Placebo Analgesia Enhances Descending Pain-Related Effective Connectivity: A Dynamic Causal Modeling Study of Endogenous Pain Modulation


      • Small placebo analgesia produces changes in effective connectivity.
      • Descending pain modulation is likely implicated.
      • Network approaches are necessary in identifying neural mechanisms of placebo.


      The use of placebo to reduce pain is well documented; however, knowledge of the neural mechanisms underlying placebo analgesia remains incomplete. This study used functional magnetic resonance imaging data from 30 healthy individuals and dynamic causal modeling to investigate changes in effective connectivity associated with the placebo analgesic response. Before scanning, participants were conditioned to expect less thermal pain at 2 of 4 sites on their feet. Visual analog scale pain ratings revealed a significant but small difference between the baseline and placebo sites (mean difference = 6.63, t(29) = 3.91, P ≤ .001, d = .97), confirming an analgesic effect. However, no significant differences in the magnitude of brain activation between conditions were observed via traditional random effects general linear modeling. Dynamic causal modeling was then used to investigate changes in effective connectivity during placebo analgesia. The results indicate that during placebo analgesia but not baseline condition, couplings between brain regions, including those involved in cognitive processes (eg, attention, expectation, evaluation), were significantly enhanced. Specifically, a significantly consistent decrease in the dorsolateral prefrontal cortex → periaqueductal gray coupling was found. These findings highlight the differences between pain processing and modulation at the network level. Moreover, our results suggest that small placebo effects may be better characterized via changes in the temporal dynamics among pain modulatory regions than only via changes in the magnitude of blood oxygenation level dependent activation. Further application of nuanced analytical approaches that are sensitive to temporal dynamics of pain-related processes such as dynamic causal modeling are necessary to better understand the neural mechanisms underlying pain processing in patient populations.


      Changes in effective connectivity among pain-related brain regions may be more sensitive detectors of the neural representation of small placebo effects than are changes in the magnitude of brain activation. Knowledge of these mechanisms highlights the importance of integrated neural networks in the understanding of pain modulation.

