Patient experiences and neuroimaging findings in Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is characterized by pain in combination with sensory, trophic, motor- or autonomic changes. The symptoms often present themselves in a stock- or glove-like pattern on the affected part, and fractures, tissue damage, surgical traumas, and immobilization are known triggers. Severe and sustained cases are profoundly disabling for the individual, but detailed studies of patient experiences are few. The condition is relatively rare; incidence rates vary 5,5 – 26,2/100 000 person/year with 2 - 4 times more often in women than men. There is currently no consensus on any optimal treatment, but interdisciplinary approaches are frequently recommended. Interventions based on Graded Motor Imagery and mirror therapy show promising results and can be effective for pain reduction and improvement in function. 

While the condition is poorly understood, a range of potential mechanisms are suggested to be involved, including autonomic dysfunction, autoimmune involvement, exaggerated inflammation, and maladaptive neuroplasticity. Brain imaging studies have provided increased evidence for the important role of the CNS in the pathogenesis of CRPS, demonstrating reorganization of the central somatosensory and motor networks, linked to altered central processing of tactile and nociceptive stimuli as well as movement. Little is, however, known about the cortical structures associated with the processing of hyperalgesia in CRPS.

Studies indicate altered cerebral activation pattern between pain-associated circuitry and higher order motor control. In a small scale study, Pleger et al (2005) demonstrated that sensory impairment, pain, and contralateral cortical reorganization (SI and SII) was reversed after graded sensorimotor training. They suggested that repetitive application of graded desensitization, motor tasks or the combination of both might explain the observed effects. Differences in brain morphology between chronic pain patients and healthy controls have been found, but no clear pattern has been established. More studies are needed to understand how alterations in cortical thickness relate to changes in other structures of the brain and the development of CRPS. A large amount of brain imaging studies have been conducted in the recent twenty years, but review studies summarizing the status are limited.

The current project include three studies:

1. Investigate the experiences of CRPS patients who are currently receiving or have recently completed an individualized GMI and tactile treatment.

2. Review the literature on the role of the central nervous system (CNS) in CRPS established by fMRI.  

3. An MRI-study exploring cortical thickness, area, and sub-cortical volumes in CRPS patients compared to a matched healthy control group.

Study 1: Graded Motor Imagery (GMI) and tactile desensitization (D) treatment for Complex Regional Pain Syndrome (CRPS) - An interview study of patient experiences

Participants were recruited by purposeful sampling among patients treated at the Pain Department at the University Hospital of Northern Norway (UNN), diagnosed with CRPS according to the Budapest research criteria recommended by the International Association of Pain (IASP), and receiving or having completed their GMI and tactile treatment program within 12 months.

Semi-structured interviews of 1-2,5 hours were conducted. A prepared interview guide with open-ended questions was used as a starting point.

Study 2: A systematic review of brain imaging studies using functional MRI (fMRI) to investigate changes in the central nervous system in CRPS patients. The search will focus on the databases PubMed, Embase and Medline. Key words related to CRPS, neuroimaging and the brain will form the search words.

Includecion criteria: 1) Adult humans diagnosed with CRPS, 2) use of fMRI as neuroimaging technique 3) Studies from 2009 – 2023 (present).  Published studies in English language or translated to English. No restrictions on duration of the CRPS.

Study 3: A brain imaging study exploring cortical thickness, area, and sub-cortical volumes in CRPS patients compared to a matched healthy control group.

The MRI scans are the baseline examinations from patients participating in an ongoing RCT comparing treatments of CRPS.

Image processing: Surface reconstruction and volumetric segmentation will be performed with the FreeSurfer version 6.0 (FS 6.0) with the recon-allprocessing pipeline. The pipeline includes motion correction, normalization to Talairach space, intensity biascorrection, skull-stripping, surface-registration and segmentation.

Group differences in descriptive variables are analysed by analysis of variance (ANOVA). The statistical analyses of cortical thickness (CTh) and cross-sectional area (CSA) will be performed within the software package Permutation Analysis of Linear Models. The preprocessing of the cortical surfaces will be performed in the mris preproc module in FS 6.0. The permutation analyses will be performed with 5,000 iterations, and threshold-freecluster enhancement will be used to correct for multiple comparisons, and a family-wise error rate (FWER) corrected p< .05 was considered significant. The joint analyses of surface and CTh will be performed in PALM with nonparametric combination using Fisher's method for combining p-values. The Desikan-Killiany atlas incorporated in FS 6.0 will be used for annotation of the cortices.