Functional MRI of the amygdala and bed nucleus of the stria terminalis during conditions of uncertainty in generalized anxiety disorder

Abstract

Generalized anxiety disorder (GAD) is a common psychiatric disorder characterized by constant worry or anxiety over every day life activities and events. The neurobiology of the disorder is thought to involve a wide cortical and subcortical network that includes but is not limited to the amygdala and the bed nucleus of the stria terminalis (BNST). These two regions have been hypothesized to play different roles in stress and anxiety; the amygdala is thought to regulate responses to brief emotional stimuli while the BNST is thought to be involved in more chronic regulation of sustained anxiety. In this study, we exposed medication-free GAD patients as well as non-anxious controls to a gambling game where one of the conditions involved non-contingent monetary loss. This condition of high uncertainty was intended to elicit a stressful response and sustained anxiety. Functional MRI scans were collected simultaneously to investigate BOLD activity in the amygdala and BNST during performance of this task. Compared to controls, we found that GAD patients demonstrated decreased activity in the amygdala and increased activity in the BNST. Skin conductance measures showed a consistent early versus late effect within block where GAD patients demonstrated higher arousal than controls late in the task blocks. Based on these results, we hypothesize that GAD patients disengage the amygdala and its response to acute stress earlier than non-anxious controls making way for the BNST to maintain a more sustained response. Future studies are needed to investigate the temporal dynamics of activation and deactivation in these regions.

Figure 1

(A) Task blocks and timing parameters for each run. (B) Trial sequence for stress trials (“ready” screen, followed by “choice” screen, followed by feedback, and (C) Trial sequence for control trials (“ready” screen, followed by “choice” screen and no feedback is given).

Figure 2

(A) Group contrast of Controls minus GAD patients shown at an uncorrected P value of .05 with a 10-voxel cluster threshold. Increases in activity in controls compared to GAD patients are shown in red (bilateral amygdala) while decreases are shown in blue (bilateral BNST). These maps are not restricted to the anatomical ROIs and thus some additional activity overlapping with the hippocampus and the caudate is also shown. Only activity inside our anatomical ROIs entered the statistical analysis. Representative coronal and axial slices are depicted. (B) Statistical comparison of bilateral amygdala and BNST activity in GAD patients and controls showing decreased amygdala activity and increased BNST activity in patients.

Figure 3

Comparison of group × ROI activity across active task conditions.

Figure 4

Analysis of skin conductance within-block temporal effects. (A) a second-by-second depiction of group × task condition conductance showing a possible group difference that could have been obscured by the time-averaged analysis, (B) A more quantitative evaluation of early vs. middle vs. late temporal effects and comparison across groups, demonstrating clear evidence of decreased conductance at the beginning of the block and increased conductance at the end of the block in GAD patients compared to controls.

Figure 5

Correlations between z-transformed skin conductance response in the uncertainty conditions and the z-transformed fMRI BOLD response in the amygdala. There is a significant correlation between amygdala activation and SCR response in controls (B) but not in GAD patients (A).