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Objective: Spinal cord stimulation has become an established method within the therapy of chronic pain allowing for significant pain relief. Surgical leads usually must be implanted via a surgical procedure involving unilateral or bilateral muscle detachment and partial laminectomy., Methods: We present the application of a novel minimal invasive microsurgical approach for lead placement, which combines the beneficial advantages of anatomic midline lead placement while preserving the midline structures, avoiding muscle detachments, and thus ensuring spinal stability: spinal process splitting laminotomy., Conclusions: The spinal process splitting laminotomy technique can be successfully applied to introduce the surgical leads for spinal cord stimulation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Traumatic peripheral nerve injuries (PNI) often result in severe neuropathic pain which typically becomes chronic, is recalcitrant to common analgesics, and is associated with sleep disturbances, anxiety, and depression. Pharmacological treatments proven to be effective against neuropathic pain are not well tolerated due to side effects. Neuromodulative interventions such as peripheral nerve or spinal cord stimulation have generated mixed results and may be limited by reduced somatotopic specificity. Dorsal root ganglion (DRG) stimulation may be more effective in this etiology., Materials and Methods: Twenty-seven patients were trialed with a DRG neurostimulation system for PNI; trial success (defined as ≥50% pain relief) was 85%, and 23 patients received a permanent stimulator. However, 36-month outcome data was only available for 21 patients. Pain, quality of life, mental and physical function, and opioid usage were assessed at baseline and at 3-, 6-, 12-, 18-, 24-, and 36 months post-permanent implant. Implant-related complications were also documented., Results: Compared to baseline, we observed a significant pain relief (p < 0.001) at 3 (58%), 12 (66%), 18 (69%), 24 (71%), and 36 months (73%) in 21 patients (52.5 ± 14.2 years; 12 female), respectively. Mental and physical function showed immediate and sustained improvements. Participants reported improvements in quality of life. Opioid dosage reduced significantly (p < 0.001) at 3 (30%), 12 (93%), 18 (98%), 24 (99%), and 36 months (99%), and 20 of 21 patients were completely opioid-free after 36 months. There were five lead migrations and two electrode fractures (corrected by surgical intervention) and one wound infection (conservatively managed)., Conclusions: DRG neuromodulation appears to be a safe, effective, and durable option for treating neuropathic pain caused by PNI. The treatment allows cessation of often ineffective pharmacotherapy (including opioid misuse) and significantly improves quality of life., (© 2020 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC. on behalf of International Neuromodulation Society.)

Background and Objectives: Multiple variables play a role in spinal cord stimulation (SCS) treatment outcomes, including patient anatomy, pain pattern, lead location, stimulation parameters, and so on. A wide range of stimulation parameters are considered safe and on-label, and as a result a growing number of new frequencies and frequency-combinations are being incorporated into standard practice. A standardized approach to therapy delivery may provide more consistent outcomes for more patients. The Vectors study evaluated whether there is significant sustained improvement in pain and functional outcomes when therapy is delivered using a standardized approach., Materials and Methods: Vectors, a post-market, single-arm study evaluated the safety and efficacy of SCS with an implantable neurostimulator starting with 1 kHz stimulation, targeting the T9-T10 disc space following paresthesia mapping. Subjects with chronic intractable low back and leg pain (visual analogue scale [VAS] ≥ 50 mm) were enrolled. The primary endpoint was change in overall pain (VAS) at the three-month visit compared to baseline. Subjects were followed through 12 months. Secondary endpoints included changes in low back and leg pain, quality of life (European Quality of Life - Five Dimensions, EQ-5D-5L), disability (Oswestry Disability Index, ODI), individual subject goals, and subject satisfaction., Results: There was a significant reduction in overall pain (VAS; 45.4 mm) through the three-month visit, which was sustained through 12 months. At 12 months, 79% of subjects had ≥50% improvement in at least one pain domain (overall, lowback or leg) with 85% of subjects reporting therapy satisfaction. There was a decrease in disability and an improvement in quality of life with 70% of subjects achieving a personal activity goal by the three-month visit., Conclusions: Long-term pain relief and improvement in quality of life and function were achieved when following a standardized workflow., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT03345472., (© 2020 Medtronic. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC on behalf of International Neuromodulation Society.)

