Dissociated neural effects of cortisol depending on threat escapability

Abstract

Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brain's fear systems when humans are under virtual-predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear-related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormone's crucial role in the adaptive flexibility of fear behaviors.

Keywords: cortisol; salience network; threat escape.

Figure 1

Outline of the fear‐and‐escape task. Participants are repeatedly attacked by rapidly approaching pictures. Participants can escape by pressing a button, but when they fail to do so they will be presented with a highly aversive noise (AN). The pictures are manipulated to be escapable, imminent (escapable at chance‐level) or inescapable, and all conditions are compared with an equivalent safe‐context control condition involving exactly the same procedure but without the threat of AN exposure. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Effects of threat anticipation within the placebo condition. Threat activated the anterior salience network, consisting of anterior insular cortices and dorsal anterior cingulate cortices together with supplementary motor cortex and midbrain. Statistical map is overlaid on a template brain in MNI‐space and thresholded at P < 0.001 uncorrected (T‐threshold is T = 3.17) for illustrative purposes only (for statistical analyses see Table 3). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3

Effects of inescapable versus escapable threat in contrast to the safe conditions ([escapable threat > escapabale safe] > [inescapable threat > inescapable safe]). Modulation of the salience and default mode networks of the brain when threat was inescapable compared with escapable. Increased activity in the anterior salience network: the anterior insular cortex (AIC) and dorsal anterior cingulate (dACC) (shown in red), and decreased activity in the default mode network: posterior cingulate, prefrontal and parietal cortices (shown in blue). Statistical maps are overlaid on a template brain in MNI‐space and based on placebo condition and thresholded at P < 0.001 uncorrected (T‐threshold is T = 3.17) for illustrative purposes only (for statistical analyses see Table 3). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 4

Effects of cortisol. (A) All three salience structures were modulated by cortisol depending on threat escapability. Statistical map is overlaid on a template brain in MNI‐space and thresholded at P< 0.001 uncorrected (T‐threshold is T = 3.17) for illustrative purposes only (for statistical analyses see Table 4). (B) Plots of bilateral threat‐specific parameter estimates (threat minus safe) from the midbrain, anterior insular cortex (AIC) and dorsal anterior cingulate cortex (dACC). Cortisol attenuated midbrain and AIC activity when threat was inescapable, and upregulated dACC and AIC when threat was escapable. Error bars depict standard errors. (C) Threat versus safe contrast maps for the inescapable and escapable conditions in cortisol and placebo conditions separately show cortisol's diametric modulation of AIC, the upregulation of dACC during escapable threat and the attenuation of midbrain activation during escapable threat. Statistical map is overlaid on a template brain in MNI‐space and thresholded at P < 0.001 uncorrected (T‐threshold is T = 3.17) for illustrative purposes only (for statistical analyses see Table 4). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]