Threat-induced anxiety during goal pursuit disrupts amygdala\u2013prefrontal cortex connectivity in posttraumatic stress disorder

Delin Sun,Andrea L Gold,Courtney C Haswell,Daniel Stjepanović ,Kevin S Labar,Chelsea Swanson ,Vanessa M Brown,Rajendra A Morey

doi:10.1038/s41398-020-0739-4

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.

Highlights

Imminent threat elicits fear and is accompanied by phasic fight or flight responses, whereas unpredictable threat is associated with anxiety and sustained hypervigilance and apprehension[1]
We explored the functional connectivity of the left amygdala, right amygdala and ventromedial prefrontal cortex (vmPFC) with the rest of the brain based on voxel-wise analyses in response to the threat vs. nonthreat contrast and its between-group difference
As shown in Supplementary Data, after removing the oldest subject in Posttraumatic stress disorder (PTSD) patients and the youngest subject in controls, the two groups were not significantly different in age, and showed results consistent with the findings reported in the main text

Summary

Introduction

Imminent threat elicits fear and is accompanied by phasic fight or flight responses, whereas unpredictable threat is associated with anxiety and sustained hypervigilance and apprehension[1]. Posttraumatic stress disorder (PTSD) is characterized by symptoms of hyperarousal and hypervigilance that produce considerable distress and functional impairment[2]. The most widely adopted behavioral models for studying PTSD are based on fear conditioning and extinction[3,4], but few studies have examined the brain response associated with the anxiety elicited by the uncertainty resulting from unpredictable threat[5]. Rodents consistently prefer predictable shocks and their associated contexts, and predictability attenuates the negative effects of stress[5]. Rodents exposed to unpredictable threats display a behavioral syndrome akin to PTSD, such as hypervigilance, insomnia, and impaired attention[6,7].

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Conclusion