Do we really understand the role of the prefrontal cortex in placebo analgesia?

Several reviews have strongly implicated prefrontal cortical engagement in expectation-based placebo analgesia. We recently found a robust placebo analgesic response and associated decreases in pain-related cortical activations, without observable prefrontal engagement. We hypothesized our substantial conditioning and weak verbal instructions diminished expectation-related prefrontal activation. To test this, we examined the same subjects during a conditioning procedure, in which expectancy of pain relief was high. In two conditioning sessions, noxious heat was applied to a leg region treated with an “analgesic” cream and another treated with a “moisturizing” cream. In reality, both creams were inert, but the temperature applied to the moisturizing-cream area was 2°C higher than that applied to the analgesic-cream area. Functional MRI was acquired during the second conditioning session. Pain ratings were lower for the low heat than the high heat, with corresponding reduced activations in pain-related regions. Similar to previous studies with strong expectation for pain relief, we observed more prefrontal activations during the “analgesic” than the control condition. Nevertheless, contrary to the idea of active prefrontal engagement, the relative activation was based on differences in negative BOLD signals. A literature review revealed that only a few studies conclusively showed active engagement of prefrontal cortex, i.e. increased positive BOLD signal during high expectation compared to a control, with variable timing and spatial-specificity. We suggest that this variability is due to the heterogeneous influence of cognitive, emotional and motivational factors. Future studies should attempt to unravel the multiple contributions to placebo responsiveness in the prefrontal cortex. ### Competing Interest Statement The authors have declared no competing interest.