Paresthesia during spinal cord stimulation depends on synchrony of dorsal column axon activation

Abstract

Spinal cord stimulation (SCS) reduces chronic pain. Conventional (40-60 Hz) SCS engages spinal inhibitory mechanisms by activating low-threshold mechanoreceptive afferents with axons in the dorsal columns (DCs). But activating DC axons typically causes a buzzing sensation (paresthesia) that can be uncomfortable. Kilohertz-frequency (1-10 kHz) SCS produces analgesia without paresthesia and is thought, therefore, not to activate DC axons, leaving its mechanism unclear. Here we show in rats that kilohertz-frequency SCS activates DC axons but causes them to spike less synchronously than conventional SCS. Spikes desynchronize because axons entrain irregularly when stimulated at intervals shorter than their refractory period, a phenomenon we call overdrive desynchronization. Effects of overdrive desynchronization on evoked compound action potentials were verified in simulations, rats, pigs, and a chronic pain patient. Whereas synchronous spiking in DC axons is necessary for paresthesia, asynchronous spiking is sufficient to produce analgesia. Asynchronous activation of DC axons thus produces paresthesia-free analgesia.

Model-based analysis of subthreshold mechanisms of spinal cord stimulation for pain

“…This effect is not accounted for in our model, in which axons could continue to fire indefinitely in regular patterns, and it is a current limitation in the current gold standard MRG-based modeling approach. However, our results do predict that kilohertz-frequency SCS will produce bursts of action potentials at suprathreshold amplitudes (figure 8), which agrees with recent recordings during kilohertzfrequency stimulation by Sagalajev et al [60].…”

“…Recent experiments have demonstrated that stimulating DC fibers at amplitudes just above activation threshold will produce asynchronous firing responses [68]. While deterministic fiber models provide qualitatively accurate approximations of the response to SCS, incorporating the stochastic ion channel properties produced results that demonstrated fluctuations in spike timing that more closely resemble experimental recordings [60,68].…”

“…Next, we investigated the effects on spike timing when the amplitude was increased to slightly above threshold, as it is possible that SCS may activate DC fibers without concomitant paresthesia [60]. Thus, the amplitude is above the threshold for activating the specific fiber under consideration, but not necessarily strong enough to generate a perceptible sensation.…”

“…This result highlights the need to understand realistic DC fiber firing patterns during SCS to better maximize pain relief, which our results demonstrate are noticeably affected by including stochasticity. Next, recent evidence suggests that paresthesia may rely on the synchrony of DC fiber activation [60]. Thus, asynchronous firing due to these stochastic ion channel properties could increase the paresthesia perception amplitude, and future waveforms could be designed to exploit these properties to reduce synchronization and thereby increase the therapeutic range of stimulation at subparesthetic levels.…”

“…While this biophysical analysis is generalizable to any given axon, it is possible that stimulation could be above threshold for a given axon but still below the necessary amplitude for perceptible sensation. Future work investigating the neural correlates of paresthesia will better inform future studies and clinical SCS practice [60].…”