Article Figures & Data
Figures
- Figure 1.
Balanced placebo design. We used a full factorial, balanced placebo design to examine the relationship between remifentanil analgesia and expectancy-based (placebo) analgesia in the behavioral experiment. Remifentanil was delivered during Hidden and Open administration with the pharmacokinetic profile pictured in the inset. Subjects were told that they would receive remifentanil during Placebo and Open conditions, and were told that they would receive no drug during Control and Hidden administration.
- Figure 2.
FMRI design and behavioral results. A, Subjects received intravenous remifentanil during scanning in the FMRI experiment. We used a within-subjects design, where order of runs (Open or Hidden) was counterbalanced across subjects. Remifentanil infusion proceeded identically in both runs, allowing us to examine whether drug effects on the brain differ as a function of expectancy. Imaging began with a baseline period, followed by infusion (gray box), and we used a pharmacokinetic model to estimate the brain concentration of remifentanil across time (black line). Subjects received low and high painful thermal stimulation throughout the imaging run. B, Example fMRI model showing regressors for one run of high pain stimulation (Open or Hidden administration). For each run, we modeled average responses to high-pain events (black), a parametric regressor for drug concentration in brain tissue based on the pharmacokinetic model (orange; Drug effects), and a parametric regressor for Instruction-related expectancies, orthogonalized with respect to drug concentration effects (purple). C, Pain reports during Open administration (blue) were influenced by Instructions about drug administration, and the overall Context. However, the magnitude of the Drug effect on pain reports was identical during both Open and Hidden administration. This figure depicts a moving average of pain reports during high pain stimulation, smoothed within-subjects with a 5-point FWHM filter, which was used to create our behavioral regressor (Fig. 5B). The shaded area reflects SEM.
- Figure 3.
Drug effects on PPN responses. Increases in the brain concentration of remifentanil were associated with reductions in pain-evoked responses throughout the PPN, evident in both ROI (red, top row) and voxelwise analyses (second row). Drug effects were similar during both Open administration (third row) and Hidden administration (fourth row), leading to no meaningful Drug × Context interactions (bottom row).
- Figure 4.
Region of interest results. We defined 13 pain-processing network ROIs, using independent datasets, and averaged across voxels within each ROI. We tested whether each was modulated by remifentanil during Open administration (blue bars) and Hidden administration (red bars). While most regions showed significant differences between high and low intensity stimulation (gray bars), estimated Drug effects did not differ between Open and Hidden administration in any ROIs. We tested the following ROIs: pre-SMA, bilateral dACC, rdACC, secondary somatosensory cortex (SII), right dorsal posterior insula (R dpIns), bilateral insula (Ins), bilateral anterior insula (AIns), thalamus, and midbrain surrounding the periacqueductal gray. One-tailed *p < 0.05; **p < 0.01; ***p < 0.001.
- Figure 5.
Expectancy effects during drug treatment. A, Information about drug delivery during Open administration was accompanied by increases in left DLPFC, relative to the same period during Hidden administration (“Instruction-related expectancy effects”). We also observed expectancy-related decreases in the left amygdala (Amyg.). B, A number of brain regions showed differences in activation that tracked within-subjects expectancy effects on pain reports over time (“Correlates of expectancy-related pain relief”). In particular, we observed report-related changes within the medial orbitofrontal cortex (mOFC), as well as several PPN regions, including right primary somatosensory cortex (SI), bilateral SII, bilateral thalamus, and pre-SMA. dACC showed significant expectancy-related reductions at a more liberal threshold, p < 0.005.
Tables
No remifentanil administration Remifentanil administration Control Placebo Hidden Open Average pain 4.1021 3.6364 3.6993 3.4372 Region x y z No. of voxels Volume (mm3) −log(Min. p value) Drug-induced increases Left fusiform gyrus −40 −68 −18 990 7920 11.77 Left cerebellum VI −36 −34 −30 29 232 8.89 Right inferior occipital gyrus 44 −64 −14 2426 19408 13.84 Left rectal gyrus −2 18 −20 118 944 7.29 Right lingual gyrus (BA18) 12 −56 −4 52 416 7.6 Right superior temporal gyrus 60 −28 4 450 3600 10.17 Left middle temporal gyrus −60 −42 4 404 3232 10.47 Left middle temporal gyrus −44 −64 6 36 288 10.4 Right superior occipital gyrus 22 −78 36 233 1864 9.5 Left inferior parietal lobule −36 −40 42 93 744 7.54 Left postcentral gyrus (BA2) −42 −40 64 319 2552 10.29 Drug-induced decreases Left cerebellum crus 1 −20 −70 −34 135 1080 12.08 Right ventral striatum, contiguous with right anterior insula, rdACC, bilateral thalamus, right amygdala, preSMA, DMPFC, PAG, pons 6 8 12 8471 67768 16.35 Left insula lobe −42 4 −8 206 1648 8.79 Right inferior occipital gyrus (BA17) 30 −98 −8 33 264 8.52 Right supramarginal gyrus 56 −40 38 609 4872 8.76 Left angular gyrus −38 −72 48 177 1416 11.73 Left supramarginal gyrus −60 −48 44 295 2360 13.46 Right middle frontal gyrus 34 34 40 132 1056 8.27 Anatomy toolbox x y z No. of voxels Volume (mm3) −log(Min. p value) Open remifentanil > Hidden remifentanil Left parahippocampal gyrus/amygdala −16 4 −20 23 184 7.79 Right middle frontal gyrus (DMPFC) 26 56 26 21 168 9.25 Left supramarginal gyrus −48 −12 58 19 152 7.75 Right middle frontal gyrus 38 24 54 17 136 10.03 Right inferior parietal lobule 58 −38 54 15 120 7.91 Hidden remifentanil > Open remifentanil Left cerebellum IV–V −8 −60 −14 37 296 9.05 Right insula lobe 46 0 4 18 144 7.94 Right calcarine gyrus (BA17) 22 −74 12 24 192 9.79 - Table 4.
