The dorsal medial prefrontal (anterior cingulate) cortex–amygdala aversive amplification circuit in unmedicated generalised and social anxiety disorders: an observational study

Background In four previous studies, we have delineated the role of positive circuit coupling between the dorsal medial prefrontal (anterior cingulate) cortex and the amygdala during aversive processing in healthy people under stress. This translational circuit—the aversive amplification circuit—is thought to drive adaptive, harm-avoidant behaviour in threatening environments. We assess the role of this circuit in the pathological manifestation of anxiety disorders. Methods For this single-site study, 45 unmedicated participants (22 with generalised and/or social anxiety disorder and 23 healthy controls) were recruited via advertisements from the metropolitan area of Washington, DC (USA). People who applied to participate in the study had to pass an initial telephone screen and comprehensive screening by a clinician at the National Institutes of Health (NIH; Bethesda, MD, USA). People with a contraindicated medical disorder, past or current psychiatric disorders other than anxiety disorders, and those using psychoactive medications or illicit drugs were excluded. Eligible individuals could participate as either a healthy control or a patient, depending on diagnosis. They were asked to use a button box to complete a simple emotion identification task (fearful vs happy faces; 44 trials of each) during functional MRI at the NIH. Functional imaging analysis consisted of event-related activation analysis and psychophysiological interaction connectivity analysis of regions coupled with the amygdala during task performance. Findings A diagnosis-by-valence interaction was recorded in whole-brain amygdala connectivity within the dorsal medial prefrontal (anterior cingulate) cortex clusters identified in our previous study, driven by significantly increased circuit coupling during processing of fearful faces versus happy faces in anxious, but not healthy, participants. Importantly, and in accordance with contemporary theoretical approaches to psychiatry, circuit coupling correlated positively with self-reported anxious symptoms, which provides evidence of a continuous association between the circuit and subjective symptoms. Interpretation In this study and our previous work, we track the functional role of one neural circuit from its involvement in adaptive threat biases under stress, to its chronic engagement in anxiety disorders in the absence of experimentally induced stress. Thus, we uniquely map a mood and anxiety-related circuit across its adaptive and maladaptive stages. Clinically, this study could provide a step towards a more mechanistic continuum-based approach to anxiety disorder diagnosis and might ultimately lead to more targeted treatments for patients with anxiety disorders.