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Objective. Spinal cord stimulation (SCS) is a common treatment for chronic pain. For decades, SCS maximized overlap between stimulation-induced paresthesias and the patient's painful areas. Recently developed SCS paradigms relieve pain at sub-perceptible amplitudes, yet little is known about the neural response to these new waveforms or their analgesic mechanisms of action. Therefore, in this study, we investigated the neural response to multiple forms of paresthesia-free SCS. Approach. We used computational modeling to investigate the neurophysiological effects and the plausibility of commonly proposed mechanisms of three paresthesia-free SCS paradigms: burst, 1 kHz, and 10 kHz SCS. Specifically, in C- and A β -fibers, we investigated the effects of different SCS waveforms on spike timing and activation thresholds, as well as how stochastic ion channel gating affects the response of dorsal column axons. Finally, we characterized membrane polarization of superficial dorsal horn neurons. Main results. We found that none of the SCS waveforms activate nor modulate spike timing in C-fibers. Spike timing was modulated in A β -fibers only at suprathreshold amplitudes. Ion channel stochasticity had little effect on A β -fiber activation thresholds but produced heterogeneous spike timings at suprathreshold amplitudes. Finally, local cells were preferentially polarized in their axon terminals, and the magnitude of this polarization was dependent on cellular morphology and position relative to the stimulation electrodes. Significance. Overall, the mechanisms of action of subparesthetic SCS remain unclear. Our results suggest that no SCS waveforms directly activate C-fibers, and modulation of spike timing is unlikely at subthreshold amplitudes. We conclude that potential subthreshold neuromodulatory effects of SCS on local cells are likely to be presynaptic in nature, as axons are preferentially depolarized during SCS., (Creative Commons Attribution license.)

Objective . Spinal cord stimulation (SCS) is a common neurostimulation therapy to manage chronic pain. Technological advances have produced new neurostimulation systems with expanded capabilities in an attempt to improve the clinical outcomes associated with SCS. However, these expanded capabilities have dramatically increased the number of possible stimulation parameters and made it intractable to efficiently explore this large parameter space within the context of standard clinical programming procedures. Therefore, in this study, we developed an optimization approach to define the optimal current amplitudes or fractions across individual contacts in an SCS electrode array(s). Approach . We developed an analytic method using the Lagrange multiplier method along with smoothing approximations. To test our optimization framework, we used a hybrid computational modeling approach that consisted of a finite element method model and multi-compartment models of axons and cells within the spinal cord. Moreover, we extended our approach to multi-objective optimization to explore the trade-off between activating regions of interest (ROIs) and regions of avoidance (ROAs). Main results . For simple ROIs, our framework suggested optimized configurations that resembled simple bipolar configurations. However, when we considered multi-objective optimization, our framework suggested nontrivial stimulation configurations that could be selected from Pareto fronts to target multiple ROIs or avoid ROAs. Significance . We developed an optimization framework for targeted SCS. Our method is analytic, which allows for the fast calculation of optimal solutions. For the first time, we provided a multi-objective approach for selective SCS. Through this approach, we were able to show that novel configurations can provide neural recruitment profiles that are not possible with conventional stimulation configurations (e.g. bipolar stimulation). Most importantly, once integrated with computational models that account for sources of interpatient variability (e.g. anatomy, electrode placement), our optimization framework can be utilized to provide stimulation settings tailored to the needs of individual patients., (Creative Commons Attribution license.)