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Background: Individuals with intermittent explosive disorder (IED) were previously found to exhibit amygdala hyperactivation and relatively reduced orbital medial prefrontal cortex (OMPFC) activation to angry faces while performing an implicit emotion information processing task during functional magnetic resonance imaging (fMRI). This study examines the neural substrates associated with explicit encoding of facial emotions among individuals with IED., Method: Twenty unmedicated IED subjects and twenty healthy, matched comparison subjects (HC) underwent fMRI while viewing blocks of angry, happy, and neutral faces and identifying the emotional valence of each face (positive, negative or neutral). We compared amygdala and OMPFC reactivity to faces between IED and HC subjects. We also examined the relationship between amygdala/OMPFC activation and aggression severity., Results: Compared to controls, the IED group exhibited greater amygdala response to angry (vs. neutral) facial expressions. In contrast, IED and control groups did not differ in OMPFC activation to angry faces. Across subjects amygdala activation to angry faces was correlated with number of prior aggressive acts., Conclusions: These findings extend previous evidence of amygdala dysfunction in response to the identification of an ecologically-valid social threat signal (processing angry faces) among individuals with IED, further substantiating a link between amygdala hyperactivity to social signals of direct threat and aggression., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Behavioral and brain research indicates that administration of Δ(9)-tetrahydrocannabinol (THC) alters threat perception and enhances the suppression of conditioned fear responses via modulation of the frontolimbic circuit. No prior studies, however, have examined whether THC also affects volitional forms of emotion processing such as cognitive reappraisal. The aim of the current study was therefore to examine the effects of THC on frontolimbic activation and functional connectivity during cognitive reappraisal in a sample of healthy adults. The study was a randomized, double-blind, placebo-controlled, between-subject design and all participants ingested either an oral dose of synthetic THC (n=41) or placebo (n=37) before completion of an emotion regulation task during functional magnetic resonance imaging (fMRI). Functional connectivity was assessed using generalized psychophysiological interaction (gPPI) analyses. Results indicated that although there were no group differences in self-reported attenuation of negative affect during cognitive reappraisal, relative to placebo, THC increased amygdala activation and reduced amygdala and dorsolateral prefrontal cortex (dlPFC) functional coupling during cognitive reappraisal of emotionally negative pictures. This suggests that in addition to automatic emotional processes, THC affects frontolimbic functioning during cognitive reappraisal.

Anxiety disorders are associated with abnormalities in amygdala function and prefrontal cortex-amygdala connectivity. The majority of functional magnetic resonance imaging studies have examined mean group differences in amygdala activation or connectivity in children and adolescents with anxiety disorders relative to controls, but emerging evidence suggests that abnormalities in amygdala function are dependent on the timing of the task and may vary across the course of a scanning session. The goal of the present study was to extend our knowledge of the dynamics of amygdala dysfunction by examining whether changes in amygdala activation and connectivity over scanning differ in pediatric anxiety disorder patients relative to typically developing controls during an emotion processing task. Examining changes in activation over time allows for a comparison of how brain function differs during initial exposure to novel stimuli versus more prolonged exposure. Participants included 34 anxiety disorder patients and 19 controls 7 to 19 years old. Participants performed an emotional face-matching task during functional magnetic resonance imaging scanning, and the task was divided into thirds in order to examine change in activation over time. Results demonstrated that patients exhibited an abnormal pattern of amygdala activation characterized by an initially heightened amygdala response relative to controls at the beginning of scanning, followed by significant decreases in activation over time. In addition, controls evidenced greater context-modulated prefrontal cortex-amygdala connectivity during the beginning of scanning relative to patients. These results indicate that differences in emotion processing between the groups vary from initial exposure to novel stimuli relative to more prolonged exposure. Implications are discussed regarding how this pattern of neural activation may relate to altered early-occurring or anticipatory emotion-regulation strategies and maladaptive later-occurring strategies in children and adolescents with anxiety disorders.

