Neural Correlates of Placebo Analgesia and Emotion Regulation: A Coordinate-Based Neuroimaging Meta-Analysis

Abstract

Background: Placebo analgesia and emotion regulation engage overlapping cognitive and affective mechanisms, yet the extent of shared versus distinct neural circuits remains unclear. This study aimed to: (i) identify brain regions consistently activated during placebo response and emotion regulation, (ii) quantify neural overlap between these processes, and (iii) characterize top-down versus bottom-up network engagement through contrast analyses.

Method: A coordinate-based meta-analysis was performed using Activation Likelihood Estimation (ALE) across published fMRI studies of placebo analgesia and emotion regulation in healthy adults. Conjunction analyses identified shared neural substrates, while contrast analyses isolated process-specific regions reflecting top-down (emotion regulation) versus bottom-up (placebo) mechanisms. Literature was systematically searched using the NeuroSynth Compose tool, applying stringent inclusion/exclusion criteria: only studies with healthy adults (≥18 years), fMRI-based paradigms, sample size ≥15, and direct investigation of placebo analgesia or emotion regulation were included. Data extraction followed a uniform template to ensure consistency. ALE maps of local maxima were generated, and subsequent conjunction and subtraction analyses were conducted to delineate overlapping and distinct activation patterns.

Results: Conjunction analysis revealed bilateral insula activation as a shared hub integrating interoceptive awareness and cognitive appraisal. Contrast analyses demonstrated that emotion regulation preferentially engaged the middle temporal gyrus, hippocampus/amygdala complex, inferior frontal gyrus, and supplementary motor area (SMA), reflecting top-down control, semantic processing, and emotion modulation. In contrast, placebo analgesia elicited stronger activation in the mid-cingulate cortex, Rolandic operculum, basal ganglia, and bilateral insula, consistent with bottom-up expectancy, sensory integration, interoceptive processing, and reward-related learning.

Conclusions: These findings support a dual-process model wherein both placebo response and emotion regulation share salience and interoceptive processing via the insula, but differ in their engagement of top-down versus bottom-up networks. This work advances our understanding of the neural architecture underlying internally generated versus expectancy-driven affective modulation and informs the development of non-pharmacological interventions for pain and emotion regulation.