While numerous studies and patient experiences have demonstrated the efficacy of spinal cord stimulation as a treatment for chronic neuropathic pain, the exact mechanism underlying this therapy is still uncertain. Recent studies highlighting the importance of microglial cells in chronic pain and characterizing microglial activation transcriptomes have created a focus on microglia in pain research. Our group has investigated the modulation of gene expression in neurons and glial cells after spinal cord stimulation (SCS), specifically focusing on transcriptomic changes induced by varying SCS stimulation parameters. Previous work showed that, in rodents subjected to the spared nerve injury (SNI) model of neuropathic pain, a differential target multiplexed programming (DTMP) approach provided significantly better relief of pain-like behavior compared to high rate (HRP) and low rate programming (LRP). While these studies demonstrated the importance of transcriptomic changes in SCS mechanism of action, they did not specifically address the role of SCS in microglial activation. The data presented herein utilizes microglia-specific activation transcriptomes to further understand how an SNI model of chronic pain and subsequent continuous SCS treatment with either DTMP, HRP, or LRP affects microglial activation. Genes for each activation transcriptome were identified within our dataset and gene expression levels were compared with that of healthy animals, naïve to injury and interventional procedures. Pearson correlations indicated that DTMP yields the highest significant correlations to expression levels found in the healthy animals across all microglial activation transcriptomes. In contrast, HRP or LRP yielded weak or very weak correlations for these transcriptomes. This work demonstrates that chronic pain and subsequent SCS treatments can modulate microglial activation transcriptomes, supporting previous research on microglia in chronic pain. Furthermore, this study provides evidence that DTMP is more effective than HRP and LRP at modulating microglial transcriptomes, offering potential insight into the therapeutic efficacy of DTMP.

Background: Clinical research suggests that a novel spinal cord stimulation (SCS) waveform, known as Burst-SCS, specifically targets cognitive-motivational aspects of pain. The objective of the present study was to assess the cognitive-motivational aspects of Tonic- and Burst SCS-induced pain relief, by means of exit latency in the mechanical conflict-avoidance system (MCAS), in a rat model of chronic neuropathic pain., Methods: Exit latency on the MCAS operant testing setup was evaluated at various probe heights for rats (n = 26) with chronic neuropathic pain induced by a partial sciatic nerve ligation (PSNL). Von Frey paw withdrawal analysis was performed to assess mechanical hypersensitivity. In a second experiment (n = 12), the behavioral effect of Tonic SCS or biphasic Burst SCS on both Von Frey analysis and MCAS exit latency was assessed., Results: Burst SCS exit latencies differed significantly from Tonic SCS exit latencies at 4 mm probe height (3.8 vs. 5.8 sec, respectively; p < 0.01) and 5 mm probe height (3.2 vs. 5.4 sec respectively; p < 0.05). This difference was not detected with reflex-based Von Frey testing (Tonic-SCS vs. Burst-SCS at 30 min stimulation: p = 0.73, and at 60 min stimulation; p = 0.42)., Conclusions: Testing of MCAS exit latency allows for detection of cognitive-motivational pain relieving aspects induced by either Tonic- or Burst-SCS in treatment of chronic neuropathic rats. Our behavioral findings strongly suggest that Burst-SCS specifically affects, much more than Tonic-SCS, the processing of cognitive-motivational aspects of pain., (© 2019 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals, Inc. on behalf of International Neuromodulation Society.)

Objectives: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS., Methods: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner., Results: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas., Conclusions: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst., (© 2020 World Institute of Pain.)

Introduction: ACCURATE, a randomized controlled trial comparing dorsal root ganglion (DRG) stimulation to spinal cord stimulation, showed that DRG stimulation is a safe and effective therapy in individuals with lower extremity chronic pain due to complex regional pain syndrome (CRPS) type I or II. Investigators noted that DRG stimulation programming could be adjusted to minimize, or eliminate, the feeling of paresthesia while maintaining adequate pain relief. The present study explores treatment outcomes for DRG subjects who were paresthesia-free vs. those who experienced the sensation of paresthesia, as well as the factors that predicted paresthesia-free analgesia., Methods: A retrospective analysis of therapy outcomes was conducted for 61 subjects in the ACCURATE study who received a permanent DRG neurostimulator. Outcomes of subjects who were paresthesia-free were compared to those who experienced paresthesia-present therapy at 1, 3, 6, 9, and 12-month follow-ups. Predictor variables for the presence or absence of paresthesias with DRG stimulation were also explored., Results: The percentage of subjects with paresthesia-free pain relief increased from 16.4% at 1-month to 38.3% at 12-months. Paresthesia-free subjects generally had similar or better outcomes for pain severity, pain interference, quality of life, and mood state as subjects with paresthesia-present stimulation. Factors that increased the odds of a subject feeling paresthesia were higher stimulation amplitudes and frequencies, number of implanted leads, and younger age., Conclusions: Some DRG subjects achieved effective paresthesia-free analgesia in the ACCURATE trial. This supports the observation that paresthesia is not synonymous with pain relief or required for optimal analgesia with DRG stimulation., (© 2019 International Neuromodulation Society.)

