The Impact of Electrical Charge Delivery on Inhibition of Mechanical Hypersensitivity in Nerve-Injured Rats by Sub-Sensory Threshold Spinal Cord Stimulation

Abstract

Objectives Spinal cord stimulation (SCS) represents an important neurostimulation therapy for pain. A new ultra‐high frequency (10,000 Hz) SCS paradigm has shown improved pain relief without eliciting paresthesia. We aim to determine whether sub‐sensory threshold SCS of lower frequencies also can inhibit mechanical hypersensitivity in nerve‐injured rats and examine how electric charge delivery of stimulation may affect pain inhibition by different patterns of subthreshold SCS. Materials and Methods We used a custom‐made quadripolar electrode (Medtronic Inc., Minneapolis, MN, USA) to provide bipolar SCS epidurally at the T10 to T12 vertebral level. According to previous findings, SCS was tested at 40% of the motor threshold, which is considered to be a sub‐sensory threshold intensity in rats. Paw withdrawal thresholds to punctate mechanical stimulation were measured before and after SCS in rats that received an L5 spinal nerve ligation. Results Both 10,000 Hz (10 kHz, 0.024 msec) and lower frequencies (200 Hz, 1 msec; 500 Hz, 0.5 msec; 1200 Hz; 0.2 msec) of subthreshold SCS (120 min) attenuated mechanical hypersensitivity, as indicated by increased paw withdrawal thresholds after stimulation in spinal nerve ligation rats. Pain inhibition from different patterns of subthreshold SCS was not governed by individual stimulation parameters. However, correlation analysis suggests that pain inhibition from 10 kHz subthreshold SCS in individual animals was positively correlated with the electric charges delivered per second (electrical dose). Conclusions Inhibition of neuropathic mechanical hypersensitivity can be achieved with low‐frequency subthreshold SCS by optimizing the electric charge delivery, which may affect the effect of SCS in individual animals.

Spinal Cord Stimulation Attenuates Below-Level Mechanical Hypersensitivity in Rats After Thoracic Spinal Cord Injury

“…Changes in mechanical hypersensitivity after SCS are also presented as PWTs in Supporting Information Figure S2. Overall, the inhibitory effects from both SCS paradigms in SCI rats were rather modest as compared to those we have reported for nerve-injured rats in our previous studies (24,25,29).…”

“…Motor threshold (MoT) was determined by slowly increasing the amplitude of 4 Hz (0.2 msec) stimulation from zero until muscle contraction was observed in the mid‐lower trunk or hind limbs. Based on recent findings (20, 24, 25), we considered sensory threshold in awake rats to be near 50% MoT. Thus, conventional SCS (50 Hz, 0.2 msec) was conducted at 80% MoT (supra‐sensory threshold), and 1200 Hz, low‐intensity SCS (0.2 msec) was applied at 40% MoT (sub‐sensory threshold).…”

“…Previous studies showed that low-intensity SCS at 1000-1200 Hz inhibited mechanical hypersensitivity in nerveinjured rats (24,25). Yet, clinical studies have reported variable efficacy of this new paradigm in pain patients (19,26).…”

Animal Pain Models for Spinal Cord Stimulation

“…In a follow-up report, Guan and coworkers [54] explored how charge delivery affects pain inhibition by different frequencies at intensities that seem to be below the sensory threshold (40% MT), and which component of stimulation runs the therapeutic actions. Epidural electrodes were implanted 5 to 7 days post-SNL, in a similar fashion described by this group previously [53].…”

Real-World Outcomes Using a Spinal Cord Stimulation Device Capable of Combination Therapy for Chronic Pain: A European, Multicenter Experience

“…Numerous basic and clinical studies have now demonstrated that SCS can be therapeutically applied below the threshold of perception (i.e., sub-perception stimulation), in contrast to conventional methodologies traditionally utilized at or above perception threshold (i.e., supra-perception stimulation) [1,[11][12][13][14]. Although distinct mechanisms that underlie both of these SCS approaches have not been definitively identified, an assortment of reported studies and clinical observations seem to suggest that differences likely do exist with regard to how the analgesic outcomes induced by sub-and supra-perception SCS are manifested [15][16][17][18]. Given this probability and the dynamic nature of the chronic pain experience, there is now a growing interest in the clinical application of sub-and supra-perception SCS as a combination therapy versus the exclusive use of either subor supra-perception SCS alone [6,19,20].…”