Elsevier

NeuroImage

Volume 112, 15 May 2015, Pages 197-207
NeuroImage

Distinct neural representations of placebo and nocebo effects

https://doi.org/10.1016/j.neuroimage.2015.03.015Get rights and content

Highlights

  • We investigated placebo/nocebo effects in the same cohort of subjects.

  • Expectancy (positive & negative) significantly modulated subjective pain ratings.

  • Positive/negative expectancy modulates pain with distinct brain networks.

  • Placebo/nocebo responses as indicated by pain ratings are significantly associated.

  • Placebo/nocebo brain responses in the pain matrix are not significantly associated.

Abstract

Expectations shape the way we experience the world. In this study, we used fMRI to investigate how positive and negative expectation can change pain experiences in the same cohort of subjects. We first manipulated subjects' treatment expectation of the effectiveness of three inert creams, with one cream labeled “Lidocaine” (positive expectancy), one labeled “Capsaicin” (negative expectancy) and one labeled “Neutral” by surreptitiously decreasing, increasing, or not changing respectively, the intensity of the noxious stimuli administered following cream application. We then used fMRI to investigate the signal changes associated with administration of identical pain stimuli before and after the treatment and control creams. Twenty-four healthy adults completed the study. Results showed that expectancy significantly modulated subjective pain ratings. After controlling for changes in the neutral condition, the subjective pain rating changes evoked by positive and negative expectancies were significantly associated. fMRI results showed that the expectation of an increase in pain induced significant fMRI signal changes in the insula, orbitofrontal cortex, and periaqueductal gray, whereas the expectation of pain relief evoked significant fMRI signal changes in the striatum. No brain regions were identified as common to both “Capsaicin” and “Lidocaine” conditioning. There was also no significant association between the brain response to identical noxious stimuli in the pain matrix evoked by positive and negative expectancies. Our findings suggest that positive and negative expectancies engage different brain networks to modulate our pain experiences, but, overall, these distinct patterns of neural activation result in a correlated placebo and nocebo behavioral response.

Introduction

Expectations shape the way we experience the world, for better or for worse (Tracey, 2010). Physicians and clinical investigators have found that positive expectancy of relief can enhance the therapeutic effect of treatment and negative expectancy can diminish it (Atlas and Wager, 2012, Atlas et al., 2012, Bingel et al., 2011, Carlino et al., 2014, Finniss and Benedetti, 2005, Finniss et al., 2010, Tracey, 2010). In the context of pain perception, positive expectations of treatment can elicit analgesia while negative expectation can elicit hyperalgesia. In a clinical setting, it has been demonstrated that either or both placebo (positive expectancy of pain relief) and nocebo effects (negative expectancy of increased pain) influence the effectiveness of medical treatment (Kam-Hansen et al., 2014, Pollo et al., 2001).

There is an increasing body of literature suggesting that placebo effects can enhance the therapeutic benefits of care through the context in which the treatment is administered (Brody and Miller, 2011, Cleophas, 1995, de la Fuente-fernandex et al., 2002, Di Blasi et al., 2001, Finniss et al., 2010, Kaptchuk, 1998, Price et al., 2008, Thomas, 1994). Similarly, there is evidence suggesting that negative expectations can contribute to a variety of side effects and adverse events in clinical trials and medical care (Amanzio et al., 2009, Barsky et al., 2002, Colloca and Finniss, 2012, Petersen et al., 2014). Investigators have explored the neurobiological mechanisms underlying placebo analgesia extensively over the past decades. Many have employed brain imaging technologies (Amanzio et al., 2013, Atlas and Wager, 2012, Benedetti, 2008, Benedetti et al., 2006, Buchel et al., 2014, Enck et al., 2008, Finniss and Benedetti, 2005, Finniss et al., 2010, Kong et al., 2007, Miller et al., 2009, Tracey, 2010, Zubieta and Stohler, 2009). Relatively fewer studies have focused on nocebo hyperalgesia (Benedetti et al., 2003, Colloca and Benedetti, 2007, Colloca and Finniss, 2012, Geuter and Buchel, 2013, Kong et al., 2008, Schmid et al., 2013, Scott et al., 2008).

