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

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


J Psychiatry Neurosci 2014;39(5):321-29

Katherine E. Vytal, PhD; Cassie Overstreet, BA; Danielle R. Charney, BA; Oliver J. Robinson, PhD; Christian Grillon, PhD

Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, NIH, Bethesda, MD, USA


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.

Submitted July 17, 2013; Revised Nov. 8, Dec. 24, 2013; Accepted Jan. 6, 2014; Early-released June 3, 2014.

Acknowledgements: We thank Hang Joon Jo for help with ANATICOR implementation, and Richard Reynolds for assistance with AFNI analysis.

Competing interests: This research was supported by the Intramural Research Program of the National Institutes of Mental Health (grant # MH002798). The authors declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Contributors: All authors designed the study, acquired and analyzed the data, wrote the article and reviewed and approved the final version for publication.

DOI: 10.1503/jpn.130145

Correspondence to: K.E. Vytal, National Institute of Mental Health, 15K North Dr., MSC 2670, Bethesda MD 20892-2670;