Expectancy-related changes during high intensity stimulation: Instruction effects
Region x y z No. of voxels Volume (mm3) −log(Min. p value) Expectancy-induced increases (Open > Hidden) Right lingual gyrus (BA17) 10 −96 −8 47 376 8.15 Left inferior occipital gyrus −52 −72 −6 57 456 8.36 Left inferior frontal gyrus p. triangularis (BA45; DLPFC) −54 18 26 433 3464 10.35 Left precuneus −4 −60 50 10 80 9.02 Left middle frontal gyrus (DLPFC) −44 14 58 105 840 10.51 Left superior frontal gyrus −22 0 58 40 320 9.63 Right precuneus 10 −52 68 32 256 9.05 Expectancy-induced decreases (Hidden > Open) Left parahippocampal gyrus −28 −16 −28 90 720 8.29 Left fusiform gyrus −34 −48 −16 85 680 10.37 Left amygdala −18 4 −24 37 296 9.57 Internal globus pallidus −10 −4 −10 21 168 8.78 Left caudate nucleus −10 10 −2 25 200 7.73 Left posterior thalamus −12 −28 10 165 1320 9.99 Left rolandic operculum (dorsal posterior insula) −38 −18 18 102 816 10.89 Left precentral gyrus (BA6) −42 −18 58 224 1792 11.14 - Table 5.
Expectancy-related differences in pain report-related responses during remifentanil administration
Regions x y z No. of voxels Volume (mm3) −log(Min. p value) Expectancy-related increases associated with pain relief (Open > Hidden) Left hippocampus (CA) −34 −22 −18 22 176 8.77 Inferior temporal gyrus 44 −38 −10 239 1912 13.58 Right midorbital gyrus 16 58 −6 398 3184 13.85 Left amygdala −20 −8 −12 53 424 8.16 Right subgenual anterior cingulate cortex 4 14 −10 378 3024 11.03 Left middle temporal gyrus −58 −50 8 344 2752 10.65 Right middle temporal gyrus 66 −26 −4 157 1256 10.81 Right middle temporal gyrus 52 −56 16 290 2320 8.02 Right inferior frontal gyrus, pars opercularis 38 26 20 18 144 10.12 Right superior occipital gyrus 28 −66 30 166 1328 14.47 Right angular gyrus 46 −60 34 75 600 7.93 Left inferior parietal lobule −48 −50 40 25 200 10.59 Left angular gyrus −32 −82 48 28 224 8.91 Expectancy-related decreases associated with pain relief (Hidden > Open) Left amygdale −14 0 −24 37 296 13.23 Right amygdale 34 12 −22 372 2976 10.16 Right cerebellum III 12 −40 −22 119 952 9.26 Left thalamus −12 −20 2 237 1896 10.32 Right thalamus 12 −14 4 350 2800 14.82 Left SII/Postcentral gyrus −50 −20 18 82 656 10.02 Right middle frontal gyrus 26 52 22 95 760 8.85 Left dorsal posterior insula −36 −20 18 14 112 10.19 Right dorsal posterior insula 48 −16 24 64 512 8.43 Left S1/Postcentral Gyrus (BA3a) −36 −24 46 43 344 9.94 Left superior parietal lobule −26 −68 48 33 264 7.74 Right paracentral lobule (BA4a) 4 −30 64 72 576 11.74 Left precuneus (BA3a) −12 −42 66 60 480 11.56 Right S1/Postcentral gyrus 30 −34 66 148 1184 9.68 Left paracentral lobule (BA4a) −8 −40 76 8 64 8.07 Right postcentral gyrus (BA4a) 14 −38 76 6 48 8.43
