The human insula processes both modality-independent and pain-selective learning signals

Abstract

Prediction errors (PEs) are generated when there are differences between an expected and an actual event or sensory input. The insula is a key brain region involved in pain processing, and studies have shown that the insula encodes the magnitude of an unexpected outcome (unsigned PEs). In addition to signaling this general magnitude information, PEs can give specific information on the direction of this deviation-i.e., whether an event is better or worse than expected. It is unclear whether the unsigned PE responses in the insula are selective for pain or reflective of a more general processing of aversive events irrespective of modality. It is also unknown whether the insula can process signed PEs at all. Understanding these specific mechanisms has implications for understanding how pain is processed in the brain in both health and in chronic pain conditions. In this study, 47 participants learned associations between 2 conditioned stimuli (CS) with 4 unconditioned stimuli (US; painful heat or loud sound, of one low and one high intensity each) while undergoing functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. We demonstrate that activation in the anterior insula correlated with unsigned intensity PEs, irrespective of modality, indicating an unspecific aversive surprise signal. Conversely, signed intensity PE signals were modality specific, with signed PEs following pain but not sound located in the dorsal posterior insula, an area implicated in pain intensity processing. Previous studies have identified abnormal insula function and abnormal learning as potential causes of pain chronification. Our findings link these results and suggest that a misrepresentation of learning relevant PEs in the insular cortex may serve as an underlying factor in chronic pain.

Fig 1. Experimental protocol.

(A) Overall structure of the experiment. Calibration took approximately 15 minutes, each session approximately 20 minutes. (B) Devices used for heat stimulation (thermode) and sound stimulation (headphones), with standardized locations on the left arm for pain calibration and either of the 2 experimental sessions. (C) Trial structure with associated durations. After displaying CS, participants were asked to choose which US they expected to follow. The US was then applied and rated in terms of its painfulness (for pain)/unpleasantness (for sound). EDA, electrodermal activity; CS, conditioned stimuli; US, unconditioned stimuli.

Fig 2. Learning protocol aspects of the experiment.

(A) Set of CS; 2 were randomly selected for each participant (constraint: stimuli in row 2 could never both be selected due to high similarity). (B) Possible US associated with a CS at any particular trial (low pain, high pain, low sound, and high sound). Arrows indicate possible reversals; notably, no combined intensity and modality (cross)reversals occurred. (C) Example for contingencies of CS1 (black solid line) and CS2 (white solid line) for their 32 trials per session each. Vertical dotted lines indicate reversals, with light dotted lines for modality reversals and dark dotted lines for intensity reversals. (D) Example for an actual trial sequence of 64 trials with interspersed CS1 (black diamonds) and CS2 (white diamonds) and their associated US (rows). Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/7JBV3. CS, conditioned stimuli; US, unconditioned stimuli.

Fig 3. Behavioral results for pain ratings and performance.

(A) Results for low and high unconditioned pain and sound stimuli; aggregate ratings of all pain and sound trials. Circles with error bars show the mean ± standard errors over all participant means. Participant means are displayed as smaller circles. Violin plots aggregate over participant means. The gray dashed line is the “intended” rating as per calibration (VAS 25 for low and VAS 75 for high intensities). (B) Performance pre- and postreversals, aggregated over all participants. Circles indicate the performance during (peri)reversal trials, first averaged within and then between participants (mean ± standard errors). The dashed horizontal line marks chance level (25%, i.e., 1 of 4 options). The dashed vertical line indicates contingency reversal, with relative trial number 0 as the reversal trial. Note that no difference arose between trials preceding and following modality versus intensity reversals (also see Fig 2 for aspects concerning contingency reversals). Furthermore, the steep increase in performance after trial number 0 indicates, on average, rapid learning of the new contingency. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/7JBV3.

Fig 4. Results from SCR measurements.

All plots are based on log- and z-transformed data. (A) SCR in relation to US onsets, by US modality/intensity. Note the differences in latencies between the 2 modalities (pain in red/yellow has a later onset, sound in dark blue/light blue earlier), which determined the response windows used for mean SCR calculation in panel b. (B) Mean SCR by US, calculated within each modality’s response window. On average, SCR is not significantly different between modalities; differences arise between intensities, and in the interaction of modality and intensity (see text for parameters). (C) Mean SCR by US and PE type. Over all modalities and intensities, differences arise between each PE type. Within specific modality/intensity combinations, differences between no PEs and intensity PEs only arise in the high sound condition. (D) Mean SCR in and around reversal trials. Within trials, data are pooled over all modalities, intensities, and expectations, i.e., does not consider whether participants correctly predicted the subsequent stimulus. The dashed vertical line indicates contingency reversal, with relative trial number 0 as the reversal trial. SCR rises sharply after reversal, but quickly adapts postreversal to a stable level. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/7JBV3. intPE, intensity prediction error; modPE, modality prediction error; noPE, correct prediction; PE, prediction error; SCR, skin conductance response; US, unconditioned stimulus.

Fig 5. Brain activation following pain (red/yellow) and sound (blue), including overlaps as per conjunction analyses (green).

