In this study, we combined an expectancy manipulation procedure with both verum and sham acupuncture to investigate the brain networks involved in acupuncture analgesia, expectancy/conditioning induced placebo analgesia and their interrelationship. Our results showed that, although acupuncture analgesia and placebo analgesia show comparable magnitudes of behavioral efficacy, each has a different pattern of associated brain activation. Our results show that relatively different brain networks can be involved in the expectancy effect in verum acupuncture as compared with sham acupuncture. For the verum acupuncture group, there were only a few small differences between the high expectancy side and control side. For the sham acupuncture group, however, a more complicated network, particularly involving a number of areas in the frontal gyrus, was significantly involved. These results suggest that expectancy may involve distinct mechanisms under different circumstances.
In this experiment, we found that the verum and sham acupuncture treatments yielded comparable magnitudes of reported analgesia. This finding is consistent with previous RCTs (Brinkhaus et al., 2006
; Haake et al., 2007
; Kaptchuk, 2000
; Leibing et al., 2002
; Linde et al., 2005
; Melchart et al., 2005
) reporting no significant differences between verum and sham acupuncture treatment, but significant positive clinical effects beyond no treatment controls.
To investigate the role of expectancy in acupuncture, Linde and colleagues (Linde et al., 2007
) recently reviewed four acupuncture RCTs of 864 patients with migraine, tension-type headache, chronic low back pain, and knee osteoarthritis. Their results showed positive expectations and attitudes towards acupuncture treatment predicted positive outcomes independent of whether or not the treatments were real or sham. Consistent with this finding, we found that, even within the same verum acupuncture group on the same right forearm, if subjects were manipulated to expect that acupuncture could only work for him or her on a particular side of the arm (HE side) but not on the other side (Control side), verum acupuncture’s analgesia effect on reported pain rating changes could be significantly different, indicating the power of expectancy on acupuncture efficacy reports.
However, contrary to the behavioral subjective pain rating reports, fMRI analysis showed that, compared with sham treatment, verum acupuncture could significantly inhibit the brain response to calibrated pain stimuli, as indicated by fMRI signal decreases in left insula, putamen, and superior temporal gyrus, regardless of where the pain was applied (HE or Control side). This brain response reduction is consistent with the interpretation that acupuncture treatment suppresses pain perception not only by cognitive modulation but also by a more peripheral site of action involving inhibition of ascending nociceptive information (Han, 2003
; Melzack, 1989
; Pomeranz, 1997
For instance, in a previous study, Zhang and colleagues (Zhang et al., 2003b
) found that after 2 Hz electric acupoint stimulation (EAS), brain activation to calibrated cold pain was reduced in brain regions including contralateral SI, LPFC, and inferior temporal (BA20, 37) cortices; bilateral caudal ACC (BA24), parietal (BA7) cortex, medial cuneus, midbrain, pons, and cerebellum; and ipsilateral parietal (BA 39) cortex. In another study (Zhang et al., 2003a
), this same group found that, after 2 Hz electrical acupoint stimulation, positive correlations could be observed in contralateral primary motor area, supplementary motor area, and ipsilateral superior temporal gyrus. Although the experimental paradigm and treatment modality of these studies are not exactly the same as ours, (for example, a differential use of superficial electric acupoint stimulation vs electroacupuncture stimulation with needle insertion), results are partly consistent.
More interestingly in this study, we also found that on the HE side, where subjects expected that acupuncture would produce an analgesic effect, more extensive fMRI signal decreases were observed in brain regions including right insula, putamen, claustrum and superior temporal gyrus, bilateral medial frontal gyrus, inferior parietal lobule, left dACC, and rACC when we compared the fMRI signal change differences between verum and sham acupuncture groups. This result suggests that expectancy is able to enhance acupuncture analgesia initiated by an inhibited brain response to calibrated pain stimuli. Given the roles of dACC in affective components of pain (Price, 2000
) and rACC in emotional modulation (Bush et al., 2000
; Vogt, 2005
), we speculate that positive expectancy may enhance acupuncture analgesia efficacy through the emotional modulation pathway. We believe this is the first brain imaging study to elucidate the brain mechanisms behind how positive expectancy can influence the therapeutic effect of verum acupuncture treatment.
As another interesting finding, we observed that the brain network involved in expectancy modulation can vary under different situations. In the verum acupuncture group, when we compared the HE side with the Control side, only minimal differences were observed in left M1 (HE > Control) and right middle frontal gyrus (BA 10) (Control > HE). While in the sham acupuncture group, when we calculated the contrast of HE minus Control (HE > Control), significant fMRI signal changes were observed in in left operculum. The opposite comparison (Control > HE) showed fMRI signal change in right insula, right inferior frontal gyrus (BA 47, 44), medial frontal gyrus and superior frontal gyrus (BA 10). This result is partly consistent with our previous placebo analgesia study using a similar expectancy manipulation (we used RP in that study to test placebo analgesia while we use IP in this experiment), in which we found a greater fMRI signal increase in response to calibrated noxious stimuli after sham acupuncture treatment in brain regions such as anterior insula and dACC/medial frontal gyrus, lateral and orbital prefrontal cortex on HE side. It is also partly consistent with other studies (Price et al., 2007
) that observed fMRI signal decreases after placebo treatment in brain regions such as bilateral insula/operculum.
