Activation likelihood estimation meta‐analysis of brain correlates of placebo analgesia in human experimental pain

Abstract

Placebo analgesia (PA) is one of the most studied placebo effects. Brain imaging studies pub lished over the last decade, using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), suggest that multiple brain regions may play a pivotal role in this process. However, there continues to be much debate as to which areas consistently contribute to placebo analgesia-related networks. In the present study, we used activation likelihood estimation (ALE) meta-analysis, a state-of-the-art approach, to search for the cortical areas involved in PA in human experimental pain models. Nine fMRI studies and two PET studies investigating cerebral hemodynamic changes were included in the analysis. During expectation of analgesia, activated foci were found in the left an terior cingulate, right precentral, and lateral prefrontal cortex and in the left periaqueductal gray (PAG). During noxious stimulation, placebo-related activations were detected in the anterior cingulate and medial and lateral prefrontal cortices, in the left inferior parietal lobule and postcentral gyrus, an terior insula, thalamus, hypothalamus, PAG, and pons; deactivations were found in the left mid-and posterior cingulate cortex, superior temporal and precentral gyri, in the left anterior and right posterior insula, in the claustrum and putamen, and in the right thalamus and caudate body. Our results sug gest on one hand that the modulatory cortical networks involved in PA largely overlap those involved in the regulation of emotional processes, on the other that brain nociceptive networks are downregulated in parallel with behavioral analgesia.

Placebo improves pleasure and pain through opposite modulation of sensory processing

“…Nevertheless, there were no significant differences between analgesia and hyperhedonia within emotion appraisal circuitry. Moreover, the observation that placebo-induced vmPFC-PAG coupling correlated with reduction in sensory processing during pain supports a role of the PAG in the current study consistent with previous investigations of placebo analgesia (15,16).…”

“…A well-known feature of placebo treatment is individual variability in the magnitude of the placebo response. These behavioral differences are known to reflect differences in central placebo processing (15,23). We identified covariance with the behavioral placebo response within emotion appraisal circuitry by adding a regressor with each subject's average placebo improvement (placebo > control) for each stimulus type to the fMRI group analysis setup (placebo > control) for each stimulus.…”

“…Placebo analgesia is characterized by decreases in the thalamus, posterior insula (pINS), and primary and secondary somatosensory areas (SI and SII) (15)(16)(17). Placebo reduction of affective responses to unpleasant visual stimuli is similarly underpinned by suppression of visual processing (8).…”

“…Activity in these regions predicts individual placebo analgesia more accurately than regions involved in cognitive control or pain processing (21). This network is dependent on endogenous opioids (16,19,22) and interacts with the mesolimbic dopamine system (23)(24)(25) to reduce pain by inhibiting nociceptive signaling (15). Because these regions collectively are involved in valuation and reward-related processing more generally (26,27), and for reasons of clarity and brevity, we will refer to this set of regions as "emotion appraisal circuitry.…”

Acupuncture-Related Modulation of Pain-Associated Brain Networks During Electrical Pain Stimulation: A Functional Magnetic Resonance Imaging Study

“…[15][16][17] The prefrontal cortex (PFC) is considered to play a role in cognitive distraction or mechanisms of expectation and anticipation of a painful stimulus. 18,19 Functional measurements of pain in a cortical pattern include all these areas.…”