Integrated Spinal and Supraspinal Mechanisms of Spinal Cord Stimulation Analgesia: A Systematic Review of Bidirectional Neural Modulation.

Spinal cord stimulation (SCS) is an established therapy for refractory neuropathic pain, yet its spinal-level gating and supraspinal modulatory actions have rarely been unified into a single framework. Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search and rigorous selection of animal studies that investigated both spinal and supraspinal circuitry involved in SCS-induced analgesia. Through this process, we identified and systematically reviewed seven rodent studies employing tonic, burst, or sub-perception SCS in mononeuropathy and spared-nerve-injury models, extracting electrophysiological, molecular, lesion, and imaging data. Across these models, SCS consistently restored dorsal-horn inhibitory tone, enhancing GABAergic and glycinergic signaling, suppressing wide-dynamic-range neuron hyperactivity, and attenuating mitogen-activated protein kinase (MAPK) and microglial activation. At the same time, epidural stimulation sent signals up the spinal cord that activated key brainstem pain-control centers: the periaqueductal gray, rostroventromedial medulla, and locus coeruleus. It also normalized abnormal cortical oscillations in somatosensory and limbic regions. Lesion and receptor-blockade experiments revealed that disruption of either ascending afferents or descending tracts halved analgesic efficacy, confirming a bidirectional feedback loop. Functional MRI further showed that burst versus tonic waveforms differentially recruit sensory versus affective networks. Together, these findings support a unified spinal-supraspinal model of SCS-mediated analgesia and highlight opportunities to refine electrode placement, waveform design, and stimulation parameters. While translational implications are tempered by variability in preclinical study designs, this integrated framework provides a roadmap for next-generation, mechanism-driven neuromodulation therapies tailored to individual pain needs.