Anterior insula integrates information about salience into perceptual decisions about pain

Abstract

The decision as to whether a sensation is perceived as painful does not only depend on sensory input but also on the significance of the stimulus. Here, we show that the degree to which an impending stimulus is interpreted as threatening biases perceptual decisions about pain and that this bias toward pain manifests before stimulus encounter. Using functional magnetic resonance imaging we investigated the neural mechanisms underlying the influence of an experimental manipulation of threat on the perception of laser stimuli as painful. In a near-threshold pain detection paradigm, physically identical stimuli were applied under the participants' assumption that the stimulation is entirely safe (low threat) or potentially harmful (high threat). As hypothesized, significantly more stimuli were rated as painful in the high threat condition. This context-dependent classification of a stimulus as painful was predicted by the prestimulus signal level in the anterior insula, suggesting that this structure integrates information about the significance of a stimulus into the decision about pain. The anticipation of pain increased the prestimulus functional connectivity between the anterior insula and the midcingulate cortex (MCC), a region that was significantly more active during stimulation the more a participant was biased to rate the stimulation as painful under high threat. These findings provide evidence that the anterior insula and MCC as a "salience network" integrate information about the significance of an impending stimulation into perceptual decision-making in the context of pain.

Figure 1.

Experimental design. A graphic representation of the six stimulation sites was shown before stimulus application. Fully approved sites were shown in a different color than sites approved with reservations. The site stimulated in the current trial was highlighted by a gray square. Subsequently, the laser stimulus calibrated to pain-threshold intensity was applied to the right foot. Participants were then prompted to indicate by a button press (here, left button for “yes” = pain and right button for “no” = no pain) whether the stimulus had been perceived as painful or not. Assignment of buttons was varied from trial to trial. Following the button press, the presentation of a fixation cross ended the trial.

Figure 2.

Behavioral data. A, In the high threat condition, participants perceived significantly more trials as painful compared with the low threat condition. B, C, At the end of the experiment, participants rated the high-threat trials as more painful relative to low-threat trials (B) and felt significantly more anxious (C). Error bars indicate SEs. ***: p < 0.001; **: p < 0.01.

Figure 3.

Anterior insula integrating information about threat-value into the decision about pain (L, left; R, right). A, As revealed by a conjunction analysis, the right and left anterior insula encoded the anticipation of pain (i.e., pain > no pain) and the processing of threat information (i.e., high > low threat) in the anticipation period (p < 0.005 uncorrected). For visualization, activations are shown at a threshold of 0.05 uncorrected. B, C, Parameter estimates for the peak voxels in left (B) and right anterior insula (C) plotted for illustration purpose (adjusted for effects of interest). Error bars indicate SEs.

Figure 4.

MCC showing a significant context-dependent covariation with the left anterior insula during anticipation.

Figure 5.

Second-level analysis showing a positive correlation between the threat-related bias toward pain and brain activation in high threat vs low threat trials during stimulation. A, The simple linear regression analysis showed a positive correlation in the MCC between the bias index used (number of pain decisions in high threat trials divided by number of pain decisions in low threat trials) and contrast maps for high > low threat during stimulation. As shown in the insert this MCC activation cluster overlapped with the cluster showing heightened connectivity with the anterior insula during anticipation as revealed by PPI analyses (shown in yellow). B, Scatterplot of the bias index and parameter estimates of the MCC in the simple regression analysis. Note that on the x-axis, 1 indicates an equal amount of decisions for pain in the high threat and low threat condition (i.e., no bias).