Background: Collectively, functional neuroimaging studies implicate frontal-limbic dysfunction in the pathophysiology of posttraumatic stress disorder (PTSD), as reflected by altered amygdala reactivity and deficient prefrontal responses. These neural patterns are often elicited by social signals of threat (fearful/angry faces) and traumatic reminders (combat sounds, script-driven imagery). Although PTSD can be conceptualized as a disorder of emotion dysregulation, few studies to date have directly investigated the neural correlates of volitional attempts at regulating negative affect in PTSD., Methods: Using functional magnetic resonance imaging and a well-validated task involving cognitive regulation of negative affect via reappraisal and known to engage prefrontal cortical regions, the authors compared brain activation in veterans with PTSD (n = 21) and without PTSD (n = 21, combat-exposed controls/CEC), following military combat trauma experience during deployments in Afghanistan or Iraq. The primary outcome measure was brain activation during cognitive reappraisal (i.e., decrease negative affect) as compared to passive viewing (i.e., maintain negative affect) of emotionally evocative content of aversive images, Results: The subjects in both groups reported similar successful reduction in negative affect following reappraisal. The PTSD group engaged the dorsolateral prefrontal cortex (dlPFC) during cognitive reappraisal, albeit to a lesser extent than the CEC group. Although the amygdala was engaged in both groups during passive viewing of aversive images, neither group exhibited attenuation of amygdala activation during cognitive reappraisal., Conclusions: Veterans with combat-related PTSD showed less recruitment of the dlPFC involved in cognitive reappraisal, suggesting focal and aberrant neural activation during volitional, self-regulation of negative affective states., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

In the current study, we evaluated the test-retest reliability of amygdala response using an emotional face-matching task that has been widely used to examine pathophysiology and treatment mechanisms in psychiatric populations. Activation within the fusiform face area (FFA) was also examined. Twenty-seven healthy volunteers completed a variation of the face-matching paradigm developed by Hariri et al. (2000) at two time points approximately 90 days apart. Estimates of test-retest reliability of amygdala response to fearful faces were moderate, whereas angry and happy faces showed poor reliability. Test-retest reliability of the FFA was moderate to strong, regardless of facial affect. Collectively, these findings indicate that the reliability of the BOLD MR signal in the amygdala varies substantially by facial affect. Efforts to improve measurement precision, enlarge sample sizes, or increase the number of assessment occasions seem warranted., (Copyright © 2013 Society for Psychophysiological Research.)

Background: Generalized social anxiety disorder (gSAD) is characterized by exaggerated amygdala reactivity to social signals of threat, but if and how the amygdala interacts with functionally and anatomically connected prefrontal cortex (PFC) remains largely unknown. Recent evidence points to aberrant amygdala connectivity to medial PFC in gSAD at rest, but it is difficult to attribute functional relevance without the context of threat processing. Here, we address this by studying amygdala-frontal cortex connectivity during viewing of fearful faces and at rest in gSAD patients., Methods: Twenty patients with gSAD and 17 matched healthy controls (HCs) participated in functional magnetic resonance imaging of an emotional face matching task and a resting state task. Functional connectivity and psychophysiological interaction analysis were used to assess amygdala connectivity., Results: Compared to HCs, gSAD patients exhibited less connectivity between amygdala and the rostral anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) while viewing fearful faces. gSAD patients also showed less connectivity between amygdala and rostral ACC at rest in the absence of fearful faces. DLPFC connectivity was negatively correlated with LSASFear (where LSAS is Liebowitz Social Anxiety Scale)., Conclusions: Task and rest paradigms provide unique and important information about discrete and overlapping functional networks. In particular, amygdala coupling to DLPFC may be a phasic abnormality, emerging only in the presence of a social predictor of threat, whereas amygdala coupling to the rostral ACC may reflect both phasic and tonic abnormalities. These findings prompt further studies to better delineate intrinsic and externally evoked brain connectivity in anxiety and depression in relation to amygdala dysfunction., (© 2012 Wiley Periodicals, Inc.)

