the relatively uncommon combination of high defensiveness and high anxiousness. Compared with healthy women FM patients were more alexithymic, showed a higher level of affective-autonomic response dissociation, and lower within-subject emotional variability. The groups showed opposite attributional patterns, with FM patients attributing symptoms less to psychological causes and more to somatic causes. There was no evidence of a shift in these attributions caused by the emotional stimuli. CONCLUSIONS: The results provide preliminary support for the hypotheses. Both at trait and at state level, FM showed restricted emotional processing on most of the parameters measured, and a high ratio of somatic to psychological symptom attribution, coupled with high negative affectivity.     

The amygdala and persistent pain.

A reciprocal relationship exists between persistent pain and negative affective states such as fear, anxiety, and depression. Accumulating evidence points to the amygdala as an important site of such interaction. Whereas a key role of the amygdala in the neuronal mechanisms of emotionality and affective disorders has been well established, the concept of the amygdala as an important contributor to pain and its emotional component is still emerging. This article will review and discuss evidence from anatomical, neuroimaging, behavioral, electrophysiological, pharmacological, and biochemical data that implicate the amygdala in pain modulation and emotional responses to pain. The latero-capsular division of the central nucleus of the amygdala is now defined as the "nociceptive amygdala" and integrates nociceptive information with poly-modal information about the internal and external bodily environment. Dependent on environmental conditions and affective states, the amygdala appears to play a dual facilitatory and inhibitory role in the modulation of pain behavior and nociceptive processing at different levels of the pain neuraxis. Only recently, electrophysiological, pharmacological, and biochemical neuroplastic changes were shown in the nociceptive amygdala in persistent pain. It is conceivable, however, that amygdala plasticity plays an important role in emotional pain behavior and its modulation by affective state.     

Amygdala reactivity to negative stimuli is influenced by oral contraceptive use

The amygdala is a highly interconnected region of the brain that is critically important to emotional processing and affective networks. Previous studies have shown that the response of the amygdala to emotionally arousing stimuli can be modulated by sex hormones. Because oral contraceptive pills dramatically lower circulating sex hormone levels with potent analogs of those hormones, we performed a functional magnetic resonance imaging experiment to measure amygdala reactivity in response to emotional stimuli in women using oral contraceptives, and compared their amygdala reactivity with that of naturally cycling women. Here, we show that women who use oral contraceptive pills have significantly decreased bilateral amygdala reactivity in response to negatively valenced, emotionally arousing stimuli compared with naturally cycling women. We suggest that by modulating amygdala reactivity, oral contraceptive pills may influence behaviors that have previously been shown to be amygdala dependent—in particular, emotional memory.     

Interaction of neuropeptide Y genotype and childhood emotional maltreatment on brain activity during emotional processing

Neuropeptide Y (NPY) has been associated with stress reactivity in affective disorders and is most densely expressed in the amygdala. An important stressor associated with affective disorders is the experience of childhood emotional maltreatment (CEM). We investigated whether the interaction of NPY risk genotype and CEM would affect brain activation. From the Netherlands Study of Depression and Anxiety, 33 healthy controls and 85 patients with affective disorders were scanned with functional magnetic resonance imaging while making gender decisions of emotional facial expressions. Results showed interactions between genotype and CEM, within carriers of the risk genotype, CEM was associated with higher amygdala activation, whereas CEM did not influence activation in non-risk carriers. In the posterior cingulate cortex (PCC), less activation was seen in those with CEM and the risk genotype, whereas genotype did not influence PCC activation in those without CEM. In addition, those carrying the risk genotype and with experience of CEM made a faster gender decision than those without CEM. Thus, the combined effect of carrying NPY risk genotype and a history of CEM affected amygdala and PCC reactivity, areas related to emotion, self-relevance processing and autobiographical memory. These results are consistent with the notion that the combination of risk genotype and CEM may cause hypervigilance.     

An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder

The pathophysiology of pediatric bipolar disorder (PBD) impacts both affective and cognitive brain systems. Understanding disturbances in the neural circuits subserving these abilities is critical for characterizing developmental aberrations associated with the disorder and developing improved treatments. Our objective is to use functional neuroimaging with pediatric bipolar disorder patients employing a task that probes the functional integrity of attentional control and affect processing. Ten euthymic unmedicated pediatric bipolar patients and healthy controls matched for age, sex, race, socioeconomic status, and IQ were scanned using functional magnetic resonance imaging. In a pediatric color word matching paradigm, subjects were asked to match the color of a word with one of two colored circles below. Words had a positive, negative or neutral emotional valence, and were presented in 30-s blocks. In the negative affect condition, relative to the neutral condition, patients with bipolar disorder demonstrated greater activation of bilateral pregenual anterior cingulate cortex and left amygdala, and less activation in right rostral ventrolateral prefrontal cortex (PFC) and dorsolateral PFC at the junction of the middle frontal and inferior frontal gyri. In the positive affect condition, there was no reduced activation of PFC or increased amygdala activation. The pattern of reduced activation of ventrolateral PFC and greater amygdala activation in bipolar children in response to negative stimuli suggests both disinhibition of emotional reactivity in the limbic system and reduced function in PFC systems that regulate those responses. Higher cortical cognitive areas such as the dorsolateral PFC may also be adversely affected by exaggerated emotional responsivity to negative emotions. This pattern of functional alteration in affective and cognitive circuitry may contribute to the reduced capacity for affect regulation and behavioral self-control in pediatric bipolar disorder.     

Neural signatures of cognitive and emotional biases in depression

Functional brain imaging studies suggest that depression is a system-level disorder affecting discrete but functionally linked cortical and limbic structures, with abnormalities in the anterior cingulate, lateral, ami medial prefrontal cortex, amygdala, ami hippocampus. Within this circuitry, abnormal corticolimbic interactions underlie cognitive deficits ami emotional impairment in depression. Depression involves biases toward processing negative emotional information and abnormal self-focus in response to emotional stimuli. These biases in depression could reflect excessive analytical self-focus in depression, as well as impaired cognitive control of emotional response to negative stimuli. By combining structural and functional investigations, brain imaging studies mav help to generate novel antidepressant treatments that regulate structural and factional plasticity within the neural network regulating mood and affective behavior.Functional and structural neuroimaging studies have assumed a unique position in defining the neuroanatomy of depression. Studies of cerebral blood flow and glucose metabolism with positron emission tomography (PET) scans in primary depression and depression associated with brain lesions have consistently revealed that major depressive disorder is a system-level disorder.^1,2