Multiple mediators of expectancy effects on pain perception:

1. Path b Path a PAIN PERIOD ACTIVATION EXPECTANCY PAIN PERIOD ACTIVATION PERCEIVED PAIN 5 5 5 5 a. a. 4 4 4 4 Reported Pain Reported Pain Reported Pain Reported Pain 3 3 3 3 Pain Regions 2 2 2 2 Pain Regions 1 1 1 1 rdACC R. Ant. Insula Mid. Cingulate Cerebellum Right SII Left Anterior Insula Right Thalamus Pons Columbia Psychology SCAN group http://www.scan.psych.columbia.edu/ b. b. HE-Med > LE-Med Negative effect LE-Med > HE-Med Positive effect Right DMPFC Left DLPFC Right IFG Left Amygdala Right latPFC Medial OFC Medial OFC Right VLPFC 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. RESULTS **** L. DLPFC TPJ L. Ant. Insula L. Putamen, Caudate Pain Localizer - HH>LL Middle Occipital Gyrus L (Ipsilateral) R (Contralateral) Region A? B? AB? Bilateral Cerebellum† Y Y N dACC R. dmPFC Mid. Cing CB Vermis Y Y Y R. SII Y N N R. Thalamus R. Thalamus* Y N Y R. Anterior Insula† Y Y N pgACC L. Anterior Insula Y Y Y Vermis Pons rdACC R. Middle Insula Y N N R sgACC L. Middle Insula Y N N IV, V. Mediation effect: Pain matrix regions and higher order regions mediate expectancy effects on reported pain. dACC* N Y Y PAG N N N Pons* Y N Y IV. Pain matrix mediators dACC R. Thalamus CB Vermis L. Anterior Insula Perceived Pain Expectancy (HM-LM) Pons 2.24 (0.77)** 6.25 (1.72) *** 0.20 (0.08)** Expectancy (HM-LM) Perceived Pain A*B 0.4333(.21)* 0.5039 (.25)* 0.3749(.11)** 0.2468(.18)* Region L VS L Amyg R SII mOFC 42.52 (6.18)*** Multiple mediators of expectancy effects on pain perception: Interactions among higher-order brain regions and the pain matrix Lauren Y. Atlas1, Niall Bolger1, Martin Lindquist2, Tor D. Wager1 1Columbia University Department of Psychology, 2Columbia University Department of Statistics 324 Schermerhorn Hall Department of Psychology 1190 Amsterdam Ave. New York, NY 10027 Contact: laurenatlas@gmail.com Reprints: http://www.columbia.edu/cu/psychology/tor/ INTRODUCTION • 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” regions1,2, increases in control regions, particularly rACC2,3,4 • Placebo analgesia brain-behavior correlations = between-subjects only. • Event-related (cue-based) expectancy manipulations: modulation of pain matrix and striatal regions5,6 • 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. WHOLE BRAIN MULTI-LEVEL MEDIATION ANALYSIS Pain Rating Pain Rating Expectancy (HM-LM) Perceived Pain (Pain Reports) LM HM LM HM Path c/c’ Path b A*B: Which brain regions mediate expectancy effects on pain perception? Path a Brain Mediators • Hypotheses III. Path b: Controlling for expectancy and temperature, brain activity predicts perceived pain. Expectancies modulate pain reports. Expectancies modulate pain matrix activity (Path a). Pain matrix activity affects perceived pain (Path b). Expectancy effects in pain matrix regions lead to changes in perceived pain (Mediation effect, A*B). Higher order regions involved in cognitive control and value processing also mediate expectancy effects on perceived pain. Interactions among these mediators predict perceived pain. II. Path a: Expectancies modulate brain activity during pain. METHODS • 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 • Experimental design 1. Pain calibration Level 2 (Slightly painful) Level 5 (Moderate pain) Level 8 (Max tolerable pain) Pons 2. Learning Task: Tones predict low or high pain, counterbalanced across subjects; Sinformed of cue-pain pairings, must correctly identify 90% of tones to proceed 2s + VI. Secondary mediation analysis: Expectancy-based interactions between pain matrix and higher-order mediators contribute to perceived pain. 6s 3. Two conditioning runs + fMRI 10s + + 14s 4. Six experimental runs + fMRI 4s CUE + 8s *:Activity averaged across pain matrix mediators. Perceived Pain Delay Expectancy (HM-LM) Pain Matrix Mediators* How Painful? Low Pain (Level 2) LL Low pain cue HEAT + Secondary mediation 1 Secondary mediation 2 Path c b ISI Low pain cue Med Pain (Level 5) LM Mediating expectancy effects on pain matrix a ISI Path c Independent of pain matrix b a Med Pain (Level 5) HM Contrast HM vs LM during pain period: identical stimulation, high vs low pain expectancy High pain cue Left Ventral Striatum Expectancy Region Report Region High pain cue High Pain (Level 8) HH Thick arrows depict paths identified in primary mediation (Hypoth IV). Dashed arrows depict effects potentially being mediated. Right dmPFC Left Amygdala Trial level parameters Basis functions 0.2252 (.05)** • Voxelwise single trial analysis -6.3994 (2.44)** SII Fit basis functions trial-by-trial Estimate trial-by-trial area under the curve (AUC) Use trial level parameters in multi-level mediation Expectancy Pain Matrix Mediators Perceived Pain Pain Matrix Mediators Perceived Pain Expectancy Trial-by-trial estimates Medial OFC Positive path coefficients Negative path coefficients References SUMMARY DD Priceet al. Pain, 127, 63-72 (2007). TD Wager et al.Science, 303, 1162-7 (2004). U Bingel et al.Pain, 120, 8-15 (2006). P Petrovic, E Kalso, KM Petersson, M Ingvar. Science, 295, 1737-40, (2002). T Koyama, JG McHaffie, PJ Laurienti, RC Coghill. PNAS, 102, 12950-12955 (2005). JR Keltner et al. JNeuroscience, 26, 4437-4443 (2006). • Whole-brain multi-level mediation • 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. A test for mediation should satisfy the following criteria: M should be related to X (a effect) M should be related to Y after controlling for X (b effect) 3. The indirect relationship (a*b)should be significant Three linear equations: y = cx + ey m = ax + em y = bm + c'x + e'y