Dose-dependent dorsal column activation drives analgesic effects of spinal cord stimulation in a rat model of neuropathic pain.

Abstract

Spinal cord stimulation (SCS) is typically dosed to the perception threshold, defined as the onset of stimulation-induced sensations. The evoked compound action potential threshold (ECAPT) is an objective marker of dorsal column fiber activation onset. It approximates the perception threshold, and ECAPT-guided dosing improves clinical outcomes. Preclinical models are valuable for investigating the mechanisms of SCS, yet dosing strategies in animal studies commonly rely on motor threshold-based stimulation intensities, with limited translational relevance. Here, we establish a causal relationship between ECAPT, dorsal column activation, and analgesic efficacy, demonstrating for the first time that ECAPT provides a clinically comparable marker to guide preclinical SCS dosing based on neural activation. Adult male Sprague-Dawley rats with spared nerve injury (SNI)-induced neuropathic pain (n=25) were implanted epidurally with an eight-contact lead covering T12-L2. SCS (50 Hz, 100 µs) was delivered at individualized doses of 0×ECAPT, 0.5×ECAPT (open loop), or 1.1-1.4×ECAPT (closed loop). Additional SNI and sham controls (n=6 each) received no lead implantation or stimulation. Analgesic efficacy was assessed by paw withdrawal responses to mechanical (von Frey filaments) and cold (acetone) stimuli. ECAPT-based SCS doses of 1.2-1.3×ECAPT achieved the most sustained reduction in mechanical and cold hypersensitivity, whereas 1.1×ECAPT was less effective and 1.4×ECAPT provided no additional benefit. Subthreshold doses (0-0.5×ECAPT) were ineffective. These findings validate ECAP as a translationally relevant measure of neural activation and demonstrate that dorsal column fiber recruitment is a key driver of SCS-induced analgesia, supporting ECAPT-guided dosing to enhance the clinical relevance and standardization of preclinical stimulation protocols.