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 published 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 anterior 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, anterior 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 suggest 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.

Figure 1

Placebo treatment can target each of the three stages described in the figure and the final outcome of pain. The treatment is considered as a function of time. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Illustration

Graph 1: Trial flow: Selection of study reports (see Appendix I for more details).

Figure 2

Areas of increased activity associated with placebo analgesia in the expectation stage 1 and during noxious stimulation stage 2. Areas of decreased activity associated with placebo analgesia in stage 2 are also shown. ALE maps were computed using GingerALE 2.0.4 at an FDR‐corrected threshold of P < 0.05, with a minimum cluster size of K > 50 mm³ and visualized using MRIcron. They were projected onto a 3D rendering model of the brain.

Figure 3

Areas of increased activity associated with placebo analgesia in the expectation stage 1. ALE maps were computed using GingerALE 2.0.4 at an FDR‐corrected threshold of P < 0.05, with a minimum cluster size of K > 50 mm³ and visualized using MRIcron.

Figure 4

Areas of increased activity associated with placebo analgesia during noxious stimulation stage 2. ALE maps were computed using GingerALE 2.0.4 at an FDR‐corrected threshold of P < 0.05, with a minimum cluster size of K > 50 mm³ and visualized using MRIcron.

Figure 5

Areas of decreased activity associated with placebo analgesia during noxious stimulation stage 2. ALE maps were computed using GingerALE 2.0.4 at an FDR‐corrected threshold of P < 0.05, with a minimum cluster size of K > 50 mm³ and visualized using MRIcron.

Figure 6

Reliability of increased activity associated with placebo analgesia in stage 1 (A) and in stage 2 (B). In (C), reliability of decreased activity associated with placebo analgesia in stage 2. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]