Threat-induced Changes in Amygdala-Ventral Prefrontal Cortex Functional Connectivity and Risk for Posttraumatic Stress Disorder

In a series of psychophysiology and functional magnetic resonance imaging (fMRI) experiments, we investigated threat-related changes in arousal and in the functional relationships of brain regions comprising critical neural circuitry in the cognitive regulation of emotion. We designed a novel paradigm to manipulate threat during a goal-directed task. We then validated this paradigm in separate neuroimaging and psychophysiological studies in healthy adults. In this paradigm, participants navigated a spatial maze to capture prey for monetary reward and avoid capture by a predator that would result in monetary losses. On threat trials, participants could receive unpredictable and inescapable shocks. On non-threat trials, participants would never be shocked. Visual cues were used to indicate whether the current trial was threat or non-threat. This paradigm was then used to study the cognitive regulation of emotion in trauma-exposed veterans with and without PTSD.;Our hypothesis was that participants would regulate the affective interference and associated anxiety caused by the threat of shock in order to maintain performance at a high level and thus maximize their monetary payout. We hypothesized that this regulation would be evident in the functional connectivity between the amygdala, a subcortical region involved in threat detection, and ventral prefrontal cortex (PFC) regions, which support executive functions. In Experiment 1 with healthy adults (N = 16), we used psychophysiological interaction (PPI) analyses to test task-specific changes in functional connectivity. We demonstrated increased functional connectivity for threat compared to non-threat conditions between the amygdala and ventral PFC regions, including the inferior frontal gyrus (IFG), orbitofrontal cortex (OFC), and ventromedial PFC (vmPFC).;We observed no behavioral performance differences related to our threat manipulation. Our preferred explanation, consistent with our regulation hypothesis, was that functional connectivity changes represented compensatory neural processing supporting the maintenance of goal-directed behavior during threat. However, the absence of behavioral performance differences related to threat is also consistent with an alternate hypothesis—namely, that our manipulation of threat was ineffective and participants did not experience increased arousal associated with affective interference and anxiety. This alternative explanation was explored in Experiment 2, in which we used psychophysiological measures to determine whether our threat induction that led to changes in functional connectivity was in fact associated with the expected increases in anxiety and arousal. In a separate sample of healthy adults (N = 26), we measured skin conductance and heart rate variability, both measures of sympathetic nervous system activation, and showed greater arousal for threat compared to non-threat conditions. This result further validated our threat manipulation.;In Experiment 3, we tested two groups of trauma-exposed veterans. One group consisted of individuals who received a current diagnosis of PTSD ( N = 20), whereas the other group did not have a current or past PTSD diagnosis (N = 22). We tested PTSD group differences in amygdala functional connectivity for threat compared to non-threat conditions with region-of-interest (ROI) analysis that used the functional clusters independently identified in Experiment 1 for bilateral IFG, vmPFC, anterior cingulate cortex, and mPFC/Brodmann area 10. This analysis showed a significant interaction in vmPFC in the expected direction, with greater increased amygdala functional connectivity strength for the threat condition compared to the non-threat condition in the non-PTSD group compared to the PTSD group.