Brain Network to Placebo and Nocebo Responses in Acute Experimental Lower Back Pain: A Multivariate Granger Causality Analysis of fMRI Data

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.

Keywords: GCA; anxiety; dopamine; nocebo hyperalgesia; opioid; placebo analgesia; reward system.

Figure 1

Acute lower back pain (ALBP) model location.

Figure 2

The experimental paradigm (Scanning Session) for the subjects.

Figure 3

Flow chart of functional magnetic resonance imaging (fMRI) data analysis.

Figure 4

Map of bivariate GCA brain in placebo vs. pain of GCA fit signed-path coefficients. AMYG, amygdala; THS, thalamus; AG, angular gyrus; TP, temporal pole; HP, hippocampus; DLPFC, dorsolateral prefrontal cortex; IC, insular cortex; S2, secondary somatosensory cortex area; SMA, supplementary motor area.

Figure 5

Map of bivariate GCA brain in nocebo relative to pain of GCA fit signed-path coefficients. THS, thalamus; TP, temporal pole; HP, hippocampus; DLPFC, dorsolateral prefrontal cortex; IC, insular cortex; SMA, supplementary motor area; CAU, caudate; S1, primary somatosensory cortex area.

Figure 6

Map of bivariate GCA brain in placebo relative to nocebo of GCA fit signed-path coefficients. VMPFC, ventromedial prefrontal cortex; PHP, parahippocampal gyrus; THS, thalamus; CAU, caudate; S1, primary somatosensory cortex area; SMA, supplementary motor area; IC, insular cortex; DLPFC, dorsolateral prefrontal cortex; PCC, posterior cingulate cortex.

Figure 7

Map illustrating brain of two status (placebo vs. Pain) of multivariate GCA signed-path coefficients. Some brain regions only showed projection position. Blue/red arrows designate remarkably greater repression/activation of ensuing target activity in placebo vs. pain. Black arrow designates the bidirectional adjustment process between brain areas. ACC, anterior cingulate cortex; AMYG, amygdala; THS, thalamus; AG, angular gyrus; TP, temporal pole; HP, hippocampus; DLPFC, dorsolateral prefrontal cortex; IC, insular cortex; S2, secondary somatosensory cortex area; SMA, supplementary motor area.

Figure 8

Map illustrating brain map of two-status (nocebo vs. pain) of multivariate GCA signed-path coefficients. Some brain regions only showed projection position. Blue/red arrows show remarkably greater repression/activation of ensuing target activity in nocebo vs. pain. The black arrow shows a bidirectional adjustment process between brain areas. ACC, anterior cingulate cortex; TP, temporal pole; THS, thalamus; CAU, caudate; DLPFC, dorsolateral prefrontal cortex; IC, insular cortex; HP, hippocampus; S1, primary somatosensory cortex area; SMA, supplementary motor area.

Figure 9

Map illustrating brain map of two-status (placebo vs. nocebo) of multivariate GCA signed-path coefficients. Some brain regions only showed projection position. Blue/red arrows show remarkably greater repression/activation of ensuing target activity in placebo vs. nocebo. The black arrow shows a bidirectional adjustment process between brain areas. ACC, anterior cingulate cortex; VMPFC, ventromedial prefrontal cortex; PHP, parahippocampal gyrus; THS, thalamus; CAU, caudate; S1, primary somatosensory cortex area; SMA, supplementary motor area; IC, insular cortex; DLPFC, dorsolateral prefrontal cortex; PCC, posterior cingulate cortex.