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 acupuncture analgesia effects as evidenced by decreased subjective pain ratings as well as objective fMRI signal changes occurring during application of calibrated noxious stimuli. Brain regions including bilateral rACC/MPFC, left DOPFC and DLPFC are involved in this process. Further analysis across four groups indicated that expectancy can significantly modulate the subjective pain rating changes, and there are no significant differences between the verum and sham acupuncture treatment in analgesia effect by subjective pain rating changes. Nevertheless, the fMRI analysis has indicated significant greater fMRI signal reduction to calibrated pain stimuli in pain sensory associated brain regions comparing verum acupuncture and placebo acupuncture.
To explore the potential response predictors of acupuncture treatment, Linde and colleagues (Linde et al., 2007
) combined data from four acupuncture RCTs on chronic pain ailments, including migraine, tension-type headache, chronic low back pain, and knee osteoarthritis. They found that positive expectation and attitude towards acupuncture treatment could predict positive outcomes independent of whether or not treatments were real or sham. Consistent with this finding, we found that expectation can significantly modulate the analgesia effect of electroacupuncture stimulation to calibrated noxious stimuli in healthy subjects. In a previous study, Benedetti (Benedetti et al., 1999
) and colleagues investigated expectation of analgesia on four different parts of the body and the role of endogenous opioids in the process. They found analgesia to only occur on the regions of the body where subjects were told a powerful local anesthetic was applied (placebo cream in actuality), but not on the other untreated regions of the body. Interestingly, Benedetti et al. also found that local placebo analgesia effect could be completely blocked by an intravenous infusion of the opioid antagonist naloxone, indicating that placebo-activated opioids can selectively act on the part of the body where expectancy is directed. Consistent with this finding, our study showed that acupuncture analgesia to be selectively elicited from one area of the forearm (HE side) but not the adjacent area (Control side), demonstrating the power of expectancy to modulate the spatial specificity of acupuncture efficacy.
The primary aim of our experiment, as addressed in this manuscript, was to investigate the modulatory effect of expectancy on electroacupuncture treatment. We explicitly manipulated subjects’ expectation of acupuncture effect, either enhancing it (VH) or diminishing it (VL). Thus, the lack of analgesia effect in the VL group by no means implies that acupuncture does not work, but rather indicates the importance of expectation in the treatment process. In fact, we believe this finding is consistent with the essence of Traditional Chinese Medicine (Liu, 2008
). For instance, the oldest canonical classic of Chinese medicine, the Yellow Emperor’s Inner Classic
(Huang Di Nei Jing
) written in the first century BCE, 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). We believe this sentence is emphasizing the power of mind in acupuncture treatment, and as such, our study provides experimental evidence of this Traditional Chinese Medicine tenet.
It worth pointing out the expectancy modulation effect is not unique to acupuncture. In a previous study, Volkow and colleagues (Volkow et al., 2003
) investigated how expectation influenced response to the stimulant drug methylphenidate in 25 cocaine abusers. They found 50% larger increases in metabolism when methylphenidate was expected as opposed to when it was not. These differences were significant in cerebellum (vermis) and thalamus.
Methylphenidate-induced increases in self-reports of “high” were also approximately 50% greater when subjects expected the drug as opposed to when they did not. This result demonstrates expectancy’s amplifying and reinforcing effects of methylphenidate in brain. In a subsequent manuscript (Volkow et al., 2006
) performed in a healthy, non drug abusing cohort, a similar but milder amplified effect of expectation was also observed. The authors further suggest that state of expectation should be considered as a variable when evaluating drug effects. In our study, the pre- and post-treatment fMRI signal change comparison in meridian and non-meridian sides across the two groups showed the greatest fMRI signal decrease during administration of calibrated pain stimuli to the HE side of VH group. These decreases occurred in pain sensory encoding regions included in our a priori
mask including left insula, dorsal ACC, S1/M1, paracentral lobule, superior temporal gyrus, lentiform nucleus, and right cerebellum. In addition, a significant reduction of subjective pain sensation (pre- minus post-) in this group was observed when compared with the Control side. In the VL group, the pre- and post-treatment difference was found in the brain regions involved in affective and cognitive components/modulation of pain, such as rACC, MPFC and DLPFC (Kong et al., 2007c
). For both groups, we deliberately made subjects believe that acupuncture would not produce analgesia on the Control side, and thus assume this negative expectation somehow blunted the acupuncture analgesia effect. The activity in brain regions including rACC, MPFC and DLPFC observed in this group may be involved in this process.
