Elsevier

NeuroImage

Volume 47, Issue 3, September 2009, Pages 1066-1076
NeuroImage

An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment

https://doi.org/10.1016/j.neuroimage.2009.05.087Get rights and content

Abstract

It is well established that expectation can significantly modulate pain perception. In this study, we combined an expectancy manipulation model and fMRI to investigate how expectation can modulate acupuncture treatment. Forty-eight subjects completed the study. The analysis on two verum acupuncture groups with different expectancy levels indicates that expectancy can significantly influence acupuncture analgesia for experimental pain. Conditioning positive expectation can amplify acupuncture analgesia as detected by subjective pain sensory rating changes and objective fMRI signal changes in response to calibrated noxious stimuli. Diminished positive expectation appeared to inhibit acupuncture analgesia. This modulation effect is spatially specific, inducing analgesia exclusively in regions of the body where expectation is focused. Thus, expectation should be used as an important covariate in future studies evaluating acupuncture efficacy. In addition, we also observed dissociation between subjective reported analgesia and objective fMRI signal changes to calibrated pain in the analysis across all four groups. We hypothesize that as a peripheral-central modulation, acupuncture needle stimulation may inhibit incoming noxious stimuli; while as a top-down modulation, expectancy (placebo) may work through the emotional circuit.

Introduction

It is well known that expectation can significantly modulate pain perception (Benedetti, 2008, Benedetti et al., 2006, Kong et al., 2007c). Recent advances in brain imaging have contributed to our mechanistic understanding of how expectancy (combined with placebo/sham treatment) can produce placebo analgesia and nocebo hyperalgesia effects (Bingel et al., 2006, Colloca et al., 2008, Craggs et al., 2007, Kong et al., 2008, Kong et al., 2006a, Lieberman et al., 2004, Petrovic et al., 2002, Price et al., 2007, Scott et al., 2007, Scott et al., 2008, Wager et al., 2004, Wager et al., 2007, Zubieta et al., 2005). However, the interaction between expectancy and genuine treatment has rarely been studied.

In one of the few studies on this topic performed in human subjects, Volkow et al. investigated how expectation can influence response to the stimulant drug methylphenidate in both cocaine abusers (Volkow et al., 2003) and non abusers (Volkow et al., 2006). They found that expectation significantly modified both subjective report (Volkow et al., 2003) and pattern of brain activation in response to a challenge dose of methylphenidate (Volkow et al., 2006, Volkow et al., 2003).

To date, acupuncture has been studied in almost one thousand different randomized controlled trials (RCTs) (Ernst, 2006, Kaptchuk, 2000, Linde et al., 2001). In these trials, it is not uncommon for “placebo/sham acupuncture/minimal acupuncture” controls to induce positive therapeutic effects on the same order of magnitude as verum (genuine) acupuncture, with verum and sham groups usually demonstrating superiority and clinical benefits over wait list or standard of care controls (Brinkhaus et al., 2006, Haake et al., 2007, Kaptchuk, 2000, Kaptchuk, 2002, Leibing et al., 2002, Linde et al., 2005, Melchart et al., 2005). In an attempt to find predictors of acupuncture response, Linde et al. (2007) reanalyzed the results from several RCTs of acupuncture treatment for chronic pain and found that expectation of relief was the only factor that correctly predicted outcome. Thus, it is important to elucidate the interaction between expectancy and acupuncture treatment in a well-controlled experimental setting.

One difficulty in studying expectancy is its large heterogeneity among healthy volunteers in part due to past treatment experience or knowledge that can condition responses. To overcome this challenge we have modified an expectancy/conditioning manipulation model used in other studies (De Pascalis et al., 2002, Kong et al., 2008, Kong et al., 2006a, Montgomery and Kirsch, 1997, Price et al., 1999, Voudouris et al., 1990, Wager et al., 2004) and applied it to a treatment that is relatively novel in this culture, acupuncture. Our group's previous studies (Kong et al., 2008, Kong et al., 2006a) that employ this paradigm demonstrate successful alteration of subjects' expectancies for acupuncture analgesia following experimental pain in a relatively short period of time.

In the current study, we combined the same expectancy/conditioning manipulation model and fMRI to investigate how expectancy can modulate acupuncture analgesia to calibrated noxious stimuli. In this experiment, subjects were randomized into four groups, receiving verum or sham acupuncture paired with either a high or low expectancy/conditioning manipulation. Then analgesic response to experimental heat pain applied on the right forearm was tested. In each group, we also included a within-subject control. Subjects were told that if they responded to the acupuncture treatment they would experience analgesia only on the treated (meridian) side of their arm, but not on the untreated (non-meridian) side of their arm (Fig. 1). Forty-eight subjects (12 in each group) completed the experiment. In this manuscript, we will focus on the data from the two real (verum) acupuncture groups (High and Low Expectancy) to investigate the mechanism of how expectancy can modulate treatment effects using within-subject and between-subject comparisons. To facilitate the understanding of the data, we will also include results from the other groups as secondary endpoints of this study. Data from other groups have also been presented in a separate manuscript (Kong et al., 2009) with additional analyses still underway.

Section snippets

Subjects

Seventy-seven healthy, right-handed subjects enrolled in this experiment, which was said to be a study of acupuncture analgesia. All subjects were naive to acupuncture. Experiments were conducted with the written consent of each subject and approval by the Massachusetts General Hospital's Institutional Review Board. All subjects were debriefed at the end of the experiment.

Procedures for the delivery and assessment of noxious thermal stimuli

Subjects were recruited to participate in two behavioral testing sessions and one fMRI scanning session. Each session was

Subjects

Forty-eight of seventy-seven consenting volunteers completed the study and were used for data analysis (average age 26.4 ± 4.9; 24 males). Twelve subjects did not fit the criteria for continued inclusion in the study (average ratings for HIGH pain were not greater than average ratings for LOW pain, or IP ratings on the radial and ulnar sides of their right arm were not approximately equivalent), eleven voluntarily withdrew, two could not tolerate the heat pain in Session 1, one could not tolerate

Discussion

In this study, we combined an expectancy manipulation procedure and fMRI to investigate how expectancy can influence the analgesia effect produced by verum acupuncture. Our results showed that although electroacupuncture treatment in VH and VL groups both received identical electroacupuncture treatment and produced comparable magnitudes of acupuncture sensations as measured by MASS, analgesia effect was significantly modulated by expectancy. Positive expectation can significantly enhance

Acknowledgments

This work was supported by PO1-AT002048 to Bruce Rosen from National Center for Complimentary and Alternative Medicine (NCCAM), R21AT00949 to Randy Gollub from NCCAM, KO1AT003883 to Jian Kong from NCCAM, K24AT004095 to Ted Kaptchuk from NCCAM, M01-RR-01066 and UL1 RR025758-01 for Clinical Research Center Biomedical Imaging Core from National Center for Research Resources (NCRR), P41RR14075 for Center for Functional Neuroimaging Technologies from NCRR and the MIND Institute.

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