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        • Bingel U.
        • Lorenz J.
        • Schoell E.
        • Weiller C.
        • Buchel C.
        Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network.
        Pain. 2006; 120: 8-15
        • Bingel U.
        • Tracey I.
        Imaging CNS modulation of pain in humans.
        Physiology (Bethesda). 2008; 23: 371-380
        • Bissiere S.
        • Plachta N.
        • Hoyer D.
        • McAllister K.H.
        • Olpe H.R.
        • Grace A.A.
        • Cryan J.F.
        The rostral anterior cingulate cortex modulates the efficiency of amygdala-dependent fear learning.
        Biol Psychiatry. 2008; 63: 821-831
        • Brooks J.
        • Tracey I.
        From nociception to pain perception: Imaging the spinal and supraspinal pathways.
        J Anat. 2005; 207: 19-33
        • Brown J.E.
        • Chatterjee N.
        • Younger J.
        • Mackey S.
        Towards a physiology-based measure of pain: patterns of human brain activity distinguish painful from non-painful thermal stimulation.
        PLoS One. 2011; 6: e24124
        • Bushnell M.C.
        • Ceko M.
        • Low L.A.
        Cognitive and emotional control of pain and its disruption in chronic pain.
        Nat Rev Neurosci. 2013; 14: 502-511
        • Chung S.K.
        • Price D.D.
        • Verne G.N.
        • Robinson M.E.
        Revelation of a personal placebo response: its effects on mood, attitudes and future placebo responding.
        Pain. 2007; 132: 281-288
        • Coghill R.C.
        • Gilron I.
        • Iadarola M.J.
        Hemispheric lateralization of somatosensory processing.
        J Neurophysiol. 2001; 85: 2602-2612
        • Committee on Advancing Pain Research, Care, and Education; Institute of Medicine
        Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. The National Academies Collection: Reports funded by National Institutes of Health.
        (Washington (DC))2011
        • Craggs J.G.
        • Price D.D.
        • Perlstein W.M.
        • Verne G.N.
        • Robinson M.E.
        The dynamic mechanisms of placebo induced analgesia: evidence of sustained and transient regional involvement.
        Pain. 2008; 139: 660-669
        • Craggs J.G.
        • Price D.D.
        • Verne G.N.
        • Perlstein W.M.
        • Robinson M.M.
        Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia.
        NeuroImage. 2007; 38: 720-729
        • Craggs J.G.
        • Staud R.
        • Robinson M.E.
        • Perlstein W.M.
        • Price D.D.
        Effective connectivity among brain regions associated with slow temporal summation of C-fiber-evoked pain in fibromyalgia patients and healthy controls.
        J Pain. 2012; 13: 390-400
        • David O.
        • Guillemain I.
        • Saillet S.
        • Reyt S.
        • Deransart C.
        • Segebarth C.
        • Depaulis A.
        Identifying neural drivers with functional MRI: an electrophysiological validation.
        PLoS Biol. 2008; 6: 2683-2697
        • Elsenbruch S.
        • Kotsis V.
        • Benson S.
        • Rosenberger C.
        • Reidick D.
        • Schedlowski M.
        • Bingel U.
        • Theysohn N.
        • Forsting M.
        • Gizewski E.R.
        Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: an fMRI study in healthy placebo responders and nonresponders.
        Pain. 2012; 153: 382-390
        • Fardo F.
        • Spironelli C.
        • Angrilli A.
        Horizontal body position reduces cortical pain-related processing: evidence from late ERPs.
        PLoS One. 2013; 8: e81964
        • Faria V.
        • Fredrikson M.
        • Furmark T.
        Imaging the placebo response: a neurofunctional review.
        Eur Neuropsychopharm. 2008; 18: 473-485
        • Friston K.
        Dynamic causal modelling of brain responses.
        J Psychophysiol. 2006; 20: 322
        • Friston K.J.
        • Harrison L.
        • Penny W.
        Dynamic causal modelling.
        Neuroimage. 2003; 19: 1273-1302
        • Gaskin D.J.
        • Richard P.
        The economic costs of pain in the United States.
        J Pain. 2012; 13: 715-724
        • Geers A.L.
        • Wellman J.A.
        • Fowler S.L.
        • Helfer S.G.
        • France C.R.
        Dispositional optimism predicts placebo analgesia.
        J Pain. 2010; 11: 1165-1171
        • Groenewegen H.J.
        Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography.
        Neuroscience. 1988; 24: 379-431
        • Kong J.
        • Gollub R.L.
        • Rosman I.S.
        • Webb J.M.
        • Vangel M.G.
        • Kirsch I.
        • Kaptchuk T.J.
        Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance Imaging.
        J Neurosci. 2006; 26: 381-388
        • Lieberman M.D.
        • Jarcho J.M.
        • Berman S.
        • Naliboff B.D.
        • Suyenobu B.Y.
        • Mandelkern M.
        • Mayer E.A.
        The neural correlates of placebo effects: a disruption account.
        Neuroimage. 2004; 22: 447-455
        • Pecina M.
        • Stohler C.S.
        • Zubieta J.K.
        Neurobiology of placebo effects: expectations or learning?.
        Soc Cogn Affect Neurosci. 2014; 9: 1013-1021
        • Penny W.D.
        • Stephan K.E.
        • Mechelli A.
        • Friston K.J.
        Modelling functional integration: a comparison of structural equation and dynamic causal models.
        Neuroimage. 2004; 23: S264-S274
        • Pitman R.K.
        • van der Kolk B.A.
        • Orr S.P.
        • Greenberg M.S.
        Naloxone-reversible analgesic response to combat-related stimuli in posttraumatic stress disorder. A pilot study.
        Arch Gen Psychiatry. 1990; 47: 541-544
        • Price D.D.
        Psychological and neural mechanisms of the affective dimension of pain.
        Science. 2000; 288: 1769-1772
        • Price D.D.
        Central neural mechanisms that interrelate sensory and affective dimensions of pain.
        Mol Interv. 2002; 2 (339): 392-403
        • Price D.D.
        • Barrell J.J.
        Mechanisms of analgesia produced by hypnosis and placebo suggestions.
        Prog Brain Res. 2000; 122: 255-271
        • Price D.D.
        • Craggs J.
        • Verne G.N.
        • Perlstein W.M.
        • Robinson M.E.
        Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients.
        Pain. 2007; 127: 63-72
        • Price D.D.
        • Fillingim R.B.
        • Robinson M.E.
        Placebo analgesia: friend or foe?.
        Curr Rheumatol Rep. 2006; 8: 418-424
        • Price D.D.
        • Finniss D.G.
        • Benedetti F.
        A comprehensive review of the placebo effect: recent advances and current thought.
        Annu Rev Psychol. 2008; 59: 565-590
        • Rainville P.
        Brain mechanisms of pain affect and pain modulation.
        Curr Opin Neurobiol. 2002; 12: 195-204
        • Rigoux L.
        • Stephan K.E.
        • Friston K.J.
        • Daunizeau J.
        Bayesian model selection for group studies–revisited.
        Neuroimage. 2014; 84: 971-985
        • Stephan K.E.
        • Marshall J.C.
        • Penny W.D.
        • Friston K.J.
        • Fink G.R.
        Interhemispheric integration of visual processing during task-driven lateralization.
        J Neurosci. 2007; 27: 3512-3522
        • Stephan K.E.
        • Penny W.D.
        • Daunizeau J.
        • Moran R.J.
        • Friston K.J.
        Bayesian model selection for group studies.
        NeuroImage. 2009; 46: 1004-1017
        • Stewart-Williams S.
        • Podd J.
        The placebo effect: dissolving the expectancy versus conditioning debate.
        Psychol Bull. 2004; 130: 324-340
        • Symonds L.L.
        • Gordon N.S.
        • Bixby J.C.
        • Mande M.M.
        Right-lateralized pain processing in the human cortex: an FMRI study.
        J Neurophysiol. 2006; 95: 3823-3830
        • Voudouris N.J.
        • Peck C.L.
        • Coleman G.
        Conditioned placebo responses.
        J Pers Soc Psychol. 1985; 48: 47-53
        • Voudouris N.J.
        • Peck C.L.
        • Coleman G.
        The role of conditioning and verbal expectancy in the placebo response.
        Pain. 1990; 43: 121-128
        • Wager T.D.
        • Rilling J.K.
        • Smith E.E.
        • Sokolik A.
        • Casey K.L.
        • Davidson R.J.
        • Kosslyn S.M.
        • Rose R.M.
        • Cohen J.D.
        Placebo-induced changes in FMRI in the anticipation and experience of pain.
        Science. 2004; 303: 1162-1167
        • Wiech K.
        • Ploner M.
        • Tracey I.
        Neurocognitive aspects of pain perception.
        Trends Cogn Sci. 2008; 12: 306-313