Are gray matter changes following pain reprocessing therapy associated with clinical improvement? A voxel-based morphometry mediation analysis

Chronic back pain (CBP) has been associated with reorganization of gray matter (GM), and treatment may reverse these GM adaptations. Prior trials testing treatment effects on GM did not included a randomized control group, found no treatment vs. control differences, or did not attempt to link treatment-induced GM changes to improvements in clinical outcomes. We addressed this gap by performing a voxel-based morphometry mediation analysis testing for effects of a psychological treatment (pain reprocessing therapy, PRT, n=44) vs. two randomized control groups (treatment as usual, n=47, and open-label placebo, n=44) on GM, and testing whether treatment-specific GM changes were associated with reductions in disability (ODI) and pain intensity (BPI). Relative to both control groups, PRT increased GM in the anterior cingulate and orbitofrontal cortex. These treatment-induced GM increases, however, did not mediate PRT effects on clinical outcomes. Instead, improvements in disability and pain were associated with GM increases in the lateral prefrontal cortex and GM decreases in the thalamus and amygdala. These findings indicate that PRT vs. control increases GM in key pain-modulatory regions, and, that clinical improvement is related to different prefrontal and subcortical GM changes in regions processing nociceptive input and regulating pain. The lack of mediation may indicate either that GM changes are not a treatment mechanism, or a lack of power to detect smaller effects. Future research is needed to better understand how treatments act on neurobiology to drive clinical improvement.