The multifaceted neural architecture of pain modulation by emotion and cognition: a systematic review and...

This study aimed to systematically review functional neuroimaging literature on the neural substrates underlying contextual modulation of pain in healthy individuals.

A search was conducted in PubMed-Medline, Cochrane, and Web-of-Science databases (PROSPERO-CRD42024586392). Studies on chronic pain were excluded, and the risk of bias was assessed with Cochrane RoB2. Spatial coordinates of brain regions undergoing activity changes were included in a meta-analysis using both Activation Likelihood Estimation and frequency estimation of activated or deactivated regions in individual studies (convergence analysis).

From 224 full texts reviewed and n=100 articles retained (2735 individuals), three broad activity patterns were identified. One involved activation of prefrontal cortical areas, together with a modification of the sensory message in nociceptive cortical areas (deactivated during hypoalgesia and hyperactivated in hyperalgesia), consistent with top-down regulation via descending controls. A second configuration also involved prefrontal mobilisation, but without activity changes in nociceptive areas and was consistent with a 'perceptual decision bias'. A third configuration was associated with irregular ventromedial prefrontal involvement and significant deactivation in dorsolateral and ventrolateral prefrontal areas. While the first two patterns were observed in a range of attentional or expectation manipulations, including placebo/nocebo, the third pattern was essentially observed during tasks involving introspection and self-referential procedures such as meditation, religious prayer or nostalgia.

Similar subjective pain changes can coexist with different brain activation patterns, reflecting diverse neural strategies. Whereas prefrontal cortex-driven descending modulation is one mechanism, introspective approaches can alter perception without involving prefrontal activity. This mechanistic diversity supports multiple avenues for behavioural or neuromodulation-based pain control.