Prefrontal Mechanisms of Fear Reduction After Threat Offset

Introduction: Reducing fear when a threat has disappeared protects against a continuously elevated anxiety state. In this study, we investigated the brain mechanism involved in this process. Methods: The threat paradigm consisted of discrete cues that signaled either threat of shock or safety. Healthy participants were tested in two sessions in which eyeblink startle (n = 26) and blood oxygen level dependence (n = 23) were measured to index subjects' defensive state and brain responses respectively. Results: Startle results indicated that subjects could rapidly decrease their defensive state after the offset of shock threat. Functional magnetic resonance imaging data indicated that the termination of threat was associated with the recruitment of lateral and ventromedial prefrontal cortices. An exploratory connectivity analysis showed that activity in these prefrontal regions was linked and was also associated with activity in brain regions typically responding to threat, the right anterior insula and amygdala. Conclusions: These results provide first evidence for a prefrontal mechanism that functions to control anxiety after threat offset, which may be dysfunctional in patients who suffer from excessive sustained anxiety. Moreover, the results support a model in which the lateral prefrontal cortex controls anxiety related limbic activity through connections with ventromedial prefrontal cortex.