Sustained anxiety increases amygdala-dorsomedial prefrontal coupling: a mechanism for maintaining an anxious state in healthy adults

Abstract

Background: Neuroimaging research has traditionally explored fear and anxiety in response to discrete threat cues (e.g., during fear conditioning). However, anxiety is a sustained aversive state that can persist in the absence of discrete threats. Little is known about mechanisms that maintain anxiety states over a prolonged period. Here, we used a robust translational paradigm (threat of shock) to induce sustained anxiety. Recent translational work has implicated an amygdala-prefrontal cortex (PFC) circuit in the maintenance of anxiety in rodents. To explore the functional homologues of this circuitry in humans, we used a novel paradigm to examine the impact of sustained anticipatory anxiety on amygdala-PFC intrinsic connectivity.

Methods: Task-independent fMRI data were collected in healthy participants during long-duration periods of shock anticipation and safety. We examined intrinsic functional connectivity.

Results: Our study involved 20 healthy participants. During sustained anxiety, amygdala activity was positively coupled with dorsomedial PFC (DMPFC) activity. High trait anxiety was associated with increased amygdala-DMPFC coupling. In addition, induced anxiety was associated with positive coupling between regions involved in defensive responding, and decreased coupling between regions involved in emotional control and the default mode network.

Limitations: Inferences regarding anxious pathology should be made with caution because this study was conducted in healthy participants.

Conclusion: Findings suggest that anticipatory anxiety increases intrinsic amygdala-DMPFC coupling and that the DMPFC may serve as a functional homologue for the rodent prefrontal regions by sustaining anxiety. Future research may use this defensive neural context to identify biomarkers of risk for anxious pathology and target these circuits for therapeutic intervention.

Fig. 1

Right amygdala seed functional connectivity. The statistical map illustrates areas that showed increased positive coupling with the amygdala (orange) and decreased coupling with the amygdala (blue) during anticipatory anxiety as compared with safety. Areas with significant increases in positive coupling include the medial prefrontal cortex, insula, thalamus and basal ganglia. Areas with significant decreases in coupling include the ventromedial prefrontal cortex, inferior temporal gyrus and precuneus. Sagittal view x = −5; Coronal view y = 18. Images are in Talairach space, neurologic convention, and thresholded at q < 0.05, false discovery rate–corrected.

Fig. 2

Dorsomedial prefrontal cortex (DMPFC) seed functional connectivity. The statistical map illustrates areas that showed increased positive coupling with the DMPFC (orange) and decreased coupling with the DMPFC (blue) during anticipatory anxiety compared with safety. Areas with significant increases in positive coupling include the amygdala, anterior cingulate cortex, insula and basal ganglia. The inferior temporal gyrus showed significant decreases in coupling with DMPFC. Coronal view y = 5. Images are in Talairach space, neurologic convention, and thresholded at q < 0.05, false discovery rate–corrected.

Fig. 3

Dispositional anxiety predicts positive coupling between the amygdala and dorsomedial prefrotnal cortex (DMPFC). Trait anxiety was positively correlated with amygdala–DMPFC coupling (r = 0.457, p = 0.037). STAI-T = State Trait Anxiety Inventory Trait.

Fig. 4

Proposed anticipatory anxiety network. Schematic illustration of the amygdala and prefrontal cortex (encompassing the dorsomedial prefrontal cortex and dorsal anterior cingulate cortex) as hubs in a network associated with anticipatory anxiety. Other central components of the network include the bilateral insula and thalamus. These regions are known to support affective, cognitive and autonomic nervous system changes, and in concert they create a state of readiness to respond to potential threat.