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Interpersonal violence (IPV) is one of the most frequent causes for the development of posttraumatic stress disorder (PTSD) in women. One key component in PTSD is altered processing of trauma-related cues, leading to emotional symptoms. In the everyday environment, words with trauma-associated semantic content represent typical, albeit abstract, trauma-related stimuli for patients suffering from PTSD. However, the functional neuroanatomy associated with processing single trauma-related words in IPV-PTSD is not understood. The present event-related functional magnetic resonance imaging study investigated the neural basis of trauma-related word processing in women with IPV-PTSD relative to healthy controls (HC) during a non-emotional vigilance task in which the emotional content of the words was task-irrelevant. On the behavioral level, trauma-related relative to neutral word stimuli evoked more unpleasant feelings, higher arousal as well as anxiety in IPV-PTSD patients as compared to HC. Functional imaging data showed hyperactivation to trauma-related versus neutral words in the basolateral amygdala (BLA) and cortical language-processing regions (inferior frontal gyrus, posterior cingulate cortex, angular/supramarginal gyrus) in IPV-PTSD compared to HC. These results propose a role of the BLA in hypervigilant responding to verbal trauma associated cues in IPV-PTSD. Furthermore, the particular involvement of cortical language-processing regions indicates enhanced processing of trauma-related words in brain regions associated with analysis and memory of verbal material. Taken together, our findings suggest that both subcortical and cortical mechanisms contribute to automatic responsivity to verbal trauma cues in PTSD.

BackgroundAltered amygdala activation to fear-related stimuli has been proposed to be a potential neural correlate of heightened threat sensitivity in anxiety- and stress-related disorders. However, the role of stimulus awareness and disorder specificity remains widely unclear. Here we investigated amygdala responses to conscious and unconscious fearful faces in patients suffering from panic disorder (PD), generalized anxiety disorder (GAD), or post-traumatic stress disorder (PTSD) and in a large sample of healthy controls (HC).MethodsDuring event-related functional magnetic resonance imaging participants (n = 120; 20 PD, 20 GAD, 20 PTSD, 60 HC) were confronted with briefly presented fearful faces, neutral faces, and non-faces in a backward masking paradigm. The design allowed for the analysis of trial-by-trial face detection performance and amygdala responses to fearful v. neutral faces.ResultsAll participants exhibited increased amygdala activation to fearful v. neutral faces during conscious trials. Specifically during unconscious face processing, the PTSD, compared with all other groups, showed higher right basolateral (BLA) amygdala activity to fearful v. neutral faces.ConclusionsThe present study shows that BLA amygdala hyperactivity during unconscious, but not conscious, processing of fearful faces differentiates PTSD from the investigated disorders. This finding suggests an automatic and specific neural hyper-responsivity to general fear cues in PTSD and supports the idea of categorical differences between PTSD and other anxiety-related disorders.

Panic disorder (PD) patients show aberrant neural responses to threatening stimuli in an extended fear network, but results are only partially comparable, and studies implementing disorder-related visual scenes are lacking as stimuli. The neural responses and functional connectivity to a newly developed set of disorder-related, ecologically valid scenes as compared with matched neutral visual scenes, using event-related functional magnetic resonance imaging (fMRI) in 26 PD patients and 26 healthy controls (HC) were investigated. PD patients versus HC showed hyperactivation in an extended fear network comprising brainstem, insula, thalamus, anterior, and mid-cingulate cortex and (dorso-)medial prefrontal cortex for disorder-related versus neutral scenes. Amygdala differences between groups failed significance. Subjective levels of anxiety significantly correlated with brainstem activation in PD patients. Analysis of functional connectivity by means of beta series correlation revealed no emotion-specific alterations in connectivity in PD patients versus HC. The results suggest that subjective anxiety evoked by external stimuli is directly related to altered activation in the homeostatic alarm system in PD. With novel disorder-related stimuli, the study sheds new light on the neural underpinnings of pathological threat processing in PD. Hum Brain Mapp 37:4439-4453, 2016. © 2016 Wiley Periodicals, Inc.

