Acute changes in functional connectivity associated with first osteopathic manual treatment in chronic low back pain spatially overlap with opioid receptor expression

Background: Osteopathic Manipulative Treatment (OMT) has emerged as a therapeutic approach for chronic low back pain (cLBP). Previous Magnetic Resonance (MR) studies have demonstrated that four weeks of OMT alter resting-state functional connectivity (rs-FC) in the somatosensory cortex, prefrontal regions, and frontal operculum/insula. However, it remains unclear whether a single session of OMT can immediately affect brain rs-FC. Methods: We combined a data-driven approach with a seed-based connectivity analysis to examine the pattern of whole-brain rs-FC in a cohort of thirty cLBP patients before and after a first acute session of OMT (N = 16) or a sham treatment (N = 14). Correlation analyses were performed to explore the relationship between the resulting rs-FC maps and receptor density/gene expression maps derived from in vivo brain atlases, focusing on the opioid and cannabinoid systems. Results: Data-driven analysis revealed that, compared to the sham group, the OMT increased the intrinsic connectivity of the right dorsolateral prefrontal cortex. Seed-based connectivity analysis showed that this region increased coupling with the right frontal operculum/insula. Notably, no effect of immediate OMT was found in the somatosensory cortex. The topography of these rs-FC changes selectively overlapped with the distribution of mu-opioid receptors. Conclusions: Acute OMT in cLBP patients modulates rs-FC across cortical regions primarily involved in top-down cognitive control of pain, as well as in integrating pain intensity perception and related expectations. Spatial comparisons between rs-FC maps and receptor atlases suggest that these neural changes involve opioid, not cannabinoid, neurotransmission.