Towards a mechanistic understanding of pathological anxiety: the dorsal medial prefrontal-amygdala 'aversive amplification' circuit in unmedicated generalized and social anxiety disorders.

BACKGROUND We have delineated, across four prior studies, the role of positive dorsal medial prefrontal/anterior cingulate cortex (dmPFC/ACC)-amygdala circuit coupling during aversive processing in healthy individuals under stress. This translational circuit, termed the 'aversive amplification circuit', is thought to drive adaptive, harm-avoidant behavior in threatening environments. Here, in a natural progression of this prior work, we confirm that this circuit also plays a role in the pathological manifestation of anxiety disorders. METHODS Forty-five unmedicated participants (N=22 generalized and social anxiety disorder/N=23 controls) recruited from Washington DC metropolitan area completed a simple emotion identification task during functional magnetic resonance imaging at the National Institutes of Health, Bethesda, MD, USA. FINDINGS As predicted, a diagnosis by valence interaction was seen in whole-brain amygdala connectivity within the dmPFC/ACC clusters identified in our prior study; driven by significantly greater circuit coupling during fearful versus happy face processing in anxious, but not healthy, participants. Critically, and in accordance with contemporary theoretical approaches to psychiatry, circuit coupling correlated positively with self-reported anxious symptoms, providing evidence of a continuous circuit-subjective symptomatology relationship. INTERPRETATION We track the functional role of a single 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 may provide a step towards a more mechanistic spectrum-based approach to anxiety disorder diagnosis and may ultimately lead to more targeted treatments.