Increased resting-state brain entropy (BEN) in mild to moderate chronic low back pain

Chronic low back pain (cLBP) is a prevalent condition, and abnormal neural activity is frequently observed in cLBP. However, aberrant neural activity in mild to moderate cLBP remains insufficiently characterized in the neuroimaging literature, even though investigating neural activity alterations in mild to moderate cLBP could provide crucial insights into the dynamic processes underlying pain intensity variations. In this study, we employed novel resting-state functional magnetic resonance imaging (rs-fMRI)-based brain entropy (BEN) analysis alongside seed-based functional connectivity (FC) analysis to examine neural pathophysiological mechanisms in mild to moderate cLBP from both local brain activity and distant network connectivity perspectives, offering new conceptual frameworks for understanding this condition. This study included 49 mild to moderate cLBP patients (22 males, 27 females, age range: 37–75 years) and 31 HCs (13 males, 18 females, age range: 35–72 years). BEN and FC differences between cLBP patients and HCs were compared. To validate the findings, spatial correlation analyses between the identified brain abnormalities and a large-scale meta-analytic pain map derived from Neurosynth were performed. Additionally, gene expression analysis was conducted to explore the molecular correlations of cLBP-related BEN alterations. Furthermore, we evaluated the diagnostic capability of both BEN and FC features in distinguishing cLBP patients from HCs. Relative to HCs, patients exhibited significantly elevated BEN in key pain-processing regions, including the thalamus, midcingulate cortex (MCC), cerebellum, postcentral gyrus, and lingual gyrus (voxel p < 0.005, cluster p < 0.05, GRF-corrected). Increased BEN in the MCC was positively correlated with anxiety scores. The spatial pattern of BEN differences showed significant convergence with a large-scale meta-analytic pain map. FC analysis seeded in the right thalamus revealed reduced connectivity with the cerebellum and parahippocampal gyrus in patients. Both BEN and FC patterns effectively classified patients from HCs using machine learning. Gene enrichment analysis suggested that the spatial gene-expression pattern associated with the observed BEN abnormalities was enriched for the MAPK signaling pathway and regulation of monoatomic ion transport in the observed BEN abnormalities. Our findings demonstrate that BEN is a potential biomarker of localized neural dysregulation in mild to moderate cLBP, which is characterized by a profile of heightened regional entropy, disrupted thalamo-cerebellar connectivity, and significant emotional comorbidity. This work provides new insights into the pathophysiology of mild-to-moderate cLBP.