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 the 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 the network output and typically producing antinociceptive 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.

人们对脊髓刺激（SCS）对慢性疼痛的神经生理学影响知之甚少，导致编程方案效率低下、容易失败，并且疼痛缓解不足。尽管如此，临床上仍定期引入和采用新的刺激模式。传统上，感觉异常感觉被认为是缓解疼痛所必需的，尽管新的范例提供了没有感觉异常的镇痛。然而，与缓解疼痛一样，SCS 引起的感觉异常的神经生理学基础尚不清楚。在这里，我们将生物物理模型与临床感觉异常阈值（男女）配对，以研究刺激频率如何影响与感觉异常和镇痛相关的 SCS 神经反应。具体来说，我们模拟了背柱（DC）轴突反应、背柱核（DCN）突触传递、DC纤维侧枝内的传导故障以及背角网络输出。重要的是，我们发现高频刺激降低了直流纤维激活阈值，从而准确预测临床感觉异常感知阈值。此外，我们还表明，高频 SCS 产生异步 DC 纤维尖峰并最终产生异步 DCN 输出，这为为什么高频 SCS 不太舒适并产生与低频刺激不同的感觉提供了合理的生物物理学基础。最后，我们证明模型背角网络输出对 SCS 固有的尖峰时间变化敏感，这可能有助于缓解患者的异质疼痛。重要的是，我们表明模型直流纤维络脉不能可靠地跟随高频刺激，强烈影响网络输出，并且通常在高频下产生抗伤害作用。 总而言之，这些发现阐明了 SCS 如何影响神经系统，并提供了对感觉异常产生和疼痛缓解的生物物理学的见解。