Subcortical modulation of the salience network during negative emotional processing in mood and anxiety disorders

Dysfunctional processing of negative emotional events is a key transdiagnostic feature of mood and anxiety disorders. This dysfunction is often associated with aberrant functioning of fronto-insular/cingulate regions involved in salience processing, including the anterior insula, dorsal anterior cingulate cortex, and ventrolateral prefrontal cortex (i.e., the salience network; SN). Coordination of SN responses to negative emotional events relies on bottom-up signals from subcortical regions commonly implicated in abnormal negative emotional processing, such as the amygdala and periaqueductal gray (PAG). Here, we used dynamic causal modelling (DCM) to investigate interactions between the amygdala, PAG and SN during negative emotional processing in mood and anxiety disorders. Thirty-seven participants with mood and anxiety disorders (29 Female) and 37 age and sex-matched healthy controls completed an emotional oddball paradigm during ultra-high field 7-Tesla functional magnetic resonance imaging scanning. DCM results revealed shared bi-directional interactions between the amygdala and PAG, and the SN during negative emotional processing. Specifically, while healthy control participants exhibited an inhibitory influence from the PAG to anterior insula, this effect was not detected in participants with mood and anxiety disorders (0.34 Hz, posterior probability = 1.00). Leave-one-out cross validation revealed this effect was large enough to predict diagnostic status, negative affect, depression, and stress levels. Additional group differences emerged in modulatory amygdala-to-PAG (-0.55 Hz, posterior probability = 1.00) and intrinsic PAG self-inhibitory (0.15 Hz, posterior probability = 1.00) connections. Our work indicates that differences in PAG-inhibition of the anterior insula likely contribute to maladaptive salience attribution and affective response in mood and anxiety disorders.