In order to understand the mechanisms underlying the placebo and nocebo effects, it is important not only to understand them separately but also study the association between them. It is not yet clear whether any or all of the mechanisms that have been proposed to account for positive and negative modulation of pain perception are contributory, singly or in combination. Moreover, there is no clear consensus on whether bidirectional mechanisms contribute to placebo analgesia and nocebo hyperalgesia or whether they are completely separable cognitive constructs. To date, only a few studies have directly compared placebo and nocebo effects. Most of these studies have involved behavioral measures only (Benedetti et al., 2003, Benedetti et al., 2014, Colloca et al., 2008, Colloca et al., 2010). Based on the existing data, investigators have formed two main hypotheses regarding the relationship between placebo and nocebo effects (Petrovic, 2008, Scott et al., 2008). One postulates that placebo and nocebo are manifestations of the same type of brain network with different activation/deactivation changes or, using Petrovic's term, ‘sides of the same coin’ (Petrovic, 2008). The other posits that placebo and nocebo are separate cognitive constructs grounded in different behavioral patterns and their associated brain networks (Benedetti et al., 2006, Kong et al., 2008).

In the present experiment, we first manipulated subjects' treatment expectation of the effectiveness of three inert creams, with one cream labeled “Lidocaine” (positive expectancy), one labeled “Capsaicin” (negative expectancy), and one labeled “control” by surreptitiously decreasing, increasing or not changing, respectively, the noxious stimulus intensity after application. We then investigated the subjective pain rating and fMRI signal changes associated with administration of identical pain stimuli before and after the different “treatments.” Our study is unique in that it involved the use of a completely inert treatment, a moisturizing cream, to elicit both placebo and nocebo effects within each individual subject in the same session. This experimental design allowed us to investigate the association between the placebo and nocebo effects and directly compare the brain networks between these two important clinical phenomena in the absence of active medication.

Section snippets

Methods

The Institutional Review Board at Massachusetts General Hospital approved all study procedures. All enrolled subjects provided written informed consent before beginning any study procedures and we debriefed them at the end of the study. All subjects were offered the option to remove their data from the study if they had any concerns due to the inherent need for deception in the experimental paradigm. No subject reported any concern and all subjects allowed their data to be used.

Behavioral results

Thirty-eight volunteers consented to participate in the study. Twenty-four healthy adults (12 male) aged 21 to 49 completed the study. Three subjects withdrew from the study, one due to discomfort with the heat pain and two due to scheduling issues. Eleven subjects were excluded after Session 1, Session 2, seven due to the inability to reliably distinguish between high and low pain intensities, and four due to equipment malfunctions. Data from all 24 subjects who completed Session 3 were

Discussion

In the present study, using a within-subject design, we found that the application of inert “Lidocaine” cream with expectation of pain relief evoked a significant reduction in subjective pain ratings and fMRI signal changes in the striatum, whereas inert “Capsaicin” cream with expectancy of pain enhancement evoked a significant increase in subjective pain ratings and fMRI signal changes in the insula, OFC, and PAG. No overlapping brain regions were identified in response to both the “Capsaicin”

Acknowledgment

This work was supported by R01AT006364 (NCCAM) to Jian Kong, R01AT005280 (NCCAM) to Randy Gollub, and P01 AT006663 to Bruce Rosen.

Conflict of interest

There is no conflict of interest for any of the authors.

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    One-sentence summaries: The placebo and nocebo effects indicated by subjective pain rating changes were significantly associated; yet, the involved brain networks indicated by fMRI signal changes are different.

    1

    Sonya Freeman and Rongjun Yu are co-first authors for this study.

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