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Randomized Controlled Trial
. 2015 Nov 18;35(46):15307-25.
doi: 10.1523/JNEUROSCI.2542-15.2015.

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia

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Free PMC article
Randomized Controlled Trial

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia

Fadel Zeidan et al. J Neurosci. .
Free PMC article

Abstract

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p < 0.05). Mindfulness meditation reduced pain intensity (p = 0.032) and pain unpleasantness (p < 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation.

Significance statement: Recent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the "gold standard" for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy.

Keywords: arterial spin labeling; fMRI; mindfulness meditation; pain; placebo; psychophysics.

Figures

Figure 1.
Figure 1.
Study procedures across experimental sessions (ES) and groups. ES 1: After completing the FMI, psychophysical training (PT) was conducted. ES 2: After the anatomical scan, two “heat” (49°C) and two “neutral” (35°C) PCASL series were conducted. ES 3–6: Placebo group: noxious “heat” stimuli were first delivered to untreated skin (Series A). After administering/removing the placebo cream, we delivered another “heat” series to the treated skin region, but covertly and progressively reduced the temperature in Series B (i.e., ES-3 = 48°C; ES-4 and 5 = 47°C; ES-6 = 46.5°C). Mindfulness meditation group: subjects were taught mindfulness meditation skills. Sham mindfulness meditation group: subjects were instructed to “take a deep breath as we sit here in meditation.” Control group: subjects listened to an audiobook. We assessed perceived intervention effectiveness after each intervention session. ES 7: We first administered two “heat” and two “neutral” PCASL series. Before acquiring the anatomical MRI, we applied/removed the placebo cream to the placebo group, the mindfulness and sham mindfulness meditation groups were instructed to “begin meditating”, and the control group was instructed to keep their eyes closed. We then administered two “heat” and two “neutral” series. The FMI was administered after MRI Session B.
Figure 2.
Figure 2.
Psychophysical pain ratings (mean ± SEM) in MRI Session A. There were no significant differences among the mindfulness meditation (mindfulness), sham mindfulness meditation (sham), placebo, or book listening control (control) groups on pain intensity (left; p = 1.00) or pain unpleasantness (right; p = 0.96) ratings. A, VAS pain intensity ratings. B, VAS pain unpleasantness ratings.
Figure 3.
Figure 3.
Psychophysical pain ratings (mean ± SEM) in MRI Session B. Mindfulness meditation produced greater reductions in both pain intensity (left) and pain unpleasantness (right) compared with placebo. **Mindfulness meditation also was significantly (p < 0.05) more effective at reducing pain intensity (left) and pain unpleasantness (right) ratings than sham mindfulness meditation and control conditions. *All cognitive manipulations were significantly (p < 0.004) more effective at reducing pain intensity and unpleasantness ratings compared with the control group.
Figure 4.
Figure 4.
Brain activations and deactivations associated with the main effect of pain in each group in MRI Session B. Top, In all four groups, there was significant activation in the SI corresponding to the stimulation site, thalamus, cerebellum, midcingulate cortex, anterior/posterior insula, frontal operculum, SII, and SMA. Significant deactivations were detected in the mPFC, PCC/precuneous, and superior (S) frontal gyrus in all four groups. Bottom, Group comparisons revealed significantly greater activation in the left DLPFC in the placebo, sham mindfulness meditation, and control group compared with the mindfulness meditation group. Slice locations correspond to standard stereotaxic space.
Figure 5.
Figure 5.
Brain activations and deactivations associated with the main effect of mindfulness meditation and placebo. Compared with pre-manipulation, mindfulness meditation produced significant activation in the bilateral anterior insula cortices, putamen, inferior (I) frontal gyrus, SII, and SI corresponding to the nose and face. Mindfulness meditation was also associated with significant deactivation in the thalamus, PAG, mPFC, DLPFC, cerebellum and PCC/precuneous. Placebo was associated with deactivation in brain regions ranging from the midcingulate cortex to the ACC. Placebo produced significant activation in the left anterior insula compared with pre-manipulation. Compared with placebo, mindfulness meditation produced significantly greater activation in the ACC, bilateral anterior insula, right putamen, and SI of the nose and face. Compared with mindfulness meditation, placebo produced greater activation in the DLPFC, mPFC, thalamus, PAG, PCC/precuneous, and cerebellum. Conjunction analyses revealed significant overlapping activation between the main effect of mindfulness meditation and placebo at the border between the ventral insula and medial temporal lobe. Slice locations correspond to standard stereotaxic space.
Figure 6.
Figure 6.
Brain activations and deactivations associated with the main effect of mindfulness meditation and sham mindfulness meditation. Sham mindfulness meditation produced significant activation in the globus pallidus, putamen and right SI of the nose and significant deactivation of the subgenual ACC, PCC, cerebellum and mPFC compared with pre-manipulation. Compared with sham mindfulness meditation, mindfulness meditation produced greater activation in the right putamen/globus pallidus and the PCC. Compared with mindfulness meditation, sham mindfulness meditation was associated with greater activation in the DLPFC, thalamus, PAG, and cerebellum. Conjunction analyses revealed significant overlapping activation in the bilateral putamen and SI corresponding to the nose and deactivation in the mPFC, PCC/precuneous, and cerebellum. Slice locations correspond to standard stereotaxic space.
Figure 7.
Figure 7.
The relationship between group-manipulation-induced changes in pain ratings and brain activation during noxious stimulation. A, Top, Mindfulness meditation (meditation + heat) produced greater activation in the bilateral anterior insula, bilateral inferior (I) frontal gyrus, and the nose representation of the right SI and primary motor cortex (MI). Mindfulness meditation produced deactivation of the mPFC and PCC compared with pre-manipulation. Mindfulness-meditation-related decreases in pain intensity ratings were associated with greater activation in the bilateral OFC, subgenual ACC, right anterior insula, and putamen. Greater deactivation of the left inferior parietal lobe was associated with greater pain intensity reductions. Meditation-induced reductions in pain unpleasantness ratings were associated with greater activation in the left inferior frontal gyrus and frontal operculum. B, Bottom left, Placebo (placebo + heat) reduced pain-related activation in the bilateral frontal operculum, SII, posterior insula, and right inferior frontal gyrus. Placebo activated the ACC and DLPFC. Placebo-induced pain intensity reductions were associated with greater deactivation in the contralateral SII/parietal operculum. C, Bottom right, Sham mindfulness meditation (sham meditation + heat) produced deactivation of the ACC. Compared with pre-manipulation, there was greater sham mindfulness-meditation-related activation in the thalamus, SMA, right SI, and putamen.

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