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.

Objective: To investigate the effect of phase polarity and charge balance of spinal cord stimulation (SCS) waveforms on pain behavior and gene expression in a neuropathic pain rodent model. We hypothesized that differing waveforms will result in diverse behavioral and transcriptomics expression due to unique mechanisms of action., Materials and Methods: Rats were implanted with a four-contact cylindrical mini-lead and randomly assigned to two control (no-pain and pain model) and five test groups featuring monophasic, as well as charge-unbalanced and charge-balanced biphasic SCS waveforms. Mechanical and cold allodynia were assessed to measure efficacy. The ipsilateral dorsal quadrant of spinal cord adjacent to the lead was harvested post-stimulation and processed to determine gene expression via real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Gene expression, SCS intensity (mA), and behavioral score as percent of baseline (BSPB) were statistically analyzed and used to generate correlograms using R-Studio. Statistical analysis was performed using SPSS22.0, and p < 0.05 was considered significant., Results: As expected, BSPB was significantly lower for the pain model group compared to the no-pain group. BSPB was significantly improved post-stim compared to pre-stim using cathodic, anodic, symmetric biphasic, or asymmetric biphasic 1:2 waveforms; however, BSPB was not restored to Sham levels. RT-PCR analysis showed that eight genes demonstrated a significant difference between the pain model and SCS waveforms and between waveforms. Correlograms reveal a linear correlation between regulation of expression of a given gene in relation to mA, BSPB, or other genes., Conclusions: Our results exhibit that specific SCS waveforms differentially modulate several key transcriptional pathways that are relevant in chronic pain conditions. These results have significant implications for SCS: whether to move beyond traditional paradigm of neuronal activation to focus also on modulating immune-driven processes., (© 2019 International Neuromodulation Society.)

Objectives: Even if spinal cord stimulation (SCS) is widely used and effective in treating intractable chronic neuropathic pain conditions, little is known about its possible impacts on sensory perception. Quantitative sensory testing (QST) is a useful tool to assess this issue. The aim of this study was to review the impact of tonic SCS on somatosensory perception quantified by QST in chronic pain patients., Materials and Methods: Relevant articles and abstracts were searched in all languages from CINAHL, Cochrane, Embase, MEDLINE, and Web of Knowledge data bases. Data were extracted and included studies were assessed for risk of bias., Results: Out of 5610 records, 15 peer-reviewed articles were eligible and included. The results are heterogeneous due to inadequate comparability among studies for populations (a total of 224 patients diagnosed with more than 13 chronic pain conditions), QST parameters (22 measured with 25 different devices) and experimental procedures (study design, comparator, evaluation time, and area tested). The wide variety of studies, designs, populations, and measures included in this review did not lead to strong evidence on how conventional ("tonic") SCS affects sensory processing in patients with chronic pain., Conclusions: The data available tend to suggest that conventional SCS does not interfere with perception of external stimuli. New studies that follow a standardized procedure and consider the possible influence of sensory profile, after-effect bias, and confounding factors are required to confirm this observation. Moreover, the impact on sensory perception of other SCS modalities and alternative electrical neuromodulation therapies could also be explored., (© 2018 International Neuromodulation Society.)

