A view of the results presented, particularly those in the field of pain and in the context of other recent studies on self-regulation, is that the areas engaged by placebo may be part of a general circuit underlying the voluntary regulation of affective responses. Figure 8 shows data from 15 recent studies of placebo, regulation of emotions, and activation by actual opiate drugs. The superposition of peak coordinates of increased activation in each of these conditions reveals a set of frontal regions that appear to be consistently increased during diverse tasks in which negative affect must be suppressed. On the lateral surface, these regions include the DLPFC, VLPFC, and possibly a third cluster of activations around the rostral PFC. On the medial surface, two clusters appear around the midrostral dorsal anterior cingulate and neighboring superior medial PFC. On the orbital surface, many peaks are grouped around the medial orbital sulcus bilaterally.
Each of these regions, except those in the OFC and right VLPFC, have been shown to increase activation with delivery of an opiate analgesic (Firestone et al., 1996
; Adler et al., 1997; Wagner et al., 2001; Petrovic et al., 2002). Both dorsal and ventral PFC have also been consistently activated in the voluntary positive reinterpretation of the meaning of aversive visual stimuli (Ochsner et al., 2002, 2004; Levesque et al., 2003; Phan et al., 2005) and correlated with reduced amygdala activation (Lieberman et al., 2005) and anxiety (Bishop et al., 2004). In a study of placebo regulation of affective responses to pictures, Petrovic et al. (2005) found placebo-induced activity in both DLPFC and VLPFC and the midrostral cingulate. Both increases in these areas and placebo-induced decreases in amygdala correlated with larger placebo effects in reported emotion. Rainville et al. (1997) found that the same region of cingulate was modulated by hypnosis in a pain context. Although these different varieties of self-regulation have not been tested in the same study, the colocalization of results suggests that there may be a general system for self-regulation that applies to both emotions and pain and to both voluntary strategies and the externally generated appraisals that produce placebo effects as well.
At the psychological level, much work remains to be done to disentangle the psychological mechanisms that may be driving these common activations and placebo effects. One hypothesis is that placebo effects are driven by executive attention: appraisals of safety may lead to increased use of self-distraction strategies. Dorsal and ventral PFC are activated by a large class of cognitively demanding conditions. Numerous studies of distraction from pain (for review, see Petrovic and Ingvar, 2002) also produce activation in these regions. Meta-analyses of working memory and executive attention have also revealed similar activation patterns (Wager and Smith, 2003; Wager et al., 2004a).
Another hypothesis is that placebo effects reduce anxiety, which in turn reduces pain (Vase et al., 2003). This explanation does not seem sufficient to account for the widespread activation in frontal systems found across studies. However, the finding of placebo-induced amygdala decreases suggests that the threat value of pain-predicting cues is decreased with placebo. A third alternative is that this network is subserving the process of meaning generation and appraisal of current and predicted events (Lazarus, 1991). Effective placebo treatment may engender and active reevaluation of the significance of pain, which engages OFC and lateral prefrontal systems in the generation and maintenance of short-term context that biases ongoing nociceptive and affective processing (Miller and Cohen, 2001). Clearly, a complete psychological explanation of placebo effects remains to be elucidated. However, as evidence from the neural and psychological levels is gathered and integrated, we are gaining a surer and more complete understanding of the human self-regulatory faculties with which evolution has equipped us for effective social, emotional, and physical health.
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