Disentangling self from pain: mindfulness meditation-induced pain relief is driven by thalamic-default mode network decoupling

Abstract

For millenniums, mindfulness was believed to diminish pain by reducing the influence of self-appraisals of noxious sensations. Today, mindfulness meditation is a highly popular and effective pain therapy that is believed to engage multiple, nonplacebo-related mechanisms to attenuate pain. Recent evidence suggests that mindfulness meditation-induced pain relief is associated with the engagement of unique cortico-thalamo-cortical nociceptive filtering mechanisms. However, the functional neural connections supporting mindfulness meditation-based analgesia remain unknown. This mechanistically focused clinical trial combined functional magnetic resonance imaging with psychophysical pain testing (49°C stimulation and pain visual analogue scales) to identify the neural connectivity supporting the direct modulation of pain-related behavioral and neural responses by mindfulness meditation. We hypothesized that mindfulness meditation-based pain relief would be reflected by greater decoupling between brain mechanisms supporting appraisal (prefrontal) and nociceptive processing (thalamus). After baseline pain testing, 40 participants were randomized to a well-validated, 4-session mindfulness meditation or book-listening regimen. Functional magnetic resonance imaging and noxious heat (49°C; right calf) were combined during meditation to test study hypotheses. Mindfulness meditation significantly reduced behavioral and neural pain responses when compared to the controls. Preregistered (NCT03414138) whole-brain analyses revealed that mindfulness meditation-induced analgesia was moderated by greater thalamus-precuneus decoupling and ventromedial prefrontal deactivation, respectively, signifying a pain modulatory role across functionally distinct neural mechanisms supporting self-referential processing. Two separate preregistered seed-to-seed analyses found that mindfulness meditation-based pain relief was also associated with weaker contralateral thalamic connectivity with the prefrontal and primary somatosensory cortex, respectively. Thus, we propose that mindfulness meditation is associated with a novel self-referential nociceptive gating mechanism to reduce pain.

Figure 1:

Consolidated Standards of Reporting Trials (CONSORT) flow diagram: At screening, 79 participants were excluded for not meeting inclusion-exclusion criteria. Fifty-eight participants were enrolled into the study. After session 1, participants were dropped for low pain sensitivity (n=6), equipment not fitting (n=1), and chronic pain (n=1). After randomization, a subject from each group was dismissed for “no-shows”. In the MRI session, a total of four participants from the mindfulness group and 2 from the control group were dismissed for several reasons. Two participants completed their respective fMRI scans but were removed from the final analysis (and replaced at random) due to a procedural error and an exhibited fMRI related artifact, respectively. The targeted sample size of forty participants were included in the study.

Figure 2:

Study procedures: Session 1: After attaining informed consent, participants were trained to use pain intensity and unpleasantness visual analog scale (VAS) in response to noxious heat stimulation (psychophysical training). The experimental Heat series included ten, 10 second plateaus of 49°C interleaved with 14 seconds 35°C stimulation applied to the back of the right calf. Participants were instructed to keep their eyes closed and rest in response to, two heat series. VAS ratings were collected after each respective heat series. After two heat series, participants were instructed to “sit quietly for 10 minutes” to control for the time spent initiating meditation in Session 6. After this 10-minute period, participants were administered two more heat series and VAS ratings were collected afterward. Participants were then randomized to a four-session (20 minutes/session) mindfulness meditation or a control group that listened to the Natural History of Selborne across four, 20 minutes sessions. After successful completion of their respective regimens (Session 2–5), participants reported to the MRI center for post-intervention functional MRI sessions. Session 6: After being positioned in the scanner, we administered two Heat series while participants rested with their eyes closed during fMRI acquisition. VAS ratings were collected after each respective heat series. Before anatomical acquisition, we instructed the members of the mindfulness group to “begin meditating and to continue until the end of the experiment.” The control group was instructed to “keep eyes closed”. After 10 minutes elapsed, we administered two more Heat series during functional acquisition and collected pain ratings after each respective series.

