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Response to Learned Threat: An fMRI Study in Adolescent and Adult Anxiety
Jennifer C. Britton, Ph.D.; Christian Grillon, Ph.D.; Shmuel Lissek, Ph.D.; Maxine A. Norcross, B.S.; Kristin L. Szuhany, B.S.; Gang Chen, Ph.D.; Monique Ernst, M.D., Ph.D.; Eric E. Nelson, Ph.D.; Ellen Leibenluft, M.D.; Tomer Shechner, Ph.D.; Daniel S. Pine, M.D.
Am J Psychiatry 2013;170:1195-1204. doi:10.1176/appi.ajp.2013.12050651
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The authors report no financial relationships with commercial interests.

Supported in part by grant K99-MH-091183 from the Intramural Research Program of NIMH/NIH (to Dr. Britton).

The skin conductance results during fear acquisition partially overlap with data published by Lau et al. (see reference 12). The data are presented as an applied example of the methodology described by Chen et al. (see reference 21).

From the Department of Psychology, University of Miami, Coral Gables, Fla.; the National Institute of Mental Health, Bethesda, Md.; Department of Psychology, University of Minnesota, Minneapolis; School of Medicine, Johns Hopkins University, Baltimore; and Department of Psychology, Boston University, Boston.

Presented at the annual meeting of the American College of Neuropsychopharmacology, Miami Beach, Fla., Dec. 5–9, 2010, and Waikoloa, Hawaii, Dec. 4–8, 2011; and the annual meeting of the Anxiety and Depression Association of America, Baltimore, March 4–7, 2010, and New Orleans, March 24–27, 2011.

Address correspondence to Dr. Britton (j.britton@miami.edu).

Copyright © 2013 by the American Psychiatric Association

Received May 19, 2012; Revised August 30, 2012; January 25, 2013; March 08, 2013; March 21, 2013; Accepted March 25, 2013.

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.

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FIGURE 1. Experimental Procedures Among Anxious and Healthy Adolescents and Adultsa

a During fear acquisition, one female face (conditioned stimulus [CS+]) was paired with a fearful face coterminating with a scream (unconditioned stimulus [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).

FIGURE 2. Whole-Brain Analyses Indicate Four-Way Interactions (diagnosis-by-age group-by-cognitive instruction-by-quadratic trend)a

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

FIGURE 3. Response Patterns During Threat Appraisal and Explicit Memorya

a The graphs show group differences in the subgenual anterior cingulate cortex and the ventromedial prefrontal cortex during threat appraisal (panels A and B, respectively) and during the explicit-memory task (panels C and D, respectively). Panel A plots the percent-signal change values relative to baseline. Panels B–D plot the beta coefficients across morphed images for the quadratic response. The significance is defined as an alpha level ≤0.05.

b Group difference in neural activation.

c Significant quadratic trend across morphs.

d Group difference in the quadratic pattern.

FIGURE 4. Response Patterns Across Morphed Imagesa

a To further illustrate effects (as shown in Figure 3), the neural patterns across morphed images are plotted for the subgenual anterior cingulate cortex and the ventromedial prefrontal cortex during threat appraisal (panels A and B, respectively) and during the explicit-memory task (panels 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 an alpha level ≤0.05.

b Group difference in neural activation.

Anchor for Jump
TABLE 1.Fear Conditioning and Extinction Results in Anxious and Healthy Adolescents and Adults
Table Footer Note

a There was a significant age-group difference in IQ (p<0.005). In all initial analyses, IQ was included as a covariate of no interest, and results indicated that IQ did not alter the significant findings.

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