Cortico-spinal Mechanisms of Periphery Neuromodulation induced Analgesia

Nociceptive acute and chronic pain significantly impact the quality of life and create tremendous societal burdens. Given the side effects associated with pharmacological analgesia, noninvasive periphery neuromodulation techniques, like Transcutaneous Electrical Nerve Stimulation (TENS), have emerged as promising approaches for pain relief. Current human research, focusing partly on cerebral, brainstem, or peripheral mechanisms of neuromodulation, lacks comprehensive understanding from the perspective of the entire central nervous system. This study utilized a three-way mixed experimental design, combining cutting-edge cortico-spinal fMRI with thermal stimuli, to systematically explore the central analgesic mechanisms of two typical TENS modes: Conventional (high frequency, low intensity) and Acupuncture-Like (low frequency, high intensity). Behavioral and fMRI analysis revealed that, the direct spinal inhibition (PAG-spinal connectivity) partially mediated by PAG-vmPFC connectivity leads to local analgesic effects in Conventional TENS; a top-down diffuse noxious inhibition (PAG-S1 connectivity) fully mediated through PAG-spinal connectivity leads to diffuse analgesic effects in Acupuncture-Like TENS. Employing advanced cortico-spinal fMRI technique, our findings provide systematic neural evidence of the analgesic mechanisms induced by TENS and shed new light on future neuromodulation approaches. ### Competing Interest Statement The authors have declared no competing interest.