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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Amygdala; Dysphoria; Emotion; Event-related potentials; Late positive potential; Research domain criteria.

Figure 1.

Prospective results: heightened Negative > Neutral amygdala activation and reduced Negative > Neutral LPP interact to predict greater increases in Time 2 dysphoria. Left: one-sample voxel-wise t-maps overlaid on a canonical brain rendering (MNI coronal), showing Negative > Neutral amygdala activity; middle: grand-averaged waveforms at the centroparietal pooling where the LPP was scored, shown separately for negative and neutral pictures; and right: headmaps depicting the voltage difference (Negative > Neutral) from 3,500-7,000 ms following picture onset - shown separately for participants A) low in Time 2 minus Time 1 dysphoria and B) high in Time 2 minus Time 1 dysphoria (based on a median split, for illustrative purposes only).

Figure 2.

Prospective results: simple slopes showing that increased Negative > Neutral amygdala activation was associated with greater dysphoria at Time 2 only for individuals with small Negative > Neutral LPPs (−0.5 SD), and not large Negative > Neutral LPPs (+0.5 SD). Error bars indicate the standard error of the mean.

Figure 3.

Cross-sectional results: Negative > Neutral amygdala activation. A) Mean BOLD response (extracted β weights, arbitrary units [a.u.]) from the anatomically-defined left amygdala. Error bars indicate the standard error of the mean. Starred bars indicate p < .050. B) One-sample voxel-wise t-maps overlaid on a canonical brain rendering (MNI coronal), showing Negative > Neutral amygdala activation for each group, unmasked and depicted at p < .001.

Figure 4.

Cross-sectional results: grand-averaged negative minus neutral difference waveforms at the centroparietal pooling where the LPP was scored, shown separately for each group, as well as headmaps depicting voltage differences (Negative > Neutral) for the 400-3,500 ms (left) and 3,500-7,000 ms (right) time windows for each group.