Our understanding of altered emotional processing in social anxiety disorder (SAD) is hampered by a heterogeneity of findings, which is probably due to the vastly different methods and materials used so far. This is why the present functional magnetic resonance imaging (fMRI) study investigated immediate disorder-related threat processing in 30 SAD patients and 30 healthy controls (HC) with a novel, standardized set of highly ecologically valid, disorder-related complex visual scenes. SAD patients rated disorder-related as compared with neutral scenes as more unpleasant, arousing and anxiety-inducing than HC. On the neural level, disorder-related as compared with neutral scenes evoked differential responses in SAD patients in a widespread emotion processing network including (para-)limbic structures (e.g. amygdala, insula, thalamus, globus pallidus) and cortical regions (e.g. dorsomedial prefrontal cortex (dmPFC), posterior cingulate cortex (PCC), and precuneus). Functional connectivity analysis yielded an altered interplay between PCC/precuneus and paralimbic (insula) as well as cortical regions (dmPFC, precuneus) in SAD patients, which emphasizes a central role for PCC/precuneus in disorder-related scene processing. Hyperconnectivity of globus pallidus with amygdala, anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) additionally underlines the relevance of this region in socially anxious threat processing. Our findings stress the importance of specific disorder-related stimuli for the investigation of altered emotion processing in SAD. Disorder-related threat processing in SAD reveals anomalies at multiple stages of emotion processing which may be linked to increased anxiety and to dysfunctionally elevated levels of self-referential processing reported in previous studies.

Background: Increased automatic processing of threat-related stimuli has been proposed as a key element in panic disorder. Little is known about the neural basis of automatic processing, in particular to task-irrelevant, panic-related, ecologically valid stimuli, or about the association between brain activation and symptomatology in patients with panic disorder. Methods: The present event-related functional MRI (fMRI) study compared brain responses to task-irrelevant, panic-related and neutral visual stimuli in medication-free patients with panic disorder and healthy controls. Panic-related and neutral scenes were presented while participants performed a spatially non-overlapping bar orientation task. Correlation analyses investigated the association between brain responses and panic-related aspects of symptomatology, measured using the Anxiety Sensitivity Index (ASI). Results: We included 26 patients with panic disorder and 26 heatlhy controls in our analysis. Compared with controls, patients with panic disorder showed elevated activation in the amygdala, brainstem, thalamus, insula, anterior cingulate cortex and midcingulate cortex in response to panic-related versus neutral task-irrelevant stimuli. Furthermore, fear of cardiovascular symptoms (a subcomponent of the ASI) was associated with insula activation, whereas fear of respiratory symptoms was associated with brainstem hyperactivation in patients with panic disorder. Limitations: The additional implementation of measures of autonomic activation, such as pupil diameter, heart rate, or electrodermal activity, would have been informative during the fMRI scan as well as during the rating procedure. Conclusion: Results reveal a neural network involved in the processing of panic-related distractor stimuli in patients with panic disorder and suggest an automatic weighting of panic-related information depending on the magnitude of cardiovascular and respiratory symptoms. Insula and brainstem activations show function-related associations with specific components of panic symptomatology.

An influential framework suggests that the central nucleus of the amygdala (CeA) is involved in phasic responses to threat, while the bed nucleus of the stria terminalis (BNST) mediates sustained anxiety. However, this model has been questioned, proposing that the role of the BNST is not limited to sustained threat contexts. Rather, amygdala and BNST also seem to work in concert in the processing of discrete and briefly presented threat-related stimuli, likely dependent on inter-individual differences in anxiety. A direct test of this assumption with sufficient experimental power is missing in human research and the degree to which individual differences in trait anxiety moderate phasic responses and functional connectivity of amygdala and BNST during threat processing remains unclear. The current event-related functional magnetic resonance imaging (fMRI) study investigated activation and connectivity of amygdala and BNST, as well as modulating effects of trait anxiety, during processing of briefly presented threat-related relative to neutral standardized pictures in 93 psychiatrically healthy individuals. Both amygdala and BNST activation was increased during presentation of threat-related relative to neutral pictures. Furthermore, functional connectivity between BNST and amygdala in response to threat was positively associated with trait anxiety. These findings suggest that amygdala and BNST form a functional unit during phasic threat processing whereby their connectivity is shaped by inter-individual differences in trait anxiety.

Fear of negative evaluation, such as negative social performance feedback, is the core symptom of social anxiety. The present study investigated the neural correlates of anticipation and perception of social performance feedback in social anxiety. High (HSA) and low (LSA) socially anxious individuals were asked to give a speech on a personally relevant topic and received standardized but appropriate expert performance feedback in a succeeding experimental session in which neural activity was measured during anticipation and presentation of negative and positive performance feedback concerning the speech performance, or a neutral feedback-unrelated control condition. HSA compared to LSA subjects reported greater anxiety during anticipation of negative feedback. Functional magnetic resonance imaging results showed deactivation of medial prefrontal brain areas during anticipation of negative feedback relative to the control and the positive condition, and medial prefrontal and insular hyperactivation during presentation of negative as well as positive feedback in HSA compared to LSA subjects. The results indicate distinct processes underlying feedback processing during anticipation and presentation of feedback in HSA as compared to LSA individuals. In line with the role of the medial prefrontal cortex in self-referential information processing and the insula in interoception, social anxiety seems to be associated with lower self-monitoring during feedback anticipation, and an increased self-focus and interoception during feedback presentation, regardless of feedback valence.

