The neural correlates of placebo effects: a disruption account Matthew D. Lieberman, * Johanna M. Jarcho, Steve Berman, Bruce D. Naliboff, Brandall Y. Suyenobu, Mark Mandelkern, and Emeran A. Mayer University of California, Los Angeles, CA 90095-1563, USA Received 3 November 2003; revised 15 January 2004; accepted 15 January 2004 The neurocognitive pathways by which placebo effects operate are poorly understood. Positron emission tomography (PET) imaging was used to assess the brain response of patients with chronic abdominal pain (irritable bowel syndrome; IBS) to induced intestinal discomfort both before and after a 3-week placebo regimen. A daily symptom diary was used to measure symptom improvement. Increases in right ventrolateral prefrontal cortex (RVLPFC) activity from pre- to post- placebo predicted self-reported symptom improvement, and this relationship was mediated by changes in dorsal anterior cingulate (dACC), typically associated with pain unpleasantness. These results are consistent with disruption theory [Lieberman, M.D., 2003. Reflective and reflexive judgment processes: a social cognitive neuroscience approach. In: Forgas, J.P., Williams, K.R., von Hippel, W. (Eds.), Social Judgments: Explicit and Implicit Processes. Cam- bridge Univ. Press, New York, pp. 44–67], which proposes that activation of prefrontal regions associated with thinking about negative affect can diminish dACC and amygdala reactivity to negative affect stimuli. This is the first study to identify a neural pathway from a region of the brain associated with placebos and affective thought to a region closely linked to the placebo-related outcome of diminished pain unpleasantness. D 2004 Elsevier Inc. All rights reserved. Keywords: Neural correlates; Placebo effects; Disruption Introduction Placebo effects and the power of belief over physical outcomes in the body have a history as long as medicine itself. Only recently, however, have the neural bases of these psychophysiological phenomena begun to be examined. Current research has shown that placebos can produce changes in brain activity similar to the pharmacological agents they are replacing. For instance, placebos administered in the treatment of depression have been shown to alter brain activity in much the same way as fluoxetine, an effective antidepressant medication (Mayberg et al., 2002). Such findings suggest that the final result of placebo administration may mimic the effects of active agents; however, the mediating neurocognitive process by which ingesting a placebo and placebo-related beliefs lead to these final neural results has not yet been examined. In other words, it is unknown what placebo-specific neural activity sets in motion the subsequent symptom-specific changes in brain activity. In a positron emission tomography (PET) study of placebo effects on visceral pain, we investigated a possible mediating mechanism derived from disruption theory (Eisenberger et al., 2003; Lieberman, 2003; Lieberman et al., 2003), which suggests that thinking about affective processes has the unintended effect of diminishing the reactivity of brain regions involved in the auto- matic generation of negative affect. Neuroimaging research on placebo effects has focused primar- ily, though not exclusively, on the neural outcome of placebo effects—identifying changes in the brain regions that most directly relate to subjective changes in symptoms, and comparing these changes with those stemming from active pharmacological agents (de la Fuente-Fernandez et al., 2001; Leuchter et al., 2002; May- berg et al., 2002). This research has been critical in demonstrating that top-down, belief-related placebo effects modulate the activity of brain regions ordinarily affected by other treatments that pre- sumably operate through bottom-up mechanisms that are not belief- related. Such work speaks to the longstanding concern regarding whether placebo effects and other expectancy effects are real, experimental artifacts, or self-presentational effects (Hrobjartsson and Gotzsche, 2001). It is not clear from previous neuroimaging studies, however, whether the neural regions that have been iden- tified are the neural correlates of the placebo effect or the neural correlates of the placebo effect’s downstream consequences on symptom outcomes. Though a drug and a placebo may both affect brain region X, the drug may do so directly, whereas placebo effects are typically mediated by placebo-induced thoughts. 1 In previous studies, right prefrontal cortex, anterior cingulate and striatal dopamine have each been implicated in placebo effects, but it is not clear that these are all plausible neurocognitive candidates for transforming placebo-induced thoughts into altered experience. Petrovic et al. (2002) recently compared placebo- induced analgesia to opioid-induced analgesia and found that whereas both placebos and induced opioids led to similar changes 1053-8119/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2004.01.037 * Corresponding author. Department of Psychology, University of California, Los Angeles, Franz Hall, 405 Hilgard Avenue, Los Angeles, CA 90095-1563. Fax: +1-310-206-5895. E-mail address: lieber@ucla.edu (M.D. Lieberman). Available online on ScienceDirect (www.sciencedirect.com.) www.elsevier.com/locate/ynimg NeuroImage 22 (2004) 447 – 455 1 There are also placebo effects that stem from classical conditioning (Amanzio and Benedetti, 1999); however, the neuroimaging research that has been done to date has not focused on this type of effect. Our comments are thus limited to placebo effects in which prior conditioning to an active agent has not occurred.