In this study, behavioral analysis on subjective pain rating changes across four groups showed there is no significant difference on analgesia effect produced by verum acupuncture treatment and sham acupuncture treatment; this result is consistent with clinical studies that showed “placebo/sham acupuncture/minimal acupuncture” controls can produce similar therapeutic effects as verum (genuine) acupuncture (Brinkhaus et al., 2006
; Haake et al., 2007
; Kaptchuk, 2000
; Leibing et al., 2002
; Linde et al., 2005
; Melchart et al., 2005
). Nevertheless, fMRI analysis showed that, compared with placebo acupuncture, verum acupuncture produced more fMRI signal decrease to calibrated pain (e.g. verum acupuncture with high and low expectancy (pre-post) – placebo acupuncture with high and low expectancy (pre-post)) in brain regions including bilateral periaqueductal gray (PAG), thalamus, left insula/superior temporal gyrus/parahippocampus, pons/medulla oblongata, left superior prefrontal gyrus and inferior frontal cortex(45)/insula, right orbital prefrontal/gyrus ambiens and lentiform nucleus/insula. Most of these brain regions were within the mask of high pain minus low pain, indicating that this modulation occurred in the same brain regions that subserve pain sensory intensity encoding. This specific brain response reduction is consistent with the interpretation that acupuncture treatment suppresses pain perception by a more peripheral site of action involving inhibition of ascending nociceptive information (Han, 2003
; Melzack, 1989
; Pomeranz, 1997
; Zhang et al., 2003a
; Zhang et al., 2003b
). This result is also consistent with a previous paper based on analysis of data from this experiment (Kong et al., 2009
) comparing the verum acupuncture high expectancy group to the sham acupuncture high expectancy group, where we reported that although magnitudes of subjective acupuncture analgesia and placebo analgesia were similar, fMRI analysis showed that verum, but not sham, 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.
Recently, investigators have begun to apply neuroimaging methods to obtain sensitive, quantitative, objective biomarkers in pharmacological studies testing new analgesic agents (Chizh et al., 2008
; Schweinhardt et al., 2006
). Thus we believe that rather than conclude that acupuncture is virtually ineffective in this experimental setting as indicated by subjective pain sensory ratings, we believe that the fMRI signal decrease in pain sensory intensity associated brain regions shown above actually indicates the inhibition of noxious information after verum acupuncture treatment.
One natural question to be asked is why we did not observe differences in reported pain ratings between verum and placebo acupuncture treatments, if verum acupuncture is supposed to inhibit incoming noxious stimulation information compared with sham acupuncture treatment. 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 it is not uncommon for studies to show a discrepancy between objective and subjective improvements from placebo treatments (de Jong et al., 1996
; Feather et al., 1972
; Kelley et al., 2009
; Nickel, 1998
; van Leeuwen et al., 2006
). For instance, Fregni and colleagues (Fregni et al., 2006
) investigated the acute effect of levodopa, placebo pill or sham transcranial magnetic stimulation on patients with Parkinson’s disease on three different occasions. They found that on objective outcomes, only the levodopa group improved, but on subjective outcomes, patients in the two different controls reported improvement equal to the levodopa.
In this study, we also found a brain network involved in expectancy, which includes bilateral MPFC/rostral ACC, precentral gyrus and MPFC/paracentral lobule, left M1/S1, posterior insula/operculum, lentiform nucleus, and superior frontal gyrus and right amygdala. This result is partly consistent with previous placebo analgesia studies (Bingel et al., 2006
; Kong et al., 2006a
; Petrovic et al., 2002
; Price et al., 2007
; Wager et al., 2004
; Zubieta et al., 2005
). Particularly, the involvement of rACC/MPFC in this process (more accurately, it is located at pACC) duplicated previous findings from our own group (Kong et al., 2006a
) and others (Petrovic et al., 2002
; Zubieta et al., 2005
). It is known that pACC is linked to arousal caused by emotion/motivational process (Critchley, 2004
), closely associated with the lateral and accessory basal nuclei of the amygdala, and is engaged in positively valenced events, predominantly activated during experiences of happiness (Vogt, 2005
), and pain stimuli-induced anxiety modulation (Kalisch et al., 2005
In a recent study, Sharot and colleagues (Sharot et al., 2007
) investigated the neural mechanisms underlying a bias toward optimism. When imagining positive future events relative to negative ones, they found a specific relationship between an optimism bias and enhanced activation in the amygdala and rostral ACC. They further suggest that brain regions such as the amygdala and rostral ACC can track the subjective salience of stimuli, assess emotional, motivational and autobiographical information, and then regulate incoming signals accordingly. In this study, in addition to the rACC, we also did find involvement of the right amygdala. To further test the correlation between rACC and amygdala activity, we extracted rACC and amygdala peak voxel beta values and performed a correlation analysis. Consistent with a previous study (Sharot et al., 2007
), we found a positive correlation between the two regions (p
=0.003, r = 0.42). Our results support the view that expectancy regarding pain may exert its effects through top-down modulation of emotional responses (Kong et al., 2006a
In summary, analysis on two verum acupuncture treatment with different expectancy levels showed that expectancy can significantly modulate the analgesia effect evoked by acupuncture treatment. Positive expectation can enhance acupuncture analgesia effects as evidenced by both decreased subjective pain ratings as well as objective fMRI signal changes during application of calibrated noxious stimuli. In an analogous fashion, minimizing positive expectation may be able to diminish acupuncture analgesia effect. Expectancy not only modulates the magnitude of acupuncture analgesia, but also its spatial specificity, inducing analgesia exclusively in regions of the body where expectation is focused. In addition, we observed dissociation between subjective reported analgesia and objective fMRI signal changes to calibrated pain on the analysis across four groups. 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. We believe this is the first brain imaging study to elucidate the brain mechanisms underlying the ability of positive expectation to influence the therapeutic effects of verum acupuncture treatment. Future studies testing this hypothesis in patient populations may significantly enhance our understanding of acupuncture. We believe our study holds importance for future clinical and mechanistic studies of alternative medicine beyond acupuncture.