Biophysics of frequency-dependent variation in paresthesia and pain relief during spinal cord stimulation.

Abstract

The neurophysiological effects of spinal cord stimulation (SCS) for chronic pain are poorly understood, resulting in inefficient failure-prone programming protocols and inadequate pain relief. Nonetheless, novel stimulation patterns are regularly introduced and adopted clinically. Traditionally, paresthetic sensation is considered necessary for pain relief, although novel paradigms provide analgesia without paresthesia. However, like pain relief, the neurophysiological underpinnings of SCS-induced paresthesia are unknown. Here, we paired biophysical modeling with clinical paresthesia thresholds (of both sexes) to investigate how stimulation frequency affects the neural response to SCS relevant to paresthesia and analgesia. Specifically, we modeled the dorsal column (DC) axonal response, dorsal column nucleus (DCN) synaptic transmission, conduction failure within DC fiber collaterals, and dorsal horn network output. Importantly, we found that high-frequency stimulation reduces DC fiber activation thresholds, which in turn accurately predicts clinical paresthesia perception thresholds. Furthermore, we show that high-frequency SCS produces asynchronous DC fiber spiking and ultimately asynchronous DCN output, offering a plausible biophysical basis for why high-frequency SCS is less comfortable and produces qualitatively different sensation than low-frequency stimulation. Finally, we demonstrate that model dorsal horn network output is sensitive to SCS-inherent variations in spike timing, which could contribute to heterogeneous pain relief across patients. Importantly, we show that model DC fiber collaterals cannot reliably follow high-frequency stimulation, strongly affecting network output and typically producing anti-nociceptive effects at high frequencies. Altogether, these findings clarify how SCS affects the nervous system and provide insight into the biophysics of paresthesia generation and pain relief.Significance Statement The effects of spinal cord stimulation (SCS) on the nervous system are poorly understood, resulting in inadequate clinical success rates. Here, we use a biophysical modeling approach to investigate the neural response to SCS. We demonstrate that low- and high-frequency stimulation produce contrasting responses in the dorsal columns, brainstem, and dorsal horn. Importantly, our modeling approach was able to accurately predict clinical paresthesia thresholds as a function of frequency, as well as provide plausible biophysical explanations for frequency-dependent effects on paresthesia quality and pain relief. Overall, our results greatly enhance our understanding of the neural response to SCS, thereby offering context for interpreting clinical observations and crucial insight for development of future SCS systems.