A causal role of the ventromedial prefrontal cortex in regulating anticipated regret and risk behaviors in trait anxiety

BACKGROUND: Individuals with high trait anxiety (HA) exhibit maladaptive goal-directed behaviors, which are associated with dysfunctional counterfactual-thinking during decision-making. While lesion studies suggest the causal role of the ventromedial prefrontal cortex (vmPFC) in counterfactual-thinking, its modulatory role in anxiety-related counterfactual decision-making remains uncharacterized. Here, we bridge this gap by examining the characteristics of decision-making (forward counterfactual) and emotion responses (backward counterfactual) in trait anxiety, as well as its underlying modulatory mechanisms by targeting at the vmPFC. METHODS: A counterfactual-thinking paradigm was employed to identify the patterns of goal-directed choice and emotional responses in trait anxiety in experiment 1. In all, 107 participants with varied levels of trait anxiety were recruited and counterfactual indices were modeled. In experiment 2, the high-definition transcranial direct current stimulation (HD-tDCS) was applied to modulate forward and backward counterfactual responses targeting at the vmPFC in HA. Based on the exploratory results of experiment 1, 61 participants with HA were randomly assigned to cathodal or sham stimulation. RESULTS: High level of anxiety was associated with stronger emotional responses to backward counterfactuals, more anticipations of regret to forward counterfactuals, higher value-expectations to potential rewards, and more risk-taking behaviors. Related to sham, cathodal HD-tDCS over the vmPFC in HA showed normalized sensitivity to anticipated regret, which leads to less risk-taking behaviors during goal-directed decision-making. CONCLUSIONS: The findings provide evidences of disrupted forward and backward counterfactual processing in anxious individuals, wherein the vmPFC plays a modulatory role. Targeting vmPFC with noninvasive stimulation may normalize maladaptive decision patterns in anxiety and anxiety disorders.