Anticipation of potentially threatening social situations is a key process in social anxiety disorder (SAD). In other anxiety disorders, recent research of neural correlates of anticipation of temporally unpredictable threat suggests a temporally dissociable involvement of amygdala and bed nucleus of the stria terminalis (BNST) with phasic amygdala responses and sustained BNST activation. However, the temporal profile of amygdala and BNST responses during temporal unpredictability of threat has not been investigated in patients suffering from SAD. We used functional magnetic resonance imaging (fMRI) to investigate neural activation in the central nucleus of the amygdala (CeA) and the BNST during anticipation of temporally unpredictable aversive (video camera observation) relative to neutral (no camera observation) events in SAD patients compared to healthy controls (HC). For the analysis of fMRI data, we applied two regressors (phasic/sustained) within the same model to detect temporally dissociable brain responses. The aversive condition induced increased anxiety in patients compared to HC. SAD patients compared to HC showed increased phasic activation in the CeA and the BNST for anticipation of aversive relative to neutral events. SAD patients as well as HC showed sustained activity alterations in the BNST for aversive relative to neutral anticipation. No differential activity during sustained threat anticipation in SAD patients compared to HC was found. Taken together, our study reveals both CeA and BNST involvement during threat anticipation in SAD patients. The present results point towards potentially SAD-specific threat processing marked by elevated phasic but not sustained CeA and BNST responses when compared to HC., Highlights • fMRI in SAD during anticipation of temporally unpredictable aversive events. • Anticipation of social observation induces increased anxiety in SAD patients. • SAD patients show elevated phasic activity in fundamental anxiety network regions. • Evidence of SAD-specific threat processing.

Our understanding of altered emotional processing in social anxiety disorder (SAD) is hampered by a heterogeneity of findings, which is probably due to the vastly different methods and materials used so far. This is why the present functional magnetic resonance imaging (fMRI) study investigated immediate disorder‐related threat processing in 30 SAD patients and 30 healthy controls (HC) with a novel, standardized set of highly ecologically valid, disorder‐related complex visual scenes. SAD patients rated disorder‐related as compared with neutral scenes as more unpleasant, arousing and anxiety‐inducing than HC. On the neural level, disorder‐related as compared with neutral scenes evoked differential responses in SAD patients in a widespread emotion processing network including (para‐)limbic structures (e.g. amygdala, insula, thalamus, globus pallidus) and cortical regions (e.g. dorsomedial prefrontal cortex (dmPFC), posterior cingulate cortex (PCC), and precuneus). Functional connectivity analysis yielded an altered interplay between PCC/precuneus and paralimbic (insula) as well as cortical regions (dmPFC, precuneus) in SAD patients, which emphasizes a central role for PCC/precuneus in disorder‐related scene processing. Hyperconnectivity of globus pallidus with amygdala, anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) additionally underlines the relevance of this region in socially anxious threat processing. Our findings stress the importance of specific disorder‐related stimuli for the investigation of altered emotion processing in SAD. Disorder‐related threat processing in SAD reveals anomalies at multiple stages of emotion processing which may be linked to increased anxiety and to dysfunctionally elevated levels of self‐referential processing reported in previous studies. Hum Brain Mapp 37:1559‐1572, 2016. © 2016 Wiley Periodicals, Inc.

Background Despite considerable effort, the neurobiological underpinnings of hyper-responsive threat processing specific to patients suffering from generalized anxiety disorder (GAD) remain poorly understood. The current functional magnetic resonance imaging (fMRI) study aims to delineate GAD-specific brain activity during immediate threat processing by comparing GAD patients to healthy controls (HC), to social anxiety disorder (SAD) and to panic disorder (PD) patients. Method Brain activation and functional connectivity patterns to threat vs. neutral pictures were investigated using event-related fMRI. The sample consisted of 21 GAD, 21 PD, 21 SAD and 21 HC. Results GAD-specific elevated activity to threat vs. neutral pictures was found in cingulate cortex, dorsal anterior insula/frontal operculum (daI/FO) and posterior dorsolateral prefrontal cortex (dlPFC). Defining these effects as seed regions, we detected GAD-specific increased functional connectivity to threat vs. neutral pictures between posterior dlPFC and ventrolateral prefrontal cortex, between cingulate cortex and amygdala, between cingulate cortex and anterior insula, as well as decreased functional connectivity between daI/FO and mid-dlPFC. Conclusion The findings present the first evidence for GAD-specific neural correlates of hyper-responsive threat processing, possibly reflecting exaggerated threat sensitivity, maladaptive appraisal and attention-allocation processes., Highlights • Threat processing investigation across multiple anxiety disorders • First neural evidence of GAD-specific threat-related alterations • GAD-specific alterations primarily located in prefrontal cortex • Alterations are suggestive of exaggerated threat sensitivity