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The anterior insula has repeatedly been linked to the experience of aversive stimuli, such as pain. Previously, we showed that the anterior insula is involved in the integration of pain intensity and its prior expectation. However, it is unclear whether this integration occurs by a pain-specific expectation or a more general expectation of an aversive event. To dissociate these possibilities, we conducted an experiment using painful stimuli and aversive pictures with three levels of aversiveness on human male volunteers. Stimuli were preceded by a probabilistic, combined modality and intensity cue in a full factorial design. Subjective ratings of pain intensity and skin conductance responses were best explained by a combination of actual pain intensity and expected pain intensity. In addition, using fMRI, we investigated the neuronal implementation of the integration of prior expectation and pain intensity. Similar to subjective ratings and autonomic responses, the dorsal anterior insula represented pain intensity and expectations. The ventral anterior insula additionally represented the absolute difference of the two terms (i.e., the prediction error). The posterior insula only represented pain intensity. Importantly, the pattern observed in the anterior insula was only present if the cued modality was correct (i.e., expect pain); in case of an incorrect modality cue (i.e., expect aversive picture), the ventral anterior insula simply represented pain intensity. The stimulus expectation and prediction error specificity in the ventral anterior insula indicates the integration of expectation with painful stimuli in this area. Importantly, this pattern cannot be explained by aversiveness. SIGNIFICANCE STATEMENT The anterior insula has been shown to integrate pain intensity and their expectation. However, it is unclear whether this integration is pain-specific or related more generally to an aversive event. To address this, we combined painful stimuli and aversive pictures with three levels of aversiveness. The ventral anterior insula represented pain intensity, expectation, and their absolute difference (i.e., the prediction error). Importantly, this pattern was only observed if the cued modality was correct. In case of an incorrect modality cue, this area simply represented as pain intensity. The stimulus expectation and prediction error specificity in the ventral anterior insula indicates the integration of expectation with painful stimuli in this area. Importantly, this pattern cannot be explained by aversiveness.

Pain-Related Expectation and Prediction Error Signals in the Anterior Insula Are Not Related to Aversiveness