A Neurobiological Profile Underlying Comorbidity Load and Prospective Increases in Dysphoria in a Focal Fear Sample

Knowledge of the neural mechanisms underlying increased disease burden in anxiety disorders that is unaccounted for by individual categorical diagnoses could lead to improved clinical care. Here, we tested the utility of a joint functional magnetic resonance imaging–electroencephalography neurobiological profile characterized by overvaluation of negative stimuli (amygdala) in combination with blunted elaborated processing of these same stimuli (the late positive potential [LPP], an event-related potential) in predicting increased psychopathology across a 2-year period in people with anxiety disorders. One hundred ten participants (64 female, 45 male, 1 other) including 78 participants with phobias who varied in the extent of their internalizing comorbidity and 32 participants who were free from psychopathology viewed negative and neutral pictures during separate functional magnetic resonance imaging blood oxygen level–dependent and electroencephalogram recordings. Dysphoria was assessed at baseline and 2 years later. Participants with both heightened amygdala activation and blunted LPPs to negative pictures showed the greatest increases in dysphoria 2 years later. Cross-sectionally, participants with higher comorbidity load (≥2 additional diagnoses, n = 34) showed increased amygdala activation to negative pictures compared with participants with lower comorbidity load (≤1 additional diagnosis, n = 44) and compared with participants free from psychopathology. In addition, high comorbid participants showed reduced LPPs to negative pictures compared with low comorbid participants. Heightened amygdala in response to negative stimuli in combination with blunted LPPs could indicate overvaluation of threatening stimuli in the absence of elaborated processing that might otherwise help regulate threat responding. This brain profile could underlie the worsening and maintenance of internalizing psychopathology over time.