Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data

Abstract

The brain systems underlying placebo analgesia are insufficiently understood. Here we performed a systematic, participant-level meta-analysis of experimental functional neuroimaging studies of evoked pain under stimulus-intensity-matched placebo and control conditions, encompassing 603 healthy participants from 20 (out of 28 eligible) studies. We find that placebo vs. control treatments induce small, widespread reductions in pain-related activity, particularly in regions belonging to ventral attention (including mid-insula) and somatomotor networks (including posterior insula). Behavioral placebo analgesia correlates with reduced pain-related activity in these networks and the thalamus, habenula, mid-cingulate, and supplementary motor area. Placebo-associated activity increases occur mainly in frontoparietal regions, with high between-study heterogeneity. We conclude that placebo treatments affect pain-related activity in multiple brain areas, which may reflect changes in nociception and/or other affective and decision-making processes surrounding pain. Between-study heterogeneity suggests that placebo analgesia is a multi-faceted phenomenon involving multiple cerebral mechanisms that differ across studies.

Fig. 1. Pain-related activity in experimental placebo imaging studies.

a Statistically significant pain-responses (permutation test, controlled for FWER, two-sided p < 0.05), and b whole-brain unthresholded standardized effect size g, of acute pain stimulation > baseline, pooled across placebo and control conditions (FWER-corrected permutation test results are delineated as a back contour); range g: [−0.82, 1.68]; all: n = 543–603 individuals from 17 to 20 independent studies per voxel. Three-dimensional coronal slices are equidistantly distributed from y = 60 to −68 mm. Axial slices range equidistantly from z = −22 to 42 mm. Custom coordinates for sagittal slices are displayed in mm. Source data (results as 3d-volumes) are provided at https://osf.io/n9mb3/.

Fig. 2. Placebo-induced changes in pain-related activity.

a Areas of statistically significant placebo treatment effect, assuming random study-effect, thresholded according to z-tests (uncorrected for multiple comparisons, two-sided p < 0.01, red and blue) and thresholded according to pTFCE-enhanced permutation test (controlled for FWER, two-sided p < 0.05, light blue, activity increases did not reach statistical significance); b unthresholded standardized effect size g of placebo treatment effect (range: [−0.19, 0.17]); c between-study heterogeneity τ (range: [0, 0.43]) with permutation test results (controlled for FWER, one-sided, p < 0.05, green); τ is plotted as τ² to emphasize regions of high heterogeneity. d significant placebo-effects assuming fixed study-effect (range: [−0.22, 0.22]) thresholded according to z-tests (uncorrected for multiple comparisons, two-sided p < 0.01, red and blue) and thresholded according to pTFCE-enhanced permutation test (controlled for FWER, two-sided p < 0.05, light blue and gold); all: n = 543 to 603 individuals from 17 to 20 independent studies per voxel. b, c, and d are shown with a contour of FWER-corrected permutation test results for pain > baseline, as shown in Fig. 1a. Small FWER-corrected clusters are zoomed in insets. Three-dimensional coronal slices are equidistantly distributed from y = 60 to −68 mm. Axial slices range equidistantly from z = −22 to 42 mm. Custom coordinates for sagittal slices are displayed in mm and were chosen to highlight important areas of activation. Source data (results as 3d-volumes) are provided at https://osf.io/n9mb3/.

Fig. 3. Correlations of behavioral placebo analgesia and changes in pain-related brain activity.

a Whole-brain areas of statistically significant correlation (Pearson’s r) between behavioral placebo analgesia (pain_control − pain_placebo) and placebo-related activity changes (pain_placebo − pain_control), thresholded according to z-tests (uncorrected for multiple comparisons, two-sided p < 0.01, red and blue), and thresholded according to pTFCE-enhanced permutation test (controlled for FWER, two-sided p < 0.05, light blue, increased correlations did not reach corrected statistical significance); b unthresholded Pearson’s r, range: [−0.26; 0.17]; c between-study heterogeneity τ (range: [0, 0.32]) for the same relationship (permutation test controlled for FWER, one-sided p < 0.05, indicated no statistically significant voxels); τ is plotted as τ² to emphasize regions of high heterogeneity. all: n = 384–460 individuals from 15 to 18 independent studies per voxel. a, b, and c are shown with a contour of FWER-corrected permutation test results for pain > baseline, as shown in Fig. 1a. Correlations were computed across individual participants in the full sample, excluding between-group studies (where individual estimates of behavioral placebo analgesia are not possible). On panels a and b, red-yellow and blue-light blue shades denote increased and decreased activity associated with larger placebo analgesia, respectively. Three-dimensional coronal slices are equidistantly distributed from y = 60 to −68 mm. Axial slices range equidistantly from z = −22 to 42 mm. Custom coordinates for sagittal slices are displayed in mm. Source data (results as 3d-volumes) are provided at https://osf.io/n9mb3/.

Fig. 4. Similarity-based analysis of brain activity in functional cortical networks, insula, and thalamus.

Column 1 (header): Depiction of atlases: Row 1: whole-brain cortical networks of functional connectivity, Row 2: insular sub-regions Row 3: thalamic nuclei. See Supplementary Fig. 14 for further details. Column 2: Mean (±SEM) cosine similarity (c) of pain-related activity, n = 603 from 20 independent studies; Column 3: Mean (±SEM) cosine similarity (c) of placebo-induced changes in pain-related activity (Column 2); all: n = 603 from 20 independent studies. Column 4: Correlation (Pearson’s r ± SEM) between behavioral placebo response and cosine similarity estimates of placebo-related activity; n = 460 from 18 independent studies. In Columns 2 and 3, red and blue colors denote increased and decreased pain-related activity, respectively. In Column 4 red and blue shades denote increased and decreased activity associated with larger placebo analgesia, respectively. Asterisks (*) denote significant differences from zero, according to two-sided t-tests (p < 0.05, uncorrected for multiple comparisons). Source data (results as 3d-volumes) are provided at https://osf.io/n9mb3/. Hythal Hypothalamus, Hb Habenular, AV anterior ventral, AM anterior medial, MD mediodorsal, VM ventral medial, VA ventral anterior, LP lateral posterior, VL ventral lateral, LD lateral dorsal, Intralam intralaminary, VPM ventral posterior medial, VPL ventral posterior lateral, MGN Medial Geniculate Nucleus, LGN Lateral Geniculate Nucleus, Pulv Pulvinar.