Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception

Abstract

The neural mechanisms whereby placebo conditioning leads to placebo analgesia remain unclear. In this study we aimed to identify the brain structures activated during placebo conditioning and subsequent placebo analgesia. We induced placebo analgesia by associating a sham treatment with pain reduction and used fMRI to measure brain activity associated with three stages of the placebo response: before, during and after the sham treatment, while participants anticipated and experienced brief laser pain. In the control session participants were explicitly told that the treatment was inactive. The sham treatment group reported a significant reduction in pain rating (p=0.012). Anticipatory brain activity was modulated during placebo conditioning in a fronto-cingulate network involving the left dorsolateral prefrontal cortex (DLPFC), medial frontal cortex and the anterior mid-cingulate cortex (aMCC). Identical areas were modulated during anticipation in the placebo analgesia phase with the addition of the orbitofrontal cortex (OFC). However, during altered pain experience only aMCC, post-central gyrus and posterior cingulate demonstrated altered activity. The common frontal cortical areas modulated during anticipation in both the placebo conditioning and placebo analgesia phases have previously been implicated in placebo analgesia. Our results suggest that the main effect of placebo arises from the reduction of anticipation of pain during placebo conditioning that is subsequently maintained during placebo analgesia.

Fig. 1

Schematic of study design: each of the two scanning sessions consisted of three scans (preconditioning, conditioning, and post-conditioning). Each scan consisted of 15 trials. The laser stimulus was delivered to the right arm, and to rate the pain participants moved a cursor along a projected 0–10 scale.

Fig. 2

Mean and standard deviation of pain ratings (0–10 pain scale) during the placebo and control sessions. The same laser energy was applied in the pre-conditioning and post-conditioning blocks in both sessions, set at each individual’s moderately painful level. Mean rating during the placebo session: pre-conditioning 4.82 (0.77), conditioning 2.09 (0.69), post-conditioning 3.77 (1.29), and during the control session: preconditioning 4.68 (0.76), conditioning 2.19 (0.70), post-conditioning 4.26 (1.03).

Fig. 3

(A and B) Sites of increased activation in brain regions that correlate with the intensity of pain stimulation, contrast between the painful (pre-conditioning scan) and non-painful (control conditioning scan) laser stimuli during the control session (Z > 1.8 p = 0.05 corrected for multiple comparisons). Significant activations were seen in areas of the “pain matrix” including; bilateral cerebellum, bilateral insula, left post-central gyrus, brainstem and ACC. (C and D) Sites of increased brain activation during placebo analgesia co-varied with measures of reported pain relief. The magnitude of reduction between control and sham treatment sessions co-varied with the magnitude of reduction in neural activity (control minus sham treatment scans for the post-conditioning blocks during painful stimulation). These structures included the following areas within the “pain matrix”; the left aMCC and PCC and left post-central gyrus (Z > 1.9 p = 0.05 corrected for multiple comparisons).

Fig. 4

Significant activations for the subtraction contrast post-conditioning scan minus the preconditioning scan during the anticipation phase of the sham treatment session compared to the same in the control session [e.g., sham treatment (post-conditioning–preconditioning) minus control (post-conditioning–preconditioning)]. The map was cluster-based thresholded at Z > 1.9, p = 0.05 (corrected for multiple comparisons) and the images are shown in axial and sagittal orientations and radiological convention (right side of the brain on the left side of the picture).

Fig. 5

Common brain areas activated during pain anticipation in both the placebo conditioning (Table 1a) and post-conditioning (Table 1b) stages compared to the pre-treatment stage. DLPFC (left dorsolateral prefrontal cortex) (mni −22, 52, 18, BA 9), left BA 8, mni −6, 44, 34 and left aMCC mni −6, 32, 24. The images are shown in axial and sagittal orientations and radiological convention (right side of the brain on the left side of the picture).