Supraspinal Mechanisms of Spinal Cord Stimulation in Pain Mitigation: A Systematic Review

Spinal cord stimulation (SCS) has been established as an effective intervention for chronic pain syndromes, including persistent spinal pain syndrome type 2 (PSPS-T2) and complex regional pain syndrome (CRPS). Nevertheless, the underlying mechanisms responsible for SCS-induced analgesia remain incompletely understood, particularly regarding the supraspinal pathways, which have not been sufficiently clarified. A systematic review was conducted to aggregate evidence concerning the supraspinal influences of SCS on pain modulation. Following an extensive literature search facilitated by a professional librarian and adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a thorough selection process was executed. Animal studies that investigated the supraspinal circuitry implicated in SCS-induced analgesia were incorporated into the review. Conversely, studies that solely examined spinal effects or lacked appropriate experimental controls were excluded from consideration. Ultimately, four studies fulfilled the inclusion criteria. Collectively, these investigations revealed direct anatomical projections from the dorsal column nuclei (DCN) to the periaqueductal gray (PAG), a reduction in extracellular gamma-aminobutyric acid (GABA) levels within the PAG following SCS, which facilitates disinhibition of descending pain pathways, and heightened activity of OFF-like and serotonergic neurons in the rostral ventromedial medulla (RVM), thereby contributing to antinociceptive outcomes. SCS engages a network of supraspinal structures, particularly the DCN-PAG-RVM axis, to mediate analgesia via neurotransmitter modulation and descending inhibitory mechanisms. These results underscore a complex supraspinal contribution to the efficacy of SCS and advocate for future investigations into optimized neuromodulation protocols that target brainstem circuitry.