Cortico-spinal Mechanisms of Periphery Neuromodulation induced Analgesia

BackgroundTranscutaneous Electrical Nerve Stimulation (TENS) is widely used for pain management, yet how different parameters--Conventional (high frequency, low intensity) versus Acupuncture-Like (low frequency, high intensity)--modulate pain remains controversial. These modes produce variable analgesic effects, but their underlying brain-spinal mechanisms are unclear. Clarifying these pathways could refine TENS protocols, optimize clinical outcomes, and reduce opioid reliance, highlighting the need for more precise, non-pharmacological approaches to advanced pain care. MethodsThis single-blind, three-arm randomized trial recruited 95 healthy adults (18-30 years) and assigned them (1:1:1) to Conventional TENS, Acupuncture-Like TENS, or sham. Participants underwent a 30-minute TENS intervention on the left forearm (C5-C6 dermatome) with simultaneous brain-spinal fMRI before and after thermal nociceptive stimuli. The primary outcomes were changes in Numeric Rating Scale (NRS) pain scores and brain-spinal BOLD signals. Secondary outcomes included psycho-physiological interaction (PPI) and mediation analyses of periaqueductal gray (PAG) activity and brain- cord connectivity. FindingsBoth TENS modes significantly reduced pain but engaged distinct cortico-spinal pathways. Conventional TENS yielded local analgesia via dlPAG-driven spinal inhibition plus partial cortical involvement (PAG-vmPFC). By contrast, Acupuncture-Like TENS produced diffuse analgesia through vlPAG-linked top-down modulation reliant on spinal gating. Correlation and mediation analyses confirmed that Conventional TENS integrates spinal and cortical synergies, whereas Acupuncture-Like TENS is dominated by robust descending control. InterpretationDifferent TENS parameters yield distinct analgesic mechanisms. Conventional TENS couples direct spinal inhibition with partial cortical regulation, while Acupuncture-Like TENS relies heavily on top-down pathways passing through the spinal cord. Recognizing these unique descending networks can guide targeted TENS protocols for diverse pain conditions, optimizing clinical outcomes and reducing reliance on pharmacological approaches. FundingsThis work was supported by the National Key R&D Program of China (2022YFC3500603), the National Natural Science Foundation of China (32071061, 82072010, 82030121 and 32100861, 82330057), the Beijing Natural Science Foundation (IS23108, JQ22018).