A recent fMRI study investigated the effects of expectations of placebo analgesia in a thermal pain model (Wager et al., 2004b
). It used a single-trial design to separate activity induced by placebo treatment in anticipation of pain from subsequent changes in pain processing. In addition, the investigators defined pain-responsive regions of interest in the group of participants and looked for evidence of decreased pain response in these regions with the placebo. Comparing results across two separate studies in different pain modalities provided convergent evidence for the reliability of findings. Evidence for prefrontal cortex increases during expectation of pain would suggest that placebo expectancies are active neurobiological processes that involve the frontal lobes. Evidence for decreases during pain would suggest that placebo treatment alters nociceptive sensory and/or affective processing, not just retrospective judgments about pain (Kienle and Kiene, 1997; Hrobjartsson and Gotzsche, 2001, 2004).
Placebo treatment decreased both reported pain and pain-evoked activity in the brain. There was a 22% reduction in reported pain (p 70% of participants showing placebo-induced reductions. Although placebo effects were significant in both experiments in this study, these particularly large effects were induced in experiment 2 using an expectancy manipulation procedure to enhance belief in the placebo (Price et al., 1999). Placebo also diminished the brain responses in a subset of pain-responsive regions, including the anterior insula and thalamus (contralateral to stimulation) and the anterior cingulate cortex. Furthermore, the greatest placebo effects in pain response were found late in stimulation. These late effects suggest that a substantial portion of the placebo response may reflect a modulation of limbic and paralimbic regions that are involved in the appraisal of pain. Activity in the anterior cingulate and, in particular, the anterior insula is associated with the subjective experience of pain (Craig et al., 2000) and other aversive emotional states (Wager et al., 2003; Singer et al., 2004; Wager and Feldman Barrett, 2004). Paradoxically, placebo-induced increases in activity were found in secondary somatosensory cortex. Clearly, future studies must disentangle the roles of each region of the "pain matrix" in pain processing, and interventions such as the ones described in this symposium can provide leverage points for characterizing the function of the system.
Because placebo-induced expectancies are formed and maintained in anticipation of pain, fMRI signal in the prefrontal cortex during pain anticipation might reflect the generation and maintenance of placebo-related expectancies. It was hypothesized that placebo treatment would induce increases in DLPFC (BA 9 and 46) and ventrolateral prefrontal cortex (VLPFC) (BA 45 and 47) because of their roles in generating and maintaining cognitive expectancies that guide memory retrieval and attention. Activity in these regions is also thought to play a key role in shaping perceptual processing in posterior brain regions (Posner, 1980; Allport, 1989; Desimone and Duncan, 1995; Handy et al., 2001). During the anticipation of pain, placebo increased activity in DLPFC, orbitofrontal cortex (OFC) (BA 11), and rostral dorsal anterior cingulate cortex (BA 24). Lateral and medial frontal increases with placebo continued through the pain period (results for experiment 2 shown in Fig. 5). These results indicated that placebo treatment engaged active prefrontal processing mechanisms, and their colocalization with activations from studies of working memory and cognitive control suggest that these regions may play a general role in representing expectancies and other elements of situational context across both cognitive and affective domains.
The gate control theory posits and much subsequent work on central regulation of pain has shown that the periaqueductal gray (PAG) exerts central control over spinal pain pathways (Melzack and Wall, 1965; Fields, 2004). The PAG receives projections from insula, anterior cingulate, nucleus accumbens, amygdala, and frontal cortex (Bragin et al., 1984; Ma and Han, 1991; Rizvi et al., 1992). Micro-stimulation of ventrolateral OFC in rats transiently attenuates nociceptive reflex responses, and this effect is blocked by lesion of the PAG (Zhang et al., 1997, 1998). Consistent with the notion that descending control is a mechanism of placebo analgesia, placebo treatment by Wager et al. (2004) induced activity in PAG during anticipation of pain. Surprisingly, the strongest increases were linked in time to the onset of the warning cue signaling upcoming pain. In addition, these increases were positively correlated with increases in OFC and DLPFC (Fig. 5), suggesting that opioid systems are engaged by positive expectations of analgesia.
However, this interpretation must be viewed cautiously. PAG neurons project upwards to the telencephalon as well as downwards to the spinal cord, and it may well be that PAG modulates the central representation of pain through the activation of opioid release in cortical and limbic regions (Zubieta et al., 2005a). Another issue is the timing of PAG activity, which was found during expectation but not during pain. One explanation may be that both placebo and pain itself may increase PAG activity. During pain, placebo-induced increases in PAG may be offset by decreases attributable to reduced pain processing. This issue highlights the potential fruitfulness of separating brain measures of expectation and experience in disentangling the functions of interlocking feedback circuits in the brain.
As reviewed above, there is ample evidence that expectancy-based placebo effects are mediated by endogenous opioids. Future studies may clarify the role of opioids in descending control versus modulation of affective elements of pain. The functions of descending and ascending opioid projections may be closely coupled; indeed, given the recurrent connectivity that is a hallmark of brain circuitry, it would be surprising if they were not. However, they may be functionally separable; the issue at stake is the level of the CNS at which nociceptive signals are modulated by placebo.
This review focuses on the effects of expectation, which may be directly linked to opioid activity that relieves pain. Positive expectations may also induce changes in several other systems that could impact pain: they could increase positive emotions and activate incentive motivational ("reward") systems, as suggested by the recent results of Zubieta et al. discussed above, or they could decrease anxiety. Little is known yet about the scope of psychological and neural systems that may be affected by placebo. However, the fMRI studies of Wager et al. (2004b) provide a hint that placebo treatment for pain may act by reducing anxiety: placebo-induced decreases in anticipatory responses were found in the amygdala and temporal poles, both of which have been associated with aversive expectancies (Phelps et al., 2001; Wager et al., 2003; Ochsner et al., 2004; Petrovic et al., 2005). Indeed, a recent study examining placebo-induced anxiolytic effects shares several key regions in common with Wager et al. (2004b), including rostral anterior cingulate cortex and OFC (Petrovic et al., 2005) (see Fig. 8). Changes in both anxiety and incentive motivational systems have widespread consequences for the organism, and more research is needed to understand the effects beliefs and expectations exert on brain function and the mechanisms by which they do so.
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