Stress-Related Brain Alterations in Chronic Pain

Abstract

Background: Stress symptoms are commonly experienced by people with chronic pain. Although stress and chronic pain are associated with similar effects on brain morphology, the present study aims to clarify the relationship between stress severity, chronic pain, and brain morphology.

Methods: Fifty-two people with chronic pain and 38 pain-free healthy controls (HC) underwent T1-weighted magnetic resonance imaging. Severity of stress symptoms was measured using the civilian version of the posttraumatic stress disorder checklist (PCL-C). A series of multiple linear regressions determined the main effects of group, stress symptom severity (PCL-C total score and symptom-specific scores) and their interaction on grey matter volume of selected regions of interest.

Results: The interaction term was significantly associated with variations in grey matter volume in the left and right putamen, the left middle cingulate cortex (MCC) and the right posterior insula. Results showed significantly smaller left and right putamen when reporting higher stress levels, and significantly larger left MCC and right posterior insula at lower stress levels in people with chronic pain compared to HCs. In addition, increasing stress severity was significantly associated with larger left and right putamen in HCs, and significantly associated with smaller left MCC and right posterior insula in people with chronic pain.

Conclusions: Severity of stress moderated chronic pain-related grey matter alterations. More severe stress, especially avoidance, was associated with smaller left MCC, a core region of the "pain matrix". The MCC is strongly linked with the somatosensory network and critical for empathy, especially toward pain-related stimuli.

Significance: To our knowledge, this is the first study to show that stress severity differentially impacts grey matter integrity in people with chronic pain compared to pain-free healthy controls. Briefly, our results indicate that higher levels of stress were associated with larger putamen and right posterior insula in pain-free participants, potentially reflecting mechanisms of resilience to trauma in this group. Higher levels of stress, especially avoidance symptoms, were associated with smaller left middle cingulate cortex, a region with strong links to the somatosensory network and critical for empathy, especially toward pain-related stimuli.

FIGURE 1

Moderation analyses following significant association between the group‐by‐PTSS total score interaction term and grey matter volume. The interaction term was significantly associated with variations in grey matter volume of the left and right putamen, the right posterior insula and the left middle cingulum cortex (MCC). (A) When using the PCL‐C total score as moderator of the group difference on left and right putamen volumes, analyses indicated that HCs had significantly larger left and right putamen compared to people with chronic pain, only at high levels of PTSS (brown plain lines). When using group as the moderator of the relationship between variations in PCL‐C scores and ROIs grey matter volumes, indicated that increasing levels of trauma were significantly associated with larger left and right putamen in the HC group only (blue dashed lines). (B) When using the PCL‐C total score as moderator of the group difference on right posterior insula volumes, analyses indicated that people with chronic pain had significantly larger right posterior insula compared to the HC group only at low levels of PTSS (red dashed lines). When using group as the moderator, increasing PCL‐C scores were associated with smaller right posterior insula in people with chronic pain only (yellow plain line). (C) When using the PCL‐C total score as moderator of the group difference on left MCC volume, analyses indicated that people with chronic pain had significantly larger left MCC than HCs (red dashed line). When using group as the moderator, increasing PCL_C scores were associated with smaller left MCC (yellow plain line). *p < 0.05; **p < 0.01; ***p < 0.001. Coloured band around each line represents 95% confidence intervals.

FIGURE 2

Moderation analyses following significant association between the group‐by‐PTSS interaction term and grey matter volume. (A) Re‐experiencing symptoms significantly moderated the group differences on left and right putamen and right posterior insula. Larger putamen and right posterior insula were evident in HCs compared to people with chronic pain at higher levels of re‐experiencing only (brown plain lines). In addition, increasing re‐experiencing symptoms were associated with larger left and right putamen only in HCs (blue dashed lines). (B) Avoidance symptoms significantly moderated the group differences on left MCC. Larger left MCC was evident in people with chronic pain compared to HCs at lower levels of avoidance only (red dashed lines). In addition, increasing avoidance symptoms were associated with smaller left MCC only in people with chronic pain (yellow plain lines). *p < 0.05; **p < 0.01; ***p < 0.001. Coloured band around each line represents 95% confidence intervals.

FIGURE 3

Whole‐brain association with the group‐by‐avoidance interaction. Severity of avoidance moderated the group difference on MCC volume, with the chronic pain group showing larger GMV in this cluster relative to the HC group at low levels of avoidance (left panel; red dashed line). In addition, increasing avoidance severity was associated with smaller GMV in this cluster in people with chronic pain only (right panel; yellow plain line). **p < 0.01; ***p < 0.001. Colour‐bar represents t‐statistics. Coloured band around each line represents 95% confidence intervals.