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Review
. 2025 Jun 25;17(6):e86756.
doi: 10.7759/cureus.86756. eCollection 2025 Jun.

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

Ayesha Yousaf  1 , Hideaki Yamamoto  2 , Jaden Y Fang  1 , Adam Romman  1 , Aristides P Koutrouvelis  1 , Satoshi Yamamoto  1
Affiliations
Review

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

Ayesha Yousaf et al. Cureus. .

Abstract

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.

Keywords: chronic pain management; neuromodulation; spinal cord stimulation (scs); supraspinal modulation; systematic review.

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Conflict of interest statement

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Figures

Figure 1
Figure 1. PRISMA flow diagram of the study selection process.
*Refer to the Appendices for the study selection strategy. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SCS, spinal cord stimulation
See this image and copyright information in PMC

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