Placebo Analgesia Enhances Descending Pain-Related Effective Connectivity: A dynamic causal modeling study of endogenous pain modulation.

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Placebo Analgesia Enhances Descending Pain-Related Effective Connectivity: A dynamic causal modeling study of endogenous pain modulation.

J Pain. 2015 May 25;

Authors: Sevel LS, Craggs JG, Price DD, Staud R, Robinson ME

Abstract
The use of placebo to reduce pain is well documented; however, knowledge of the neural mechanisms underlying placebo analgesia (PA) remains incomplete. This study used fMRI data from 30 healthy subjects, and dynamic causal modeling (DCM) to investigate changes in effective connectivity associated with the placebo analgesic response. Before scanning, subjects were conditioned to expect less thermal pain at 2-of-4 sites on their feet. VAS pain ratings revealed a significant but small difference between the baseline and placebo sites [mean difference = 6.63, t (29) = 3.91, p≤0.001, d =0.97], confirming an analgesic effect. However, no significant differences in magnitude of brain activation between conditions were observed via traditional random effects general linear modeling. DCM was then used to investigate changes in effective connectivity during PA. The results indicate that during the PA but not baseline condition, the couplings between brain regions including those involved in cognitive processes (e.g., attention, expectation, and evaluation) were significantly enhanced. Specifically, a significantly consistent decrease in the DLPFC→PAG coupling was found. These findings highlight the differences between pain processing and modulation at the network level. Moreover, our results suggest that small placebo effects may be better characterized via changes in the temporal dynamics among pain modulatory regions rather than only changes in the magnitude of BOLD activation. Further application of nuanced analytical approaches that are sensitive to temporal dynamics of pain-related processes such as DCM are necessary to better understand the neural mechanisms underlying pain processing in patient populations.
PERSPECTIVE: Changes in effective connectivity among pain-related brain regions may be more sensitive detectors of the neural representation of small placebo effects than changes in the magnitude of brain activation. Knowledge of these mechanisms highlights the importance of integrated neural networks in the understanding of pain modulation.

PMID: 26022539 [PubMed - as supplied by publisher]