Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain

Abstract

The development and maintenance of chronic neuropathic pain involves distorted neuroglial interactions, which result in prolonged perturbations of immune and inflammatory response, as well as disrupted synapses and cellular interactions. Spinal cord stimulation (SCS) has proven effective and safe for more than 40 years, but comprehensive understanding of its mode of action remains elusive. Previous work in our laboratory provided evidence that conventional SCS parameters modulate biological processes associated with neuropathic pain in animals. This inspired the development of differential target multiplexed programming (DTMP) in which multiple electrical signals are used for modulating glial cells and neurons in order to rebalance their interactions. This work compares DTMP with both low rate and high rate programming using an animal model of neuropathic pain. The spared nerve injury model was implemented in 48 rats equally randomized into four experimental groups: No-SCS, DTMP, low rate, and high rate. Naive animals (N = 7) served as a reference control. SCS was applied continuously for 48 h and pain-related behavior assessed before and after SCS. RNA from the spinal cord exposed to SCS was sequenced to determine changes in gene expression as a result of injury (No-SCS vs. naïve) and as a result of SCS (SCS vs. No-SCS). Bioinformatics tools (Weighted Gene Co-expression Network Analysis and Gene Ontology Enrichment Analysis) were used to evaluate the significance of the results. All three therapies significantly reduced mechanical hypersensitivity, although DTMP provided statistically better results overall. DTMP also reduced thermal hypersensitivity significantly. RNA-sequencing corroborated the complex effects of nerve injury on the transcriptome. In addition, DTMP provided significantly more effective modulation of genes associated with pain-related processes in returning their expression toward levels observed in naïve, noninjured animals. DTMP provides a more effective way of modulating the expression of genes involved in pain-relevant biological processes associated with neuroglial interactions.

Spinal cord stimulation using differential target multiplexed programming modulates neural cell-specific transcriptomes in an animal model of neuropathic pain

“…As previously reported, the pain model sets an immune and inflammatory response that involves glial cells. 3,13 The larger effect on microglia reflects the early stage of the development of chronic pain in our model. By the time tissues are dissected, animals in the FDR: false discovery rate.…”

<p>Sensing Evoked Compound Action Potentials from the Spinal Cord: Novel Preclinical and Clinical Considerations for the Pain Management Researcher and Clinician</p>

“…Balanced, biphasic stimulation with a phase pulse width of under 200 µs on 1×8 percutaneous SCS leads provides a reasonable range of pulse width choices for the newest stimulation paradigms, such as those applied in recent bioinformatics work in SCS in preclinical models, while simultaneously providing for high-fidelity resolution of the N1/P2 features of the ECAP. 25 Where longer pulse widths are desired to optimize coverage for paresthesiabased SCS therapies, for instance, caution is warranted to ensure the reported ECAP truly represents neural activation versus merely misclassification of stimulation artifact or other non-physiologic noise. 26…”

Prospective, Multicenter Feasibility Study to Evaluate Differential Target Multiplexed Spinal Cord Stimulation Programming in Subjects With Chronic Intractable Back Pain With or Without Leg Pain

“…Behavioral and molecular biology-based results from these studies have shown that the multiplexed programming approach may be more effective than standard and high-frequency (1,200-Hz) SCS programming. 7 Certain aspects of the feasibility study design deserve further discussion. Programming of standard SCS was assisted by a representative from the manufacturer of the commercially available SCS system, while a representative from the sponsor of the study assisted with the multiplexed programming.…”

“…[3][4][5][6] A new programming approach that has shown significant promise in preclinical studies is based on a Differential Target Multiplexed approach that uses multiple electrical signals that can be different from one another in aspects such as frequencies, pulse rates, and amplitudes. 7 It is the first programming approach that has been shown to be significantly better than lowrate (50-Hz) programming and high-rate (1, programming in all 3 pain-like behavior experiments (mechanical, cold, and heat hypersensitivity) using the spared nerve injury model of neuropathic pain in rats. In this model, the Differential Target Multiplexed programming approach modulated more chronic pain related biological processes back toward their state in uninjured, non-implanted (na€ ıve) animals than low-rate programming and high-rate programming.…”