Activations are overlaid on an average brain surface; for display purposes, activations in the whole brain lateral view are thresholded at p[uncorr.] < 0.001. The black line in the zoomed-in view delineates the region of interest and includes activations within the small volume FWE corrected at p[corr.] < 0.05. Peaks are shown for small volume only; bar plots show beta weights of BOLD activation obtained from a general linear model (see Materials and methods) from the respective peaks. See Supporting information for peak positions in whole brain (S4 and S6 Figs) and brain volume slices (S5 and S7 Figs). (A) Differential and shared activation following painful heat stimulation and loud sound stimulation. Peak activation following heat is located in (peri)insular areas contralateral to stimulation, namely the dorsal posterior insula (dpIns₁), and extending through the central and parietal opercula. Peak activation following sound is located in the superior temporal gyrus. Common activation (green) is located in the central operculum (CO₁) and dorsal anterior insula (aIns₁), among other regions. (B) fMRI signal (arbitrary units) for peaks detected in panel A (US onset effects) or C (parametric modulation by ratings). Black rectangles highlight the regressors used for analysis; solid line indicates analysis with the respective individual regressor, and dashed line indicates conjunction analysis. fMRI signal labels refer to the regressors used for each modality: “main” for main effects of modality, “ratings” for behavioral ratings, “modPE” for modality PEs, “uIntPE” for unsigned intensity PEs, and “sIntPE” for signed intensity PEs. (C) Differential and shared correlations with pain ratings (for heat) and unpleasantness ratings (for sound). Activation correlated with pain ratings is focused on the dorsal posterior insula (dpIns₁). Activation correlated with sound ratings is focused on the superior temporal gyrus. Conjunction activation peaks in central operculum (CO₂) and precentral gyrus. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/7JBV3. BOLD, blood oxygenation level dependent; fMRI, functional magnetic resonance imaging; FWE, family-wise error; PE, prediction error; US, unconditioned stimulus.

Fig 6. Brain activation following unsigned intensity prediction errors in pain (red/yellow) and sound (blue), including overlaps as per conjunction analyses (green).

Peak activation following either modality is located in the anterior insula (aIns₁) and is subsumed in the common activation. Activations are overlaid on an average brain surface; for display purposes, activations in the whole brain lateral view are thresholded at p[uncorr.] < 0.001. The black line in the zoomed-in view delineates the region of interest and includes activations within the small volume FWE corrected at p[corr.] < 0.05. See Supporting information for peak positions in whole brain (S8 Fig) and brain volume slices (S9 Fig). In the fMRI signal bar graph, black rectangles highlight the regressors used for analysis; solid line indicates analysis with the respective individual regressor, and dashed line indicates conjunction analysis. fMRI signal labels refer to the regressors used for each modality: “main” for main effects of modality, “ratings” for behavioral ratings, “modPE” for modality PEs, “uIntPE” for unsigned intensity PEs, and “sIntPE” for signed intensity PEs. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/7JBV3. fMRI, functional magnetic resonance imaging; FWE, family-wise error; PE, prediction error.

Fig 7. Brain activation following modality prediction errors in pain (red/yellow) and sound (blue) activation, including overlaps as per conjunction analyses (green).

As with unsigned intensity PEs, peak activation following modality PEs in either modality is located in the anterior insula (aIns₁) and is largely subsumed in the common activation. Activations are overlaid on an average brain surface; for display purposes, activations in the whole brain lateral view are thresholded at p[uncorr.] < 0.001. The black line in the zoomed-in view delineates the region of interest and includes activations within the small volume FWE corrected at p[corr.] < 0.05. Peaks are shown for the small volume only. See Supporting information for peak positions in whole brain (S10 Fig) and brain volume slices (S11 Fig). In the fMRI signal bar graph, black rectangles highlight the regressors used for analysis; solid line indicates analysis with the respective individual regressor, and dashed line indicates conjunction analysis. fMRI signal labels refer to the regressors used for each modality: “main” for main effects of modality, “ratings” for behavioral ratings, “modPE” for modality PEs, “uIntPE” for unsigned intensity PEs, and “sIntPE” for signed intensity PEs. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/7JBV3. fMRI, functional magnetic resonance imaging; FWE, family-wise error; PE, prediction error.

Fig 8. Common brain activation associated with unsigned intensity and modality prediction errors.

The fMRI signal plot shows that the peak in the anterior insula (aIns₁) encodes PEs for every contrast included in the conjunction. Activations are overlaid on an average brain surface; for display purposes, activations in the whole brain lateral view are thresholded at p[uncorr.] < 0.001. The black line in the zoomed-in view delineates the region of interest and includes activations within the small volume FWE corrected at p[corr.] < 0.05. In the fMRI signal bar graph, black rectangles highlight the regressors used for analysis; solid line indicates analysis with the respective individual regressor, and dashed line indicates conjunction analysis. fMRI signal labels refer to the regressors used for each modality: “main” for main effects of modality, “ratings” for behavioral ratings, “modPE” for modality PEs, “uIntPE” for unsigned intensity PEs, and “sIntPE” for signed intensity PEs. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/7JBV3. fMRI, functional magnetic resonance imaging; FWE, family-wise error; PE, prediction error.

Fig 9. Brain activation associated with by signed intensity prediction errors in pain (red/yellow) and sound (blue), including overlaps as per conjunction analyses (green).

Contrary to uIntPEs, circumscribed activation was detected for pain sIntPEs without any overlap with sound sIntPEs. Peak activation is located in the dorsal posterior insula (dpIns₁). For sound, several clusters in the anterior insula (e.g., aIns₃) were found, as well as middle temporal gyrus (MTG₁). Activations are overlaid on an average brain surface; for display purposes, activations in the whole brain lateral view are thresholded at p[uncorr.] < 0.001. The black line in the zoomed-in view delineates the region of interest and includes activations within the small volume FWE corrected at p[corr.] < 0.05. In the fMRI signal bar graphs, black rectangles highlight the individual regressors used for analysis. fMRI signal labels refer to the regressors used for each modality: “main” for main effects of modality, “ratings” for behavioral ratings, “modPE” for modality PEs, “uIntPE” for unsigned intensity PEs, and “sIntPE” for signed intensity PEs. Data used to produce the figure can be found at https://www.doi.org/10.17605/OSF.IO/7JBV3. fMRI, functional magnetic resonance imaging; FWE, family-wise error; PE, prediction error.