Figure 3:

Psychophysical visual analog scale (VAS) pain intensity (left) and unpleasantness (right) ratings (± 1 standard error of the mean) in response to pre-manipulation (rest) vs. post-manipulation (rest) and noxious heat (49°C) during the pre-intervention psychophysical testing session. There were no significant within or between group effects.

Figure 4:

Psychophysical visual analog scale (VAS) pain intensity (left) and unpleasantness (right) ratings (± 1 standard error of the mean) in response to pre-manipulation (rest) vs. post-manipulation (rest; meditation) and noxious heat (49°C) during the post-intervention MRI session. Mindfulness meditation produced significant reductions in pain intensity (−32%) and pain unpleasantness (−33%) ratings when compared to rest and the change in pain from pre to post-manipulation in the control group (ps<.001).

Figure 5:

All neuroimaging analyses were performed during noxious heat (49°C > 35°C). Left panel: The whole-brain independent samples t-test revealed that mindfulness meditation significantly reduced activation in the bilateral posterior insula, secondary somatosensory cortices (SII), parietal operculum, dorsal ACC (dACC), supplementary motor area (SMA), and primary visual cortex (V1) during noxious heat when compared to rest and the change in pain from pre to post-manipulation in the control group. Middle panel: A paired-samples t-test employing a change in pain (demeaned post-manipulation – pre- manipulation) found that meditation produced significant reductions in the dACC, SMA, bilateral anterior/posterior insula, amygdala, hippocampus, central-parietal operculum and SII when compared to rest. Right panel: Greater mindfulness-based pain intensity reductions, from rest to meditation, was associated with stronger vmPFC deactivation (r=.73, p<.001). R, subject right, slice locations correspond to standard stereotaxic space.

Figure 6:

Neuroimaging analyses were performed during noxious heat (49°C > 35°C). A paired-samples t-test employing a change in pain (demeaned post-manipulation – pre- manipulation) found that the controls exhibited a significant increase in occipital lobe activation in the second half of the scan when compared to the first half of the scans. Slice locations correspond to standard stereotaxic space.

Figure 7:

Left thalamic-whole brain psychophysiological interaction analyses (PPI; z = ± 3.1, p < .05) were performed during 49°C plateaus. PPI analyses were conducted during meditation as compared to rest. Pain intensity and unpleasantness ratings were regressed on the mean effect, respectively. Greater mindfulness meditation-induced pain intensity relief was moderated by weaker thalamic connectivity with the precuneus and primary visual cortex (V1) (r=.74, p<.001). R, subject right, slice locations correspond to standard stereotaxic space.

Figure 8:

Separate seed-to-seed psychophysiological interaction analyses (PPI) were conducted (Threshold-Free Cluster Enhancement, p < .05) [40] to determine if a) right orbitofrontal cortical (OFC) connectivity with the left thalamus and b) left thalamus with the primary somatosensory cortex (SI) predicted mindfulness meditation-induced pain relief, respectively. Top panel: Weaker right OFC connectivity with the contralateral thalamus predicted mindfulness-induced pain reductions from rest to meditation (r =.65, p =.001). Bottom panel: Weaker thalamic-SI functional connectivity predicted stronger meditation-induced pain intensity reductions (r =.48, p = .03). There were no other significant effects for either group. R, subject right, slice locations correspond to standard stereotaxic space.

Figure 9:

Right orbitofrontal cortex (OFC) – whole-brain psychophysiological interaction analyses (PPI) were performed during 49°C plateaus. PPI analyses (z = ± 3.1, p < .05) were conducted during meditation as compared to rest. Pain intensity and unpleasantness ratings were regressed on the mean effect, respectively. Greater mindfulness meditation-induced pain intensity reductions from rest to meditation was moderated by weaker right OFC connectivity with the contralateral posterior insula, SII, and parietal operculum (r = .80, p < .001). There were no other significant meditation-related mean effects, correlations, or control group effects. R, subject right, slice locations correspond to standard stereotaxic space.