Expectancies modulate both reported pain and responses in some brain regions, yet the key brain circuitry that mediates expectancy effects on pain experience has not been identified. –Placebo expectancy manipulations: decreases in “pain matrix” regions 1,2, increases in control regions, particularly rACC 2,3,4 –Placebo analgesia brain-behavior correlations = between-subjects only. –Event-related (cue-based) expectancy manipulations: modulation of pain matrix and striatal regions 5,6 –Have not examined relationship between brain and pain reports. For a brain region or pathway to mediate expectancy effects on reported pain, its activity must: a) be influenced by expectancy. b) predict trial-by-trial changes in reported pain, even within a single level of noxious stimulation. c) statistically explain a significant portion of expectancy effects on trial-by-trial reported pain. We used multi-level mediation (M3) software to test this compound hypothesis, and to locate regions that formally mediate the relationship between experimentally manipulated expectancy and reported pain. Multiple mediators of expectancy effects on pain perception: Interactions among higher-order brain regions and the pain matrix Lauren Y. Atlas 1, Niall Bolger 1, Martin Lindquist 2, Tor D. Wager 1 1 Columbia University Department of Psychology, 2 Columbia University Department of Statistics INTRODUCTION METHODS RESULTS Voxelwise single trial analysis Whole-brain multi-level mediation Columbia Psychology SCAN group Three linear equations: 1.y = cx + e y 2.m = ax + e m 3.y = bm + c'x + e' y Experimental design A test for mediation should satisfy the following criteria: 1.M should be related to X (a effect) 2.M should be related to Y after controlling for X (b effect) 3. The indirect relationship (a*b)should be significant Contact: 18 subjects (mean age = 25.3, 9 females) Thermal stimulation to 4 sites on left forearm with 16mm thermode (Medoc, Inc.)) FMRI acquisition: 1.5T GE scanner, Spiral In-Out, 29 slices, 2s TR 3. Two conditioning runs + fMRI 4. Six experimental runs + fMRI 1. Pain calibration Low pain cue Low Pain (Level 2) LL Med Pain (Level 5) LM High pain cue Med Pain (Level 5) HM High Pain (Level 8) HH 2. Learning Task: Tones predict low or high pain, counterbalanced across subjects; S informed of cue-pain pairings, must correctly identify 90% of tones to proceed Level 2 (Slightly painful) Level 5 (Moderate pain) Level 8 (Max tolerable pain) CUE Delay HEAT ISI 2s 6s 10s 14s 4s 8s How Painful? ISI + Contrast HM vs LM during pain period: identical stimulation, high vs low pain expectancy 1.Fit basis functions trial-by-trial 2.Estimate trial-by-trial area under the curve (AUC) 3.Use trial level parameters in multi- level mediation 324 Schermerhorn Hall Department of Psychology 1190 Amsterdam Ave. New York, NY Basis functions Trial level parameters Trial-by-trial estimates Hypotheses I.Expectancies modulate pain reports. II.Expectancies modulate pain matrix activity (Path a). III.Pain matrix activity affects perceived pain (Path b). IV.Expectancy effects in pain matrix regions lead to changes in perceived pain (Mediation effect, A*B). V.Higher order regions involved in cognitive control and value processing also mediate expectancy effects on perceived pain. VI.Interactions among these mediators predict perceived pain. Perceived Pain (6.18)*** 2.24 (0.77)** 6.25 (1.72) ***0.20 (0.08)** Expectancy (HM-LM) Perceive d Pain dACC R. Thalamus CB Vermis Pons L. Anterior Insula IV. Pain matrix mediators VI. Secondary mediation analysis: Expectancy-based interactions between pain matrix and higher-order mediators contribute to perceived pain. SUMMARY Nearly all pain matrix regions are modulated by expectancy during noxious thermal stimulation (all except dACC, PAG). Some pain matrix regions (Insula, dACC) predict perceived pain controlling for expectancy and temperature. A key subset of pain matrix regions (insula, thalamus, dACC, pons, cerebellum) mediate expectancy effects on perceived pain. Amygdala, striatum, and medial OFC mediate expectancy effects on pain matrix mediators. R. dmPFC mediates expectancy effects on pain independent of pain matrix activity. Pain Localizer - HH>LL YNYR. Thalamus* YNYPons* NNNPAG YYNdACC* NNYL. Middle Insula NNYR. Middle Insula YYYL. Anterior Insula NYYR. Anterior Insula † NNYR. SII YYYCB Vermis NYYBilateral Cerebellum † AB?B?A?Region WHOLE BRAIN MULTI-LEVEL MEDIATION ANALYSIS 1.DD Price et al. Pain, 127, (2007). 2.TD Wager et al. Science, 303, (2004). 3.U Bingel et al. Pain, 120, 8-15 (2006). 4.P Petrovic, E Kalso, KM Petersson, M Ingvar. Science, 295, , (2002). 5.T Koyama, JG McHaffie, PJ Laurienti, RC Coghill. PNAS, 102, (2005). 6.JR Keltner et al. JNeuroscience, 26, (2006). Pain Rating Reprints: I. Expectancies modulate perceived pain. HM>LM (p<.0001), allowing us to examine mediators of expectancy effects on reported pain within a single level of noxious stimulation. **** Perceived Pain (Pain Reports) Brain Mediators Expectanc y (HM-LM) A*B: Which brain regions mediate expectancy effects on pain perception? Path b Path a Path c/c’ Pons II. Path a: Expectancies modulate brain activity during pain. III. Path b: Controlling for expectancy and temperature, brain activity predicts perceived pain. LM HM PAIN PERIOD ACTIVATIONEXPECTANCY Medial OFCRight VLPFC Left DLPFCLeft Amygdala Path a HE-Med > LE-Med PonsRight ThalamusRight SIILeft Anterior Insula Pain Regions a. b. LE-Med > HE-Med Medial OFCRight DMPFCRight IFG Positive effect Right latPFC rdACC Pain Regions a. b. Negative effect PAIN PERIOD ACTIVATIONPERCEIVED PAIN Path b Reported Pain Mid. Cingulate Reported Pain R. Ant. Insula Reported Pain Cerebellum Reported Pain IV, V. Mediation effect: Pain matrix regions and higher order regions mediate expectancy effects on reported pain. L. Ant. Insula L (Ipsilateral)R (Contralateral) Vermis L. Putamen, Caudate rdACC pgACC L. DLPFC TPJ R. Thalamus Mid. Cing dACC Pons Middle Occipital Gyrus R. dmPFC R sgACC References Mediating expectancy effects on pain matrix Expectancy Perceived Pain Pain Matrix Mediators Left Amygdala Left Ventral Striatum SII Medial OFC Expectancy Perceived Pain Pain Matrix Mediators Right dmPFC (2.44)** (.05)** Expectancy (HM-LM) Perceived Pain Pain Matrix Mediators* Expectancy Region a b Path c a b * : Activity averaged across pain matrix mediators. Thick arrows depict paths identified in primary mediation (Hypoth IV). Dashed arrows depict effects potentially being mediated. Report Region Independent of pain matrix Region L VS L Amyg R SII mOFC A*B (.21)* (.25)* (.11)** (.18)* Secondary mediation 1 Secondary mediation 2 Positive path coefficients Negative path coefficients