Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits

Abstract

Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.

Keywords: chronic back pain; emotion; fMRI; longitudinal; reward.

Figures

Figure 1

Brain activity for rating back pain is distinct in early sub-acute back pain (SBPe) in comparison to CBP. (A) Individual subject examples of the trigger pulses generated from ratings of back pain, after convolving the rating with a canonical haemodynamic response in a subject with early sub-acute back pain. Arrows and green curve represent pain onset triggers and green curve represents example of durations for which subjects reported a greater than 1 SD increase in pain. (B) Shows the number of pain triggers in each subject within the scan in SBP and CBP patients. (C) Group-averaged brain activity for rating fluctuations of back pain in 94 subjects with early SBP (right), and in 59 subjects with CBP (middle). The contrast between the two groups (early SBP > CBP is shown in blue, and CBP > early SBP in red) (left). The contrasts largely reproduce corresponding group activity maps, indicating that early SBP and CBP engage separate brain regions. Results are thresholded at P < 0.05 (FWE corrected). (D) Trigger evoked blood oxygen level-dependent response in regions of interest. Pain ratings (left) and blood oxygen level-dependent signal (right) were extracted over a 30 s time window that spanned the pain onset (10 s before and 20 s after onset) for every event and averaged in each subject to construct a group early SBP and CBP average. Regions were selected based on peak activations in the General Linear Model based early SBP mean map [anterior cingulate cortex (ACC) and insula] and CBP mean map (medial; prefrontal cortex, amygdala). *P < 0.01, unpaired two-tailed t-test.

Figure 2

Early SBP (SBPe) and CBP activation maps correspond to distinct meta-analytic circuits. (A) Brain meta-analytic maps for the terms: pain, emotion and reward, from Neurosynth (Yarkoni et al., 2011). (B) Brain images represent masks derived from maps above at different thresholds (top five and one percentile voxels) for pain (red), reward (green) and emotion (blue) meta-analytic maps. Bar graphs represent the % overlap for CBP (black) and early SBP (grey) with the three meta-analytic maps at the 95th and 99th percentile thresholds. Overall SBP activity is more similar to the pain term related mask, whereas CBP activity is similar to emotion term related mask. Activity in both groups engage parts of the reward mask. (C) Brain images show the overlapping (yellow) and non-overlapping (blue) voxels for early SBP (top row) and CBP (bottom row) with the 95th percentile thresholded meta-analytical masks. Early SBP overlaps with pain mainly in bilateral insula, thalamus and anterior cingulate cortex (ACC), whereas CBP overlaps with emotion in bilateral amygdala and medial prefrontal cortex (mPFC).

Figure 3

Longitudinal changes in brain activity underlying spontaneous pain when patients transition from acute to chronic back pain state. (A) Plots show the scanning calendar dates of subjects with recovering SBP (SBPr) and persistent SBP (SBPp) for all four visits. Vertical marks represent individual persistent SBP (black) and recovering SBP (grey) subjects. Groups were scanned within the same time window (major ticks are years; minor ticks are months). (B) Recovering SBP in contrast to persistent SBP patients exhibited decreased pain in time. (C) Group average activation maps (P < 0.01 uncorrected) for recovering and persistent SBP groups at the four visits. Recovering and persistent SBP groups show activation within acute pain regions for visits 1 and 2 encompassing bilateral insula, thalamus and anterior cingulate cortex (ACC). Recovering SBP patients show no significant activity for visits 3 and 4, whereas persistent SBP shows increased activation in the medial prefrontal cortex and amygdala at visit 4. (D) Plots show the group average cope (normalized) for pain, emotion and reward masks, for each group (persistent SBP, CBP, recovering SBP), across all visits. Persistent SBP exhibited decreased presentation of their spontaneous pain within the pain mask. This decrease was coupled with an increased activity within the emotion mask. The middle panel shows CBP activity for all three masks. These values correspond to those we observe in persistent SBP at 1-year scans. In contrast to persistent SBP, the recovering SBP group exhibited decreased activity within all masks in time. (E) Classifier performance applied to individual persistent SBP activation maps for either pain/emotion or CBP/early SBP, at visits 1 and 4. Persistent SBP activity mainly classified as pain or early SBP at visit 1, and as emotion or CBP at visit 4. +P < 0.05, ++P < 0.01, within group comparison to visit 1; **P < 0.01 comparison between groups at a corresponding time.

Figure 4

Medial prefrontal cortex–nucleus accumbens (mPFC-NAc) functional connectivity strength predicts extent of shift in brain activity underlying spontaneous pain in patients with persistent SBP from pain-related to emotion-related regions. (A) Brain image shows the location and coordinates of the medial prefrontal cortex and nucleus accumbens seeds used. (B) Bar graph shows the mean ± SEM for medial prefrontal cortex–nucleus accumbens functional connectivity in persistent SBP (black) and recovering SBP (grey) at visit 1. Persistent SBP exhibited higher medial prefrontal cortex–nucleus accumbens connectivity compared with recovering SBP. (C) Scatter plots show the relationship between medial prefrontal cortex–nucleus accumbens connectivity at visit 1 and change in brain activity (Δ Parametric estimate = average cope at visit 4 − average cope at visit 1) for pain (left) and emotion (right) term related masks. High medial prefrontal cortex–nucleus accumbens connectivity showed a strong relationship with decreased activation in pain regions and increased activiations in emotional regions in patients with persistent SBP over a 1-year period (visit 4 versus visit 1).