Threat-induced anxiety during goal pursuit disrupts amygdala-prefrontal cortex connectivity in posttraumatic stress disorder

Abstract

To investigate how unpredictable threat during goal pursuit impacts fronto-limbic activity and functional connectivity in posttraumatic stress disorder (PTSD), we compared military veterans with PTSD (n = 25) vs. trauma-exposed control (n = 25). Participants underwent functional magnetic resonance imaging (fMRI) while engaged in a computerized chase-and-capture game task that involved optimizing monetary rewards obtained from capturing virtual prey while simultaneously avoiding capture by virtual predators. The game was played under two alternating contexts-one involving exposure to unpredictable task-irrelevant threat from randomly occurring electrical shocks, and a nonthreat control condition. Activation in and functional connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC) was tested across threat and nonthreat task contexts with generalized psychophysiological interaction (gPPI) analyses. PTSD patients reported higher anxiety than controls across contexts. Better task performance represented by successfully avoiding capture by predators under threat compared with nonthreat contexts was associated with stronger left amygdala-vmPFC functional connectivity in controls and greater vmPFC activation in PTSD patients. PTSD symptom severity was negatively correlated with vmPFC activation in trauma-exposed controls and with right amygdala-vmPFC functional connectivity across all participants in the threat relative to nonthreat contexts. The findings showed that veterans with PTSD have disrupted amygdala-vmPFC functional connectivity and greater localized vmPFC processing under threat modulation of goal-directed behavior, specifically related to successfully avoiding loss of monetary rewards. In contrast, trauma survivors without PTSD relied on stronger threat-modulated left amygdala-vmPFC functional connectivity during goal-directed behavior, which may represent a resilience-related functional adaptation.

Fig. 1. Schematic of the chase-and-capture game paradigm.

Participants performed five runs of the task. In each run, there were four threat (represented in red) and four nonthreat (represented in blue) blocks presented in alternating order. In each block, a text cue signaling block type was displayed for 2 s, then followed by a computer game lasting for 30 s, and ended by a fixation cross exhibiting for 12 s. During the computer game, participants were asked to move an avatar (black square) within a 2D maze on the screen through operating joystick to capture prey (green squares) and to avoid capture by a predator (purple square). Prey capture by the avatar and avatar capture by the predator were associated with monetary gain and loss, respectively. No shock was accompanied with the nonthreat block, while there was zero shock in some threat blocks, and one or two shocks in the other threat blocks (at least one shock per run, and on average 0.35 shocks per threat block). The onset of a shock was randomized relative to the onset of the embedded block. The participants had no way to distinguish between threat blocks without shock and threat blocks with unpredictable shocks before the shock delivery.

Fig. 2. Regions of interest (ROIs), self-report, and functional connectivity results.

a Three ROIs (bottom view): left amygdala (L Amy), vmPFC and right amygdala (R Amy). b Self-report results. Threat vs. nonthreat context elicited enhanced focus on avoiding predator (F(1,45) = 7.181, p = 0.010), increased initial (F(1,44) = 11.221, p = 0.002) and sustained anxiety (F(1,44) = 7.469, p = 0.009), and enhanced fear of being chased by the predator (F(1,44) = 7.299, p = 0.010). Participants with PTSD compared with controls (CONT) showed greater initial (F(1,44) = 6.266, p = 0.016) and sustained (F(1,44) = 9.937, p = 0.003) anxiety, and a trend of significance of enhanced fear to be chased by the predator (F(1,44) = 4.035, p = 0.051), but nonsignificant difference in focus on avoiding predator (F(1,45) = 0.008, p = 0.929). For better understanding, the scores of focus on avoiding predator =7—the scores of the first self-report, since the first self-report question was “did you focus more on avoiding predator (=1) or catching prey (=7)?”. c Controls (F(1,24) = 5.821, p = 0.048) but not participants with PTSD (F(1,24) = 0.988, p = 0.660) showed stronger right than left amygdala–vmPFC functional connectivity collapsed across contexts. Error bar denotes standard errors of mean.

Fig. 3. Brain-performance and brain-clinical associations.

For the threat vs. nonthreat contrast, better performance (i.e., fewer avatar captures) is associated with (a) larger vmPFC activation in PTSD (R = 0.551, p = 0.004) but not in controls (R = −0.259, p = 0.211; two correlations were significantly different, Fisher’s z = 2.935, p = 0.009), and (b) stronger left amygdala–vmPFC functional connectivity in trauma-exposed controls (R = 0.436, p = 0.029) but not in participants with PTSD patients (R = −0.223, p = 0.285; two correlations were significantly different, Fisher’s z = 2.301, p = 0.042). For observation purpose only, the x-axis reflects −1 × average number of avatar capture, so that higher values represent better performance. CAPS scores were negatively correlated with (c) vmPFC activity in controls (R = −0.485, p = 0.014) but not PTSD participant (R = 0.125, p = 0.553; two correlations were different at a trend level, Fisher’s z = −2.173, p = 0.090), and (d) right amygdala–vmPFC functional connectivity in both PTSD (R = -0.431, p = 0.032) and CONT (R = −0.427, p = 0.033) groups, in response to the threat vs. nonthreat contrast. *p < 0.05; **p < 0.005.