Functional neuroimaging studies have largely established the prominence of amygdala during emotion processing and prefrontal areas such as anterior cingulate cortex (ACC) during attentional modulation. In general, emotion processing paradigms known to probe amygdala have not been adapted to recruit prefrontal areas. In this study we used a well-known perceptual face matching paradigm, designed to elicit amygdala response, and asked volunteers to shift their focus in order to recruit regions responsible for attentional control. Stimuli comprised a trio of geometric shapes (circles, rectangles, triangles) presented alongside a trio of emotional faces (angry, fear, or happy) within the same field of view, and subjects were instructed to Match Faces or Match Shapes, as a means of attending to and away from the emotional content, respectively. We observed greater amygdala reactivity to Match Faces (>Match Shapes), and greater rostral ACC response to Match Shapes (>Match Faces). Results indicate that simply and volitionally directing attention toward or away from emotional content correspondingly modulates amygdala and ACC activity., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Alcohol is a known exogenous modulator of negative affect (anxiety, tension) in both animals and humans. It has been proposed that the anxiolytic effects of alcohol are mediated via the amygdala, an area critical to fear perception and responding. However, little is known about the acute effects of alcohol on amygdala reactivity to threatening information in humans. We used functional magnetic resonance imaging and a validated task to probe amygdala responses to social signals of threat in 12 healthy, social drinkers after a double-blind crossover administration of alcohol or placebo. We found that alcohol significantly reduced amygdala reactivity to threat signals. The current findings fit well with the notion that alcohol may attenuate threat-based responding and provide a potential brain-based mechanism for the link between alcohol and anxiety and/or social threat perception., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Patients with generalized social anxiety disorder (GSAD) exhibit heightened activation of the amygdala in response to social cues conveying threat (eg, fearful/angry faces). The neuropeptide oxytocin (OXT) decreases anxiety and stress, facilitates social encounters, and attenuates amygdala reactivity to threatening faces in healthy subjects. The goal of this study was to examine the effects of OXT on fear-related amygdala reactivity in GSAD and matched healthy control (CON) subjects. In a functional magnetic resonance imaging study utilizing a double-blind placebo-controlled within-subjects design, we measured amygdala activation to an emotional face matching task of fearful, angry, and happy faces following acute intranasal administration of OXT (24 IU or 40.32 μg) and placebo in 18 GSAD and 18 CON subjects. Both the CON and GSAD groups activated bilateral amygdala to all emotional faces during placebo, with the GSAD group exhibiting hyperactivity specifically to fearful faces in bilateral amygdala compared with the CON group. OXT had no effect on amygdala activity to emotional faces in the CON group, but attenuated the heightened amygdala reactivity to fearful faces in the GSAD group, such that the hyperactivity observed during the placebo session was no longer evident following OXT (ie, normalization). These findings suggest that OXT has a specific effect on fear-related amygdala activity, particularly when the amygdala is hyperactive, such as in GSAD, thereby providing a brain-based mechanism of the impact of OXT in modulating the exaggerated processing of social signals of threat in patients with pathological anxiety.

Using functional magnetic resonance imaging, we measured amygdala reactivity to faces varying on threat intensity in patients with generalized social phobia (GSP) and healthy controls. GSP patients exhibited greater amygdala reactivity to threat faces at high and moderate intensities. More subtle displays of social threat are sufficient to evoke a fear-related neural response., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

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.

The cannabinoid (CB) system is a key neurochemical mediator of anxiety and fear learning in both animals and humans. The anxiolytic effects of delta(9)-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, are believed to be mediated through direct and selective agonism of CB(1) receptors localized within the basolateral amygdala, a critical brain region for threat perception. However, little is known about the effects of THC on amygdala reactivity in humans. We used functional magnetic resonance imaging and a well validated task to probe amygdala responses to threat signals in 16 healthy, recreational cannabis users after a double-blind crossover administration of THC or placebo. We found that THC significantly reduced amygdala reactivity to social signals of threat but did not affect activity in primary visual and motor cortex. The current findings fit well with the notion that THC and other cannabinoids may have an anxiolytic role in central mechanisms of fear behaviors and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid system for disorders of anxiety and social fear.

Successful control of affect partly depends on the capacity to modulate negative emotional responses through the use of cognitive strategies (i.e., reappraisal). Recent studies suggest the involvement of frontal cortical regions in the modulation of amygdala reactivity and the mediation of effective emotion regulation. However, within-subject inter-regional connectivity between amygdala and prefrontal cortex in the context of affect regulation is unknown. Here, using psychophysiological interaction analyses of functional magnetic resonance imaging data, we show that activity in specific areas of the frontal cortex (dorsolateral, dorsal medial, anterior cingulate, orbital) covaries with amygdala activity and that this functional connectivity is dependent on the reappraisal task. Moreover, strength of amygdala coupling with orbitofrontal cortex and dorsal medial prefrontal cortex predicts the extent of attenuation of negative affect following reappraisal. These findings highlight the importance of functional connectivity within limbic-frontal circuitry during emotion regulation.

Using functional magnetic resonance imaging, we measured amygdala reactivity to faces varying on emotional intensity in subjects with generalized social phobia (GSP) and matched healthy controls, and observed greater bilateral activation to high (vs. low) intensity expressions in the phobic group, suggesting that more arousing social-emotional cues contribute to limbic hyperactivity in GSP.

The amygdala has been consistently isolated as a key neural substrate for processing facial displays of affect. Recent evidence from human lesion and functional neuroimaging studies have begun to challenge the notion that the amygdala is reserved for signals of threat (fear/anger). We performed a 4 T fMRI study in which 20 subjects viewed a contemporary set of photographs displaying 6 different facial expressions (fearful, disgusted, angry, sad, neutral, happy) while performing a task with minimal cognitive demand. Across subjects, the left amygdala was activated by each face condition separately, and its response was not selective for any particular emotion category. These results challenge the notion that the amygdala has a specialized role in processing certain emotions and suggest that the amygdala may have a more general-purpose function in processing salient information from faces.