A remaining question considers why different networks are involved when the same expectancy manipulation is used in different treatment groups. One speculation could contend that verum acupuncture treatment actually inhibits incoming noxious information similarly on HE and Control sides of the right forearm, thus ceiling effects denies sufficient room for an expectancy effect; while for the sham acupuncture group, more potential remains for expectancy effects. Another possibility suggested by prior research demonstrates that in different circumstances, variation between specific and non-specific effects can change (Kirsch, 2000
; Kleijnen et al., 1994
). This avenue of research has demonstrated that depending on environmental cues and the information/misinformation provided to subjects (expectancy), pharmacologically active substances such as buprenorphine, tramadol, ketorolac and metamizol (Amanzio et al., 2001
), diazepam (Colloca et al., 2004
), alcohol (McKay and Schare, 1999
), caffeine (Flaten and Blumenthal, 1999
; Kirsch and Rosadino, 1993
), oxprenolol (Landauer and Pocock, 1984
), tetrahydrocannabionol (Curran et al., 2002
), nicotine (Perkins et al., 2003
), cocaine (Muntaner et al., 1989
), phenmetrazine (Penick and Hinkle, 1964
), epinephrine (Penick and Fisher, 1965
), amphetamine (Lyerly et al., 1964
)--- or their matching placebo controls -- can have different objective and subjective effects, and that the pharmacological-placebo difference can shift indicating that pharmacological effects and their matching placebo effects interact with expectancy.
In this experiment, we have demonstrated different patterns of brain activation in response to calibrated noxious stimuli when a positive expectancy of analgesia is induced under different treatment circumstances, even when the subjective self-reported analgesia in the two conditions are comparable. We believe what we uniquely showed here is that equivalent subjective effects can be dissociated from objective functional neuroanatomical activations using brain imaging tools. To our knowledge our study is the first to examine the interaction of active treatment and expectancy on both subjective outcomes and objective neuroanatomical correlates and to show dissociation between the two effects.
A final question considers why we did not observe differences in reported pain rating between the two groups on either HE or Control sides, if verum acupuncture is supposed to inhibit incoming noxious stimulation information equally on both the HE and Control sides. Were subjects actually objectively experiencing less pain or merely reporting analgesia? We speculate some level of bias in subjective pain ratings to account for this outcome (Kong et al., 2007c
; Montgomery and Kirsch, 1997
; Price et al., 1999
). From the point of view of cognitive neuroscience, subjective pain rating is a complicated decision making process, which can be significantly biased by previous experience and expectation (Mesulam, 1998
; Miller and Cohen, 2001
). For this reason, we believe as a more objective means to study a subjective phenomenon, brain imaging can enhance our understanding of pain and pain modulation processes.
It is worth noting that such dissociation between a subjective impression and independent corroboration has also been observed in other studies. Kelly and colleagues (Kelly et al., 2008
) investigated the efficacy of a light therapy device intended to rejuvenate facial skin in 36 patients. They found that after an 8-week treatment as well as 1-month follow up, patients reported robust and statistically significant improvements in seven facial features. In sharp contrast, both the treating physician and blinded expert raters were unable to detect any improvement. Moreover, effect sizes were close to zero and in the opposite direction from improvement. Fregni and colleagues (Fregni et al., 2006
) showed similar dissociation in a acute model of Parkinson’s disease when they gave 10 patients on three different occasions either levodopa, placebo pill or sham transcranial magnetic stimulation. On objective outcomes, only the levodopa group improved, but on subjective outcomes, patients in the two different controls reported improvement equal to the levodopa.
Also, one curious historical note might be in order, as our findings are consistent with a suggestion in the oldest canonical classic of Chinese medicine, the Yellow Emperor’s Inner Classic (Huang Di Nei Jing). Written in the first century BCE, the text states that “if a patient does not consent to therapy [acupuncture] with positive engagement, the physician should not proceed as the therapy will not succeed” (SuWen Chapter 11).
One potential limitation of our study is that the sham acupuncture used in this study could be regarded as another form of verum acupuncture. For instance, Japanese style acupuncture, as compared to Chinese style, tends to insert needles shallowly. Thus, our results may indicate a difference between acupuncture styles. In objection to this argument, we would argue that our sham acupuncture needle just touched, but did not penetrate into the skin, and did not involve any aspect of therapeutic contact. Previous studies indicate that connective tissue may play an important role in acupuncture treatment (Langevin et al., 2006a
; Langevin et al., 2001
; Langevin et al., 2002
; Langevin et al., 2004
; Langevin and Sherman, 2007
; Langevin et al., 2006b
); thus, our sham acupuncture that just touched the skin seems unlikely to produce the same effects of shallow needling. In addition, we did not manipulate the needles during the sham procedure. Thus, momentary sensation produced by sham acupuncture seems unlikely to explain analgesia effects comparable to verum acupuncture.
In summary, we found that, although acupuncture analgesia and expectancy induced placebo analgesia show comparable magnitudes of behavioral efficacy, each has a unique pattern of associated brain activation change. Objective fMRI signal changes show that expectancy can significantly enhance verum acupuncture’s analgesic effect, indicated by greater fMRI signal decrease compared with sham acupuncture. Also, the brain network involved in the expectancy can be different under different treatment conditions (verum vs sham). We believe our study provides the first brain imaging evidence on how expectancy can influence real (verum) acupuncture treatment and how different brain networks can be involved in this process.