A neural mediator of human anxiety sensitivity

Abstract

Advances in the neuroscientific understanding of bodily autonomic awareness, or interoception, have led to the hypothesis that human trait anxiety sensitivity (AS)-the fear of bodily autonomic arousal-is primarily mediated by the anterior insular cortex. Despite broad appeal, few experimental studies have comprehensively addressed this hypothesis. We recruited 55 individuals exhibiting a range of AS and assessed them with functional magnetic resonance imaging (fMRI) during aversive fear conditioning. For each participant, three primary measures of interest were derived: a trait Anxiety Sensitivity Index score; an in-scanner rating of elevated bodily anxiety sensations during fear conditioning; and a corresponding estimate of whole-brain functional activation to the conditioned versus nonconditioned stimuli. Using a voxel-wise mediation analysis framework, we formally tested for 'neural mediators' of the predicted association between trait AS score and in-scanner anxiety sensations during fear conditioning. Contrary to the anterior insular hypothesis, no evidence of significant mediation was observed for this brain region, which was instead linked to perceived anxiety sensations independently from AS. Evidence for significant mediation was obtained for the dorsal anterior cingulate cortex-a finding that we argue is more consistent with the hypothesized role of human cingulofrontal cortex in conscious threat appraisal processes, including threat-overestimation. This study offers an important neurobiological validation of the AS construct and identifies a specific neural substrate that may underlie high AS clinical phenotypes, including but not limited to panic disorder.

Keywords: anxiety sensitivity; autonomic; cingulate cortex; fear; insular cortex; interoception.

© 2015 Wiley Periodicals, Inc.

Figures

Figure 1

(a) The self‐assessment manikin (SAM) used to assess bodily anxiety sensations, (b) emotional valence. Left‐to‐right, the manikins correspond to Likert scale ratings of 1–5.

Figure 2

(a) In‐scanner ratings of self‐reported anxiety sensations—scale ranging 1 = “not anxious” to 5 = “very anxious.” (b) Offline skin conductance responses during fear conditioning (SCR; µS) acquired at Week 2. Mean and standard deviations are displayed. (c) Whole‐brain FDR‐corrected activation during fear conditioning emphasizing responses in the right AIC; and (d) dACC. Color‐bar activation magnitude corresponds to SPM T values. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3

Brain mediation effect parametric mapping: the dACC cluster demonstrating significant positive path a, b and a*b effects. Mean standardized path coefficients are shown with their standard errors (in parentheses). MNI co‐ordinates (x, y, z): path a (8, 22, 34); b (8, 22, 34); a*b (6, 24, 32). Voxels emphasized yellow correspond to q < 0.05 (FDR) with those in orange representing subthreshold contiguous voxels (P < 0.05). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 4

Right AIC cluster identified as a significant path b effect from the primary ROI analysis. MNI co‐ordinates (x, y, z): path b (32, 22, 8). Voxels emphasized yellow correspond to q < 0.05 (FDR) with those in orange representing subthreshold contiguous voxels (P < 0.05). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 5

(a) Caudate nucleus cluster identified as a significant path a effect from the secondary extended ‘fear network’ analysis. MNI co‐ordinates (x, y, z): path a (10, 4, 10). (b) Dorsal anterior midbrain (∼substantia nigra) and left AIC regions that demonstrated a significant path b effects from the secondary analysis. MNI co‐ordinates (x, y, z): midbrain path b (10, −8, −12); AIC path b (−26, 20, 4). Voxels emphasized yellow correspond to q < 0.05 (FDR) with those in orange representing subthreshold contiguous voxels (P < 0.05). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]