Abstract
Background and Objective: Placebo and nocebo responses are widely observed. Herein, we investigated the nocebo hyperalgesia and placebo analgesia responses in brain network in acute lower back pain (ALBP) model using multivariate Granger causality analysis (GCA). This approach analyses functional magnetic resonance imaging (fMRI) data for lagged-temporal correlation between different brain areas.Method: After completing the ALBP model, 20 healthy subjects were given two interventions, once during a placebo intervention and once during a nocebo intervention, pseudo-randomly ordered. fMRI scans were performed synchronously during each intervention, and visual analog scale (VAS) scores were collected at the end of each intervention. The fMRI data were then analyzed using multivariate GCA.Results: Our results found statistically significant differences in VAS scores from baseline (pain status) for both placebo and nocebo interventions, as well as between placebo and nocebo interventions. In placebo network, we found a negative lagged-temporal correlation between multiple brain areas, including the dorsolateral prefrontal cortex (DLPFC), secondary somatosensory cortex area, anterior cingulate cortex (ACC), and insular cortex (IC); and a positive lagged-temporal correlation between multiple brain areas, including IC, thalamus, ACC, as well as the supplementary motor area (SMA). In the nocebo network, we also found a positive lagged-temporal correlation between multiple brain areas, including the primary somatosensory cortex area, caudate, DLPFC and SMA.Conclusion: The results of this study suggest that both pain-related network and reward system are involved in placebo and nocebo responses. The placebo response mainly works by activating the reward system and inhibiting pain-related network, while the nocebo response is the opposite. Placebo network also involves the activation of opioid-mediated analgesia system (OMAS) and emotion pathway, while nocebo network involves the deactivation of emotional control. At the same time, through the construction of the GC network, we verified our hypothesis that nocebo and placebo networks share part of the same brain regions, but the two networks also have their own unique structural features.
Highlights
Placebo and nocebo phenomena are commonly reported (Drici et al, 1995; Colloca et al, 2013)
This assessment revealed that anterior cingulate cortex (ACC) activity predicts subsequently decreased activation in the angular gyrus (AG)
The entire brain to ACC Granger causality analysis (GCA) exhibited that activity in the temporal pole (TP), HP, insular cortex (IC), and supplementary motor area (SMA), TABLE 2 | Data of bivariate GCA of placebo vs. pain of brain GCA of fit signed-path coefficients
Summary
Placebo and nocebo phenomena are commonly reported (Drici et al, 1995; Colloca et al, 2013). Nocebo and placebo responses are defined as negative and positive behavioral, emotional, and cognitive modulation of outcomes (Colloca and Grillon, 2014) These phenomena occur frequently in research and clinical practice (Ernst, 2016). Brain imaging technology is widely used to study placebo analgesia and nocebo hyperalgesia (Atlas et al, 2012; Amanzio et al, 2013; Freeman et al, 2015; Wagner et al, 2020). We investigated the nocebo hyperalgesia and placebo analgesia responses in brain network in acute lower back pain (ALBP) model using multivariate Granger causality analysis (GCA). This approach analyses functional magnetic resonance imaging (fMRI) data for lagged-temporal correlation between different brain areas
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