Response to learned threat: An FMRI study in adolescent and adult anxiety

Abstract

Objective: Poor threat-safety discrimination reflects prefrontal cortex dysfunction in adult anxiety disorders. While adolescent anxiety disorders are impairing and predict high risk for adult anxiety disorders, the neural correlates of threat-safety discrimination have not been investigated in this population. The authors compared prefrontal cortex function in anxious and healthy adolescents and adults following conditioning and extinction, processes requiring threat-safety learning.

Method: Anxious and healthy adolescents and adults (N=114) completed fear conditioning and extinction in the clinic. The conditioned stimuli (CS+) were neutral faces, paired with an aversive scream. Physiological and subjective data were acquired. Three weeks later, 82 participants viewed the CS+ and morphed images resembling the CS+ in an MRI scanner. During scanning, participants made difficult threat-safety discriminations while appraising threat and explicit memory of the CS+.

Results: During conditioning and extinction, the anxious groups reported more fear than the healthy groups, but the anxious adolescent and adult groups did not differ on physiological measures. During imaging, both anxious adolescents and adults exhibited lower activation in the subgenual anterior cingulate cortex than their healthy counterparts, specifically when appraising threat. Compared with their age-matched counterpart groups, anxious adults exhibited reduced activation in the ventromedial prefrontal cortex when appraising threat, whereas anxious adolescents exhibited a U-shaped pattern of activation, with greater activation in response to the most extreme CS+ and CS-.

Conclusions: Two regions of the prefrontal cortex are involved in anxiety disorders. Reduced subgenual anterior cingulate cortex engagement is a shared feature in adult and adolescent anxiety disorders, but ventromedial prefrontal cortex dysfunction is age-specific. The unique U-shaped pattern of activation in the ventromedial prefrontal cortex in many anxious adolescents may reflect heightened sensitivity to threat and safety conditions. How variations in the pattern relate to later risk for adult illness remains to be determined.

Figure 1. Experimental Procedures

During fear acquisition, one female face (CS+) was paired with a fearful face co-terminating with a scream (UCS). The other female face (CS−) was never paired with the UCS. During extinction, the two female faces were presented without the UCS. Several weeks later, participants viewed morphed images continuously varying in similarity from the CS− to CS+. Participants reported whether they were afraid (threat appraisal), whether the CS screamed in the past (explicit memory), or whether the CS had jet black hair (physical discrimination). CS=conditioned stimulus, UCS=unconditioned stimulus.

Figure 2. Whole-brain analyses indicate four-way interactions (diagnosis×age-group×cognitive instruction×quadratic trend)

The subgenual anterior cingulate (−9, 26, −9) and the ventromedial prefrontal cortex (4, 49, −6) survive 15 voxel cluster threshold, defined using p<0.005 voxel-wise probability, which yields a p<0.05 corrected threshold for medial prefrontal cortical regions. Images are displayed in radiological convention (left=right). Green lines in the axial slice indicate position of sagittal slices.

Figure 3. Response patterns during threat appraisal and explicit memory

Group differences are plotted in the subgenual anterior cingulate cortex (sgACC) and ventromedial prefrontal cortex (vmPFC) during threat appraisal (Panels A and B, respectively) and during the explicit memory task (C and D, respectively). Panel A plots percent signal change values relative to baseline. Panel B–D plots the beta coefficient across morphed images for the quadratic response. *Group difference in neural activation. ^Significant quadratic trend across morphs #Group difference in the quadratic pattern. Significance is defined as α=0.05.

Figure 4. Response patterns across morphed images

To further illustrate effects in Figure 3, the neural patterns across morphed images are plotted in the subgenual anterior cingulate cortex (sgACC) and ventromedial prefrontal cortex (vmPFC) during threat appraisal (Panels A and B, respectively) and during the explicit memory task (C and D, respectively). For illustrative purposes, the percent signal change values, relative to baseline, for every two morphed images other than 0%, 50%, and 100% are averaged together. Only group differences in neural activation are reflected here (*). Significance is defined as α=0.05.