Papers of the Week

Low-frequency (<200 Hz), subperception spinal cord stimulation (SCS) is a novel modality demonstrating therapeutic efficacy for treating chronic neuropathic pain. When stimulation parameters were carefully titrated, patients experienced rapid onset (seconds – minutes) pain relief without paresthesia, but the mechanisms of action are unknown. Using an integrated computational model and in vivo measurements in urethane-anesthetized rats, we quantified how stimulation parameters (placement, pulse width, frequency, and amplitude) influenced dorsal column (DC) axon activation and neural responses in the dorsal horn (DH). Both modeled and recorded DC axons responded with irregular spiking patterns in response to low-amplitude SCS. Maximum inhibition of DH neurons occurred at ∼80% of the predicted sensory threshold in both modeled and recorded neurons, and responses were strongly dependent on spatially targeting of stimulation, i.e., the complement of DC axons activated, and on stimulation parameters. Intrathecal administration of bicuculline shifted neural responses to low-amplitude stimulation in both the model and experiment, suggesting that analgesia is dependent on segmental GABAergic mechanisms. Our results support the hypothesis that low-frequency subperception SCS generates rapid analgesia by activating a small number of DC axons which inhibit DH neuron activity via surround inhibition.Spinal cord stimulation is an effective treatment from chronic pain, but conventional stimulation generates paresthesias, a buzzing sensation that some patients find uncomfortable. Recent studies have demonstrated substantial pain relief using low frequency spinal cord stimulation that does not generate paresthesia; however, it is unclear how this form of stimulation works. In this study, we used computational models and recordings of dorsal horn neurons and dorsal column axons to study low-frequency, low-amplitude SCS and proposed a novel mechanism of action. The mechanism of action we proposed may help design future parameter selection and drive the development of SCS as a therapy.