BackgroundPediatric and adult anxiety disorder patients exhibit attention bias to threat and difficulty disengaging attention away from threat. Cognitive frameworks suggest that these patterns are associated with hyperactivation of regions associated with detecting threat, such as the amygdala, and hypoactivation of regions associated with regulating attention, including the lateral prefrontal cortex and rostral anterior cingulate cortex (rACC). The aim of the present study was to examine the neural correlates of these processes in children and adolescents with anxiety disorders.MethodsParticipants with an anxiety disorder 7 to 19 years old (n = 34) and typically developing controls (n = 35) underwent fMRI scanning. During scanning, they completed a task with conditions that manipulated whether participants were instructed to match emotional faces (direct emotion processing) or match shapes in the context of emotional face distractors (attentional control).ResultsResults revealed a significant difference in rACC activation during shape versus face matching, with controls evidencing greater rACC activation relative to patients.ConclusionsThis study identifies abnormalities in rACC activation as a potential neural mediator associated with pediatric anxiety disorders, which can inform frameworks for understanding their development and treatment.

How the human brain processes social information is an increasingly researched topic in psychology and neuroscience, advancing our understanding of basic human cognition and psychopathologies. Neuroimaging studies typically seek to isolate one specific aspect of social cognition when trying to map its neural substrates. It is unclear if brain activation elicited by different social cognitive processes and task instructions are also spontaneously elicited by general social information. In this study, we investigated whether these brain regions are evoked by the mere presence of social information using an automated meta-analysis and confirmatory data from an independent study of simple appraisal of social vs. non-social images. Results of 1,000 published fMRI studies containing the keyword of “social” were subject to an automated meta-analysis (). To confirm that significant brain regions in the meta-analysis were driven by a social effect, these brain regions were used as regions of interest (ROIs) to extract and compare BOLD fMRI signals of social vs. non-social conditions in the independent study. The NeuroSynth results indicated that the dorsal and ventral medial prefrontal cortex, posterior cingulate cortex, bilateral amygdala, bilateral occipito-temporal junction, right fusiform gyrus, bilateral temporal pole, and right inferior frontal gyrus are commonly engaged in studies with a prominent social element. The social–non-social contrast in the independent study showed a strong resemblance to the NeuroSynth map. ROI analyses revealed that a social effect was credible in 9 out of the 11 NeuroSynth regions in the independent dataset. The findings support the conclusion that the “social brain” is highly sensitive to the mere presence of social information. [ABSTRACT FROM AUTHOR]

Highlights: [•] Δ9-tetrahydrocannabinol (THC) increased vmPFC and HIPP activation during extinction memory recall (vs. placebo). [•] THC attenuated amygdala activity during early extinction learning. [•] The cannabinoid system may serve as a promising target for innovative intervention strategies in PTSD and other fear learning-related disorders. [Copyright &y& Elsevier]

Background: Generalized social phobia (gSP), also known as generalized social anxiety disorder, is characterized by excessive fear of scrutiny by others and pervasive avoidance of social interactions. Pathophysiologic models of gSP implicate exaggerated reactivity of the amygdala and insula in response to social evaluative threat, making them plausible targets for treatment. Although selective serotonin reuptake inhibitor (SSRI) treatment is known to be an effective treatment, little is known about the mechanism through which these agents exert their anxiolytic effects at a brain level in gSP. Methods: We acquired functional magnetic resonance imaging data of brain response to social signals of threat (fearful/angry faces) in 21 gSP patients before and after they completed 12 weeks of open-label treatment with the SSRI sertraline. For comparison, 19 healthy control (HC) subjects also underwent two functional magnetic resonance imaging scans, 12 weeks apart. Results: Whole-brain voxelwise analysis of variance revealed significant Group×Time interactions in the amygdala and the ventral medial prefrontal cortex. Follow-up analyses showed that treatment in gSP subjects reduced amygdala reactivity to fearful faces (which was exaggerated relative to HCs before treatment) and enhanced ventral medial prefrontal cortex activation to angry faces (which was attenuated relative to HCs before treatment). However, these brain changes were not significantly related to social anxiety symptom improvement. Conclusions: SSRI treatment response in gSP is associated with changes in a discrete limbic-paralimbic brain network, representing a neural mechanism through which SSRIs may exert their actions. [ABSTRACT FROM AUTHOR]

Abstract: Using functional magnetic resonance imaging, we measured amygdala reactivity to faces varying on emotional intensity in subjects with generalized social phobia (GSP) and matched healthy controls, and observed greater bilateral activation to high (vs. low) intensity expressions in the phobic group, suggesting that more arousing social–emotional cues contribute to limbic hyperactivity in GSP. [Copyright &y& Elsevier]