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

Abstract

Spinal cord stimulation is a proven effective therapy for treating chronic neuropathic pain. Previous work in our laboratory demonstrated that spinal cord stimulation based on a differential target multiplexed programming approach provided significant relief of pain-like behavior in rodents subjected to the spared nerve injury model of neuropathic pain. The relief was significantly better than obtained using high rate and low rate programming. Furthermore, transcriptomics-based results implied that differential target multiplexed programming modulates neuronal–glial interactions that have been perturbed by the pain process. Although differential target multiplexed programming was developed to differentially target neurons and glial cells, our previous work did not address this. This work presents transcriptomes, specific to each of the main neural cell populations (neurons, microglia, astrocytes, and oligodendrocytes), obtained from spinal cord subjected to continuous spinal cord stimulation treatment with differential target multiplexed programming, high rate programming, or low rate programming compared with no spinal cord stimulation treatment, using the spared nerve injury model. To assess the effect of each spinal cord stimulation treatment on these cell-specific transcriptomes, gene expression levels were compared with that of healthy animals, naïve to injury and interventional procedures. Pearson correlations and cell population analysis indicate that differential target multiplexed programming yielded strong and significant correlations to expression levels found in the healthy animals across every evaluated cell-specific transcriptome. In contrast, high rate programming only yielded a strong correlation for the microglia-specific transcriptome, while low rate programming did not yield strong correlations with any cell types. This work provides evidence that differential target multiplexed programming distinctively targeted and modulated the expression of cell-specific genes in the direction of the healthy state thus supporting its previously established action on regulating neuronal–glial interaction processes in a pain model.

Twelve‐Month results from multicenter, open‐label, randomized controlled clinical trial comparing differential target multiplexed spinal cord stimulation and traditional spinal cord stimulation in subjects with chronic intractable back pain and leg pain

“…29,30 Analysis of neuron-specific and glia-specific gene expression in a rodent model demonstrated that treatment with DTMP modulated gene expression of such cell-specific transcriptomes toward levels found in naïve animals. 18 This supported the hypothesis that DTM SCS provides analgesia by balancing pain-related biological processes, such as neuroinflammation and ion transport, which involve neuron-glial interaction that had been affected by the establishment of neuropathic pain. 17…”

Modulation of microglial activation states by spinal cord stimulation in an animal model of neuropathic pain: Comparing high rate, low rate, and differential target multiplexed programming

“…These findings support the hypothesis that SCS stimulation parameters influence microglial activation and offer potential insight into the outcomes of DTMP in animal studies. 6 , 47 …”

The Evoked Compound Action Potential as a Predictor for Perception in Chronic Pain Patients: Tools for Automatic Spinal Cord Stimulator Programming and Control

“…For many years, the gate control theory served as the putative mechanism of action for the analgesic effects of SCS ( Melzack and Wall, 1965 ). Later work has employed bioinformatics and proteomics to elucidate the susceptibilities of the biochemical and molecular pathways of pain to SCS ( Vallejo et al, 2016 ; Cedeño et al, 2020 ; Tilley et al, 2021 ).…”