Connectomic Mapping of Chronic Musculoskeletal Pain: Neural Circuitries Identified Through a Systematic Review and...

Functional neuroimaging of the encephalon of humans with chronic musculoskeletal pain (CMP) has consistently demonstrated functional alterations in the neurophysiological properties of cortical and subcortical circuits. Nevertheless, the current knowledge on specific neural circuitries that may occur in different CMP subgroups is limited, which in turn limits the understanding of the encephalon mechanisms associated with persistent pain and clinical heterogeneity. This systematic review (CRD42022382309) and activation likelihood estimation (ALE) meta-analysis of observational functional magnetic resonance imaging (fMRI) studies on human encephalon aimed to characterize specific patterns of connectomic reorganization in different CMP subgroups. PubMed, Web of Science, and Scopus databases were searched. Two independent reviewers read titles and abstracts, full texts, assessed methodological quality using the Newcastle-Ottawa scale, and extracted X, Y, and Z coordinates. The data analyses were conducted using the GingerALE 3.0.2 software and complemented by frequency analyses. All neuroanatomical coordinates used in the ALE meta-analyses were standardized to the Montreal Neurological Institute 152 space. A 95% confidence interval (CI) for the family-wise error (FWE) rate was applied using an initial uncorrected voxel-level threshold of p  < 0.001, together with 1000 permutation tests and a minimum cluster volume of ≥200 mm³. In total, 43 studies out of 5543 records met the inclusion criteria and none presented a very high risk of bias. The seven encephalon regions comprising the basic neural circuitry of CMP (somatosensory cortex, motor cortex, anterior cingulate cortex, insula, prefrontal cortex, thalamus, and cerebellum) correspond to an integrated connectomic hub that coordinates sensory-motor discriminative, affective-emotional, and cognitive-motivational processing. Additionally, 13 other regions are specifically recruited in distinct conditions of CMP. These parallel connections expand the processing network and add dimensions related to reward, memory, descending pain modulation, and attention. This dynamic reorganization reflects a pattern of cross-modal plasticity with maladaptive mechanisms.