Figure 2. Brain mechanisms of placebo analgesia and relationship with salience, interoception, and nociceptive processing.

Placebo analgesia is associated with variations in brain responses to noxious stimuli that can be visualized in humans using FMRI or PET imaging. Left: The regions that are most commonly activated by painful stimuli include the anterior cingulate cortex (ACC), insula, primary and secondary somatosensory cortex (S1 and S2), and thalamus. Each of these are targeted by afferent nociceptive pathways and contain nociceptive neurons. FMRI studies that compare responses to placebo administration with a control treatment (i.e. no expected pain relief) indicate that pain-related responses in the ACC, thalamus, and anterior insula are reduced with placebo (blue), whereas placebos elicit increases in activation in modulatory regions (gold) including the dorsolateral prefrontal cortex, rostral ACC, and the opioid-rich periaqueductal gray. Upper middle: Meta-analysis of studies of placebo analgesia indicate reliable reductions in the dorsal ACC, anterior insula, and thalamus [75]. Lower middle: Despite placebo-induced reductions in pain-evoked responses in a subset of pain-related regions, placebos do not elicit reliable modulation of the Neurologic Pain Signature [30,92], which is a brain-based pattern that can reliably distinguish responses to painful and non-painful stimuli and is sensitive and specific to pain. This suggests that placebos might modulate non-specific affective and cognitive processes rather than affecting nociception. Right: Studies of placebo analgesia and other forms of pain modulation must carefully distinguish pain from salience processing (upper right) and interoception (lower right) since pain is highly salient and requires interoception, and the brain networks that process pain overlap substantially with the salience network and interoceptive processing. Maps depict term-based meta-analyses from Neurosynth [98] (red and yellow = association tests, green and purple = uniformity tests). Images of placebo-induced reductions (upper middle) were adapted with permissions from [75] and images of the Neurologic Pain Signature (lower middle) were adapted with permissions from [30].