Activity alterations in the bed nucleus of the stria terminalis and amygdala during threat anticipation in generalized anxiety disorder

Abstract

Sustained anticipatory anxiety is central to Generalized Anxiety Disorder (GAD). During anticipatory anxiety, phasic threat responding appears to be mediated by the amygdala, while sustained threat responding seems related to the bed nucleus of the stria terminalis (BNST). Although sustained anticipatory anxiety in GAD patients was proposed to be associated with BNST activity alterations, firm evidence is lacking. We aimed to explore temporal characteristics of BNST and amygdala activity during threat anticipation in GAD patients. Nineteen GAD patients and nineteen healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during a temporally unpredictable threat anticipation paradigm. We defined phasic and a systematic variation of sustained response models for blood oxygen level-dependent responses during threat anticipation, to disentangle temporally dissociable involvement of the BNST and the amygdala. GAD patients relative to HC responded with increased phasic amygdala activity to onset of threat anticipation and with elevated sustained BNST activity that was delayed relative to the onset of threat anticipation. Both the amygdala and the BNST displayed altered responses during threat anticipation in GAD patients, albeit with different time courses. The results for the BNST activation hint towards its role in sustained threat responding, and contribute to a deeper understanding of pathological sustained anticipatory anxiety in GAD.

Stria terminalis, amygdala, and temporoparietal junction networks facilitate efficient emotion processing under expectations

“…In psychosis, for example, there is a deficit in recognising threatening emotions (Behere, 2015;Mandal, Pandey, & Prasad, 1998;van't Wout et al, 2007) and also misattribution of threat (Premkumar et al, 2008). These abnormalities in threat processing have strong links to neurobiological factors; specifically, abnormal activation and connectivity in similar brain regions as those identified in the current study (i.e., amygdala, temporoparietal junction, BNST, ACC, and hippocampus) (Bitsch, Berger, Nagels, Falkenberg, & Straube, 2018;Bryant et al, 2008;Buff et al, 2017;Felmingham et al, 2008;Rabellino et al, 2015;Rabellino et al, 2018;Underwood, Kumari, & Peters, 2016;Underwood, Peters, & Kumari, 2015). These abnormalities in threat processing have strong links to neurobiological factors; specifically, abnormal activation and connectivity in similar brain regions as those identified in the current study (i.e., amygdala, temporoparietal junction, BNST, ACC, and hippocampus) (Bitsch, Berger, Nagels, Falkenberg, & Straube, 2018;Bryant et al, 2008;Buff et al, 2017;Felmingham et al, 2008;Rabellino et al, 2015;Rabellino et al, 2018;Underwood, Kumari, & Peters, 2016;Underwood, Peters, & Kumari, 2015).…”

Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice

“…Recently, we demonstrated that this paradigm sensitizes the expression of somatic withdrawal behaviors in both male and female C57BL/6J mice and alters inhibitory transmission in the bed nucleus of the stria terminalis (BNST), a brain region implicated in mediating anxiety‐like behavior in both rodents and humans (Buff et al, ; Cecchi, Khoshbouei, Javors, & Morilak, ; Fitzgerald et al, ; Mazzone et al, ). Moreover, we observed sex‐specific manifestations of withdrawal behavior and subsequent BNST physiology (Luster et al, ).…”

Resting‐state fMRI effective connectivity between the bed nucleus of the stria terminalis and amygdala nuclei

“…As has been reported by several studies from our lab, exaggerated phasic amygdala and sustained BNST activity in reaction to aversive stimuli seems to be characteristic for anxiety disorders. For example, female patients with posttraumatic stress disorder as well as panic disorder patients and patients with generalized anxiety disorder showed increased initial phasic amygdala and increased sustained BNST fMRI BOLD responses during the anticipation of aversive versus neutral sounds as compared to controls (Brinkmann, Buff, Feldker, et al, ; Brinkmann, Buff, Neumeister, et al, ; Buff et al, ). Considering the vast amount of research investigating the neuroplasticity that goes along with fear/anxiety learning and expression (e.g., Cardinal et al, ; Davis et al, ; Duvarci & Pare, ), it is plausible that these exaggerated responses to aversive stimuli in patients are caused by specific alterations of the connectivity structure of processing regions, affecting, among others, the BNST–amygdala circuit.…”

“…As has been reported by several studies from our lab, exaggerated phasic amygdala and sustained BNST activity in reaction to aversive stimuli seems to be characteristic for anxiety disorders. For example, female patients with posttraumatic stress disorder as well as panic disorder patients and patients with generalized anxiety disorder showed increased initial phasic amygdala and increased sustained BNST fMRI BOLD responses during the anticipation of aversive versus neutral sounds as compared to controls (Brinkmann, Buff, Feldker, et al, 2017;Brinkmann, Buff, Neumeister, et al, 2017;Buff et al, 2017).…”