A neural mechanism of direct and observational conditioning for placebo and nocebo responses

Abstract

Classical theories suggest placebo analgesia and nocebo hyperalgesia are based on expectation and conditioned experience. Whereas the neural mechanism of how expectation modulates placebo and nocebo effects during pain anticipation have been extensively studied, little is known about how experience may change brain networks to produce placebo and nocebo responses. We investigated the neural pathways of direct and observational conditioning for conscious and nonconscious conditioned placebo/nocebo effects using magnetoencephalography and a face visual cue conditioning model. We found that both direct and observational conditioning produced conscious conditioned placebo and nocebo effects and a nonconscious conditioned nocebo effect. Alpha band brain connectivity changes before and after conditioning could predict the magnitude of conditioned placebo and nocebo effects. Particularly, the connectivity between the rostral anterior cingulate cortex and middle temporal gyrus was an important indicator for the manipulation of placebo and nocebo effects. Our study suggests that conditioning can mediate our pain experience by encoding experience and modulating brain networks.

Keywords: Alpha band connectivity; Conditioning; Consciousness; Learning; Placebo; Rostral anterior cingulate cortex.

Figure 1.. Experimental design.

(A) In the conditioning phase, direct cues (faces with neutral expressions) were accompanied by heat pain stimulation of high or low intensity; observational cues (different faces with neutral expressions) were accompanied by observing a model experiencing high (top row, red) or low (bottom row, blue) pain, showing both the physical reaction and subjective pain ratings of the model. Each subject participated in both direct and observational conditioning. The sequences for direct and observational conditioning are shown in (B). We have de-identified the observational model in the paper. (C) Stimuli presentation during test phase. One of five cues (four learned from conditioning and one novel, control cue) would appear either supraliminally (500 ms) or subliminally (33 ms + 467 ms mask). Identical moderate pain (~2 s) followed all cues. Subjects were instructed to rate each stimulus on a 0–10 VAS.

Figure 2.. Behavioral scores for the test phase.

(A) Pain ratings after direct and observational conditioned cues, separated by awareness (conscious vs. nonconscious). Three-way repeated measures ANOVA (cue, awareness, and conditioning type) showed a significant main effect of cue (high, neutral, and low) and in the interaction between awareness and cue. (B) Magnitudes of direct and observational conditioned placebo and nocebo responses. Significant directly and observationally conditioned conscious placebo and nocebo effects were found, as well as directly conditioned nonconscious nocebo effects. Three-way repeated measures ANOVA (modulation mode, awareness, and conditioning type) revealed a significant main effect in modulation mode and awareness. * p < 0.05, ** p < 0.01 and *** p < 0.001.

Figure 3.. Brain connectivity significantly changed after conditioning.

Brain activity in cortical space was bandpass filtered into four different frequency bands and brain connectivity was constructed between each pair of sources. Significantly increased (red lines) and decreased (blue lines) brain connectivities after conditioning were retained as features for regression analyses. Node importance denotes the number of connections from the node to other nodes.

Figure 4.. Changes in alpha band connectivity predicted conscious conditioned placebo and nocebo effects.

The upper panel of A-D shows the identified changes of brain connectivity that were predictive for direct and observational placebo/nocebo effects. The lower panel of each sub-figure summarizes prediction performance using prediction outcome correlation (left) and mean absolute error (right).

Figure 5.. Relationships between changes in left rACC-MTG connectivity and magnitudes of placebo/nocebo effects.

Stronger direct and observational placebo/nocebo effects were associated with decreased rACC-MTG connectivity.

Figure 6.. Alpha band connectivity predicted magnitudes of directly conditioned nonconscious nocebo effect.

Changes in alpha band brain connectivity between left rACC and left cuneus, left superior frontal lobe and right precuneus, left paracentral lobe and right pars triangularis of IFG, right pars opercularis of IFG and right isthmus of cingulate cortex, and left medial OFC and right posterior cingulate cortex (PCC) predicted nonconscious nocebo effects.