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The anticipation of future adversity confers adaptive benefits by engaging a suite of preparatory mechanisms, but this process can also be deleterious when carried out in excess. Neuroscientific investigations have largely treated anticipation as a unitary process, but we show here using functional magnetic resonance imaging that distinct stages of aversive anticipation are supported by dissociable neural mechanisms. Immediate anticipatory responses were observed in regions associated with threat detection and early processing of predictive cues, including the orbitofrontal cortex and pregenual anterior cingulate cortex, as well as the amygdala for individuals with elevated anxiety symptoms. Sustained anticipatory activity was observed in the forebrain/bed nucleus of the stria terminalis, anterior insula, anterior mid-cingulate cortex (aMCC), and midbrain/periaqueductal gray, regions associated with anxiety, interoception, and defensive behavior. The aMCC showed increased functional coupling with the midbrain during sustained anticipation of aversion, highlighting a circuit critical for the expression of preparatory fear responses. These data implicate distinct sets of regions that are active during different temporal stages of anticipation, and provide insight into how the human brain faces the future both adaptively and maladaptively.

Uncertainty about potential negative future outcomes can cause stress and is a central feature of anxiety disorders. The stress and anxiety associated with uncertain situations may lead individuals to overestimate the frequency with which uncertain cues are followed by negative outcomes, an example of covariation bias. Using functional magnetic resonance imaging, we found that uncertainty-related expectations modulated neural responses to aversion. Insula and amygdala responses to aversive pictures were larger after an uncertain cue (that preceded aversive or neutral pictures) than a certain cue (that always preceded aversive pictures). Anticipatory anterior cingulate cortex (ACC) activity elicited by the cues was inversely associated with the insula and amygdala responses to aversive pictures following the cues. Nearly 75% of subjects overestimated the frequency of aversive pictures following uncertain cues, and ACC and insula activity predicted this uncertainty-related covariation bias. Findings provide the first evidence of the brain mechanisms of covariation bias and highlight the temporal dynamics of ACC, insula, and amygdala recruitment for processing aversion in the context of uncertainty.