Functional neuroanatomy of CCK-4-induced panic attacks in healthy volunteers

Abstract

Experimental panic induction with cholecystokinin tetrapeptide (CCK-4) is considered as a suitable model to investigate the pathophysiology of panic attacks. While only a few studies investigated the brain activation patterns following CCK-4, no data are available on the putative involvement of the amygdala in the CCK-4 elicited anxiety response. We studied the functional correlates of CCK-4-induced anxiety in healthy volunteers by means of functional magnetic resonance imaging (fMRI) and region of interest (ROI) analysis of the amygdala. Sixteen healthy volunteers underwent challenge with CCK-4 compared with placebo in a single-blind design. Functional brain activation patterns were determined for the CCK-4-challenge, the placebo response and anticipatory anxiety (AA). CCK-4-induced anxiety was accompanied by a strong and robust activation (random effects analysis, P < 0.00001, uncorrected for multiple testing) in the ventral anterior cingulate cortex (ACC), middle and superior frontal gyrus, precuneus, middle and superior temporal gyrus, occipital lobe, sublobar areas, cerebellum, and brainstem. In contrast, random effects group analysis for placebo and AA using the same level of significance generated no significant results. Using a more liberal level of significance, activations could be observed in some brain regions such as the dorsal part of the ACC during AA (random effects analysis, P < 0.005). Overall functional responses did not differ between panickers and nonpanickers. Only 5 of 11 subjects showed strong amygdala activation. However, ROI analysis pointed towards higher scores in fear items in these subjects. In conclusion, while overall brain activation patterns are not related to the subjective anxiety response to CCK-4, amygdala activation may be involved in the subjective perception of CCK-4-induced fear.

Figure 1

Group analysis (n = 16) of the BOLD signal related to the effects of CCK‐4 injection (random effects analysis, P < 0.00001, uncorrected for multiple testing). Activation is seen in the ventral anterior cingulate cortex, left middle frontal gyrus, left precuneus, left middle temporal gyrus, right superior temporal gyrus, left insula, left putamen, cerebellum and brainstem.

Figure 2

Group analysis (n = 16) of the BOLD signal related to effects of anticipatory anxiety (random effects analysis, P < 0.005, uncorrected for multiple testing). Activation is seen in the dorsal anterior cingulate cortex, posterior cingulate cortex and left parietal lobe.

Figure 3

Comparison between placebo and CCK‐4 condition of the number of activated voxels in the regions of interest in the right and left amygdala. Values are given as mean ± SEM. The asterisks indicate statistical significance.

Figure 4

Sum of PSS fear items (fear of dying, fear of going crazy, fear of loosing control) in subjects with high amygdala activation (n = 5) compared to subjects with low amygdala activation (n = 11). Values are given as mean ± SEM.

Figure 5

(a) Time course of activity in a right amygdala region of interest of a single subject with high amygdala activation during the whole fMRI run following CCK‐4 administration. (b) Time course of activity in a right amygdala region of interest of a single subject with high amygdala activation during the first minute after CCK‐4 injection.

Figure 6

Effect of CCK‐4 on heart rate in panickers (n = 8, squares) and nonpanickers (data from 2 subjects are missing, n = 6, triangles). Scores are given as mean ± SEM. Time is expressed as minutes relative to CCK‐4 injection. Repeated measured ANOVA indicated a significant time effect for heart rate (F _2.6,30.8 = 47.01, P < 0.001) however, no significant time × panic status interaction.