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Movement limitation is a common characteristic of chronic pain such that pain prevents the very movement and activity that is most likely to promote recovery. This is particularly the case for pathological pain states such as complex regional pain syndrome (CRPS). One clinical approach to CRPS that has growing evidence of efficacy involves progressive movement imagery training. Graded Motor Imagery (GMI) targets clinical and neurophysiological effects through a stepwise progression through implicit and explicit movement imagery training, mirror therapy and then functional tasks. Here we review experiences from over 20 years of clinical and research experience with GMI. We situate GMI in terms of its historical underpinnings, the benefits and outstanding challenges of its implementation, its potential application beyond CRPS. We then review the neuropathological targets of GMI and current thought on its effects on neurophysiological biomarkers. PERSPECTIVE: This article provides an overview of our experiences with graded motor imagery training over the last 20 years focussing on the treatment of CRPS. It does both cover the theoretical underpinnings for this treatment approach, biomarkers which indicate potential changes driven by GMI, and experiences for achieving optimal treatment results., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Complex regional pain syndrome (CRPS) is a neuropathic pain condition that is difficult to treat. For behavioral interventions, graded motor imagery (GMI) showed relevant effects, but underlying neural substrates in patient groups have not been investigated yet. A previous study investigating differences in the representation of a left/right hand judgment task demonstrated less recruitment of subcortical structures, such as the putamen, in CRPS patients than in healthy controls. In healthy volunteers, the putamen activity increased after a hand judgment task training. In order to test for longitudinal effects of GMI training, we investigated 20 CRPS patients in a wait-list crossover design with 3 evaluation time points. Patients underwent a 6 week GMI treatment and a 6 week waiting period in a randomized group assignment and treatment groups were evaluated by a blinded rater. When compared to healthy matched controls at baseline, CRPS patients showed less functional activation in areas processing visual input, left sensorimotor cortex, and right putamen. Only GMI treatment, but not the waiting period showed an effect on movement pain and hand judgment task performance. Regression analyses revealed positive associations of movement pain with left anterior insula activation at baseline. Right intraparietal sulcus activation change during GMI was associated with a gain in performance of the hand judgment task. The design used here is reliable for investigating the functional representation of the hand judgment task in an intervention study. PERSPECTIVE: Twenty chronic CRPS patients underwent a 6 week GMI intervention in a randomized wait-list crossover design. functional MRI was tested pre and post for the hand lateralization task which improved over GMI but not over WAITING. Performance gain was positively related to right parietal functional MRI activation., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Temporomandibular pain (TMD) is a frequent symptom comprising pain around the mandibular jaw with a high dependence on stressors. Chronic pain has been associated with changes of the brains gray matter volume (GMV), but previous studies on GMV alterations associated with TMD have yielded contradictory results. This might be caused by divergent samples and study methods. We here tested GMV alterations using voxel based morphometry in three clinical samples (summing up to 47 TMD patients) and a population sample with 57 participants who indicated facial pain for the last 6 months. The GMV of pain patients was compared against age-matched and gender-matched participants without chronic pain (60 for the clinical sample comparison and 381 for the cohort sample comparison) who underwent the same assessments as the patient group (MRI measurements and data evaluation using CAT12). In a region of interest analysis, only the clinical samples showed an effect of decreased GMV in the anterior medial cingulate cortex reaching into the medial prefrontal cortex, known to be especially vulnerable for chronic pain gray matter volume reduction. The analysis of the population-based sample did not reveal relevant GMV differences. Overall, an important question remains as to whether most inconsistent results from voxel based morphometry-studies in chronic pain are related to chance results facilitated by small sample size and selection of patient samples. PERSPECTIVE: Using voxel based morphometry 2 samples with chronic temperomandibular pain were compared to controls investigating the brains GMV. Only the clinical sample showed a decrease in anterior cingulate GMV. Contradicting results on GMV loss in temperomandibular pain might be based on small samples in prior studies., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Spatial integration of parts of the body is impaired in patients with complex regional pain syndrome (CRPS). Because the training of mental rotation (MR) has been shown to be among the effective therapy strategies for CRPS, impairment of MR is also important for the pathophysiological understanding of CRPS. The aim of this study was to evaluate whether differences in the neural representation of MR occur between patients with CRPS and healthy controls (HC). Therefore, we included 15 patients with chronic CRPS and 15 age- and gender-matched HC. We assessed behavioral (accuracy and reaction time for MR of both hands), clinical (Disabilities of Arm, Shoulder and Hand questionnaire) and magnetic resonance imaging (T1-weighted, function magnetic resonance imaging during MR) data. Reaction times in the patient group were delayed compared with HC without a lateralization effect for the affected hand side. Although both groups showed an activation pattern typical for MR, only HC showed a highly significant contrast for the rotated versus unrotated hands in the right intraparietal sulcus. Patients with CRPS showed a reduction of functional magnetic resonance imaging activation in areas including the subthalamic nucleus, nucleus accumbens, and putamen. Regression analysis for the CRPS group emphasized the importance of putamen and nucleus accumbens activation for MR performance. This study highlights the reduced access of patients with CRPS for mental resources modulating arousal, emotional response, and subcortical sensorimotor integration. PERSPECTIVE: This study localized the underlying neural responses for impaired mental rotation in patients with complex regional pain syndrome as a decrease in basal ganglia (putamen) and nucleus accumbens activation., (Copyright © 2019 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Chronic back pain (CBP) is associated with circumscribed atrophy in gray matter (GM) predominantly localized in areas of the so-called pain matrix and the prefrontal cortex (PFC). Previous studies applying voxel-based morphometry (VBM) for identifying structural brain alterations related to CBP have reported inconsistent results, were limited to small sample sizes, and often did not control for medication. We therefore used VBM for high-resolution magnetic resonance images to investigate the association of CBP and regional GM volume in 111 individuals with CBP and 432 pain-free controls derived from the representative Study of Health in Pomerania, controlling for effects of medication. CBP was associated with decreased regional GM in the ventrolateral PFC and dorsolateral PFC, both the ventral and dorsal medial PFC, and the anterior insula. Pain intensity showed a weak negative correlation with GM volume in the left dorsolateral PFC, ventrolateral PFC, and anterior cingulate cortex. The CBP sample showed alterations in regions commonly associated with pain processing and emotional demands. To our knowledge, this is the first VBM study reporting decreased regional GM volume in the medial PFC in a CBP sample. We were unable to confirm alterations in regions other than the dorsolateral PFC and the insula., Perspective: Previous studies reported inconsistent results for brain areas altered in chronic pain conditions, which may be in part attributable to small sample sizes, medication use, or emotional comorbidities. This study in a large and representative cohort helps to clarify these issues., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Dysfunction in the central nervous system is thought to underlie the movement disorders that commonly occur in complex regional pain syndrome (CRPS), with much of the literature focusing on reorganization of the primary motor cortex (M1). Presumed changes in the M1 representation of the CRPS-affected body part have contributed to new CRPS treatments, which are increasingly being integrated in the clinic. We systematically investigated the evidence for altered M1 function in CRPS. We adhered to rigorous systematic review procedure in our search strategy, risk-of-bias appraisal, and data extraction. Eighteen studies comprising 14 unique data sets were included. The included studies used several neuroimaging techniques, whose outcomes we grouped into M1 cortical excitability, spatial representation, reactivity, and glucose metabolism, and conducted meta-analyses where possible. Risk of bias across studies was high, mainly due to missing data and unblinded assessment of outcomes. No definitive conclusions can be drawn regarding M1 spatial representation, reactivity, or glucose metabolism in CRPS. There is limited evidence for bilateral M1 disinhibition in CRPS of the upper limb., Perspective: Despite widely held assumptions of primary motor cortex dysfunction in complex regional pain syndrome, there is only evidence to support bilateral disinhibition, and there is high risk of bias across the literature., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: That complex regional pain syndrome (CRPS) is associated with functional reorganization in the primary somatosensory cortex (S1) is widely accepted and seldom questioned. Despite more than a decade of research, there has been no systematic review of the CRPS literature concerning the changes in S1 function, and therefore the extent of these changes is unclear. Here we conduct a systematic review and meta-analysis to quantify the spatial and temporal aspects of S1 function in CRPS. A comprehensive search strategy identified functional neuroimaging studies of S1 in CRPS. We adhered to a rigorous systematic review protocol when extracting data and appraising risk of bias. Outcomes were grouped into spatial representation; activation levels, including disinhibition; peak latency of activation; and glucose metabolism. Meta-analysis was conducted where possible. Fifteen studies were included, all investigating upper-extremity CRPS. In patients with CRPS, the S1 spatial representation of the affected hand is smaller than that of the unaffected hand and that of non-CRPS controls; however, this evidence comes from only a few studies. There is no difference in activation, disinhibition, or latency of peripherally evoked S1 responses in CRPS. The risk of bias was high across studies, mainly from unclear sampling methods and unblinded analysis of outcomes., Perspective: The evidence for a difference in function of the primary somatosensory cortex in CRPS compared with controls is clouded by high risk of bias and conflicting results, but reduced representation size seems consistent., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)