Abstract
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. 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. 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. 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.
Highlights
Pathological anxiety is a large and increasing global health problem.[1]
Our work suggests that interactions between the dorsal medial prefrontal cortex and amygdala constitute an aversive-amplification circuit whereby increased positive coupling between these regions is associated with increased threat processing under stress.[7,8,9]
Betas extracted from the peak voxel from our previous study (x,y,z=2,2,40) for illustrative purposes showed that this diagnosis-byvalence interaction (F[degrees of freedom 1,43]=5·3, p=0·03; figure 2B) was driven by increased coupling during the processing of fearful faces versus happy faces in patients with anxiety disorders (t[21]=2·2, p=0·039), but not healthy controls (p=0·2)
Summary
Pathological anxiety is a large and increasing global health problem.[1]. People with the disorder go through periods of crippling anxiety that adversely affect their daily lives. Negative affective biases towards threats are recorded in healthy people experiencing transient anxiety or stress.[1] The adaptive and maladaptive anxiety-driven negative affective biases might be linked, perhaps falling at opposite ends of the same scale. Such an association would have implications for how we diagnose and treat these disorders, but evidence is scarce at present. This study extends four of our previous studies mapping the circuit-based interactions between the dorsal medial prefrontal (anterior cingulate) cortex and the amygdala during adaptive threat processing in stressed healthy people to address pathological anxiety
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