Background: Few studies have evaluated single-gene changes modulated by spinal cord stimulation (SCS), providing a narrow understanding of molecular changes. Genomics allows for a robust analysis of holistic gene changes in response to stimulation., Methods: Rats were randomized into six groups to determine the effect of continuous SCS in uninjured and spared-nerve injury (SNI) animals. After behavioral assessment, tissues from the dorsal quadrant of the spinal cord (SC) and dorsal root ganglion (DRG) underwent full-genome microarray analyses. Weighted Gene Correlation Network Analysis (WGCNA), and Gene Ontology (GO) analysis identified similar expression patterns, molecular functions and biological processes for significant genes., Results: Microarray analyses reported 20,985 gene probes in SC and 19,104 in DRG. WGCNA sorted 7449 SC and 4275 DRG gene probes into 29 and 9 modules, respectively. WGCNA provided significant modules from paired comparisons of experimental groups. GO analyses reported significant biological processes influenced by injury, as well as the presence of an electric field. The genes Tlr2, Cxcl16, and Cd68 were used to further validate the microarray based on significant response to SCS in SNI animals. They were up-regulated in the SC while both Tlr2 and Cd68 were up-regulated in the DRG., Conclusions: The process described provides highly significant interconnected genes and pathways responsive to injury and/or electric field in the SC and DRG. Genes in the SC respond significantly to the SCS in both injured and uninjured animals, while those in the DRG significantly responded to injury, and SCS in injured animals., (© 2016 International Neuromodulation Society.)

We present a case of a 43-year-old woman with a history of Parkinson's disease and chronic neuropathic pain secondary to trauma. She was implanted with a spinal cord simulator to relieve her persistent intractable pain. After the implantation of the device the patient not only was relieved of her neuropathic pain but also found significant improvement in her Parkinson symptoms., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Spinal cord stimulation (SCS) involves the utilization of an implantable neurostimulation device, stereotypically used in the treatment of patients with chronic neuropathic pain. While these devices have been shown to have significant clinical benefits, there have also been documented potential complications, including the risk of infection, fractured electrodes, electrode migration, and lack of symptom improvement. In addition, there has been minimal documentation on gastrointestinal (GI) side effects after SCS implantation. Case Description: A 42-year-old patient with chronic axial and radicular neuropathic pain in her back and left leg status post multiple lumbar surgeries underwent implantation of an open paddle lead in the T8-T9 region. After the procedure, the patient endorsed a 50% decrease in pain at the 6-week follow-up with no further concerns. However, at the 18 months follow-up, the patient endorsed severe constipation when the SCS was turned on, leading to subsequent evaluation by gastroenterology, motility studies, and a thorough bowel regimen. Symptoms persisted, and the patient ultimately opted for the removal of the SCS implant at 21 months after the initial surgery. Conclusion: While the exact mechanism behind the GI side effects endorsed in this patient is unknown, current literature postulates a variety of theories, including a SCS-induced parasympathetic blockade of the GI tract. Further, investigation is needed to determine the exact effects of SCS on the GI tract. [ABSTRACT FROM AUTHOR]

Background: High frequency stimulation (HFS) may provide pain relief without the paresthesias typical of traditional low-frequency Spinal cord stimulation (SCS). Methods: A consecutive single-center series of patients was retrospectively reviewed to evaluate safety and efficacy of HF10 therapy. In this 24-month study, 62 patients with variables pathologies (44 patients with back failure surgery syndrome (FBSS), 18 patients with chronic peripheral neuropathic pain in the lower limbs (NeppL) were included to be treated with HF10. Pain outcomes were compared from preoperative baseline and at the conclusion of each study period. Clinical features, outcomes and complications were reviewed. Results: 62 patients completed this study. All patients had a successful trial before the definitive implantation of a spinal cord stimulator at the low dorsal level. The mean follow-up period was 11 months, ranging from 6 to 24 months. 6 patients showed no change from baseline visual analogue scale (VAS) after permanent implant and 2 had improved during the trial but was aggravated after the permanent implant placement. At 1 month, 63% of implanted HF10 therapy subjects were responders and 77% at 6 months. The average baseline, trial and postoperative Visual Analogue Scale (VAS) was 8.1, 3.6 and 4.2 respectively. When compared to the baseline, the average reduction achieved during the VAS trial was 4.5 points, accounting for a 56% pain reduction. The long-term failure rate was 22%. Conclusions: This study generated preliminary evidence showing improved VAS current pain scores in absence of paresthesias and increase patient satisfaction with HF10 spinal cord stimulation.

Treatment of chronic neuropathic pain is a devastating problem when proper symptom relief is hardly achievable. Many of the treated patients become unable to work because of their disability and face psychosocial problems. Failed Back Surgery Syndrome is defined as persisting chronic neuropathic pain after a successful lumbar spine surgery. Spinal cord stimulation remains a treatment option when modern pain treatment modalities fail. Although such treatment’s efficacy is proved and it is used globally, in Lithuania very few patients had the benefit of such treatment. In this article we describe a 55-year-old male patient, treated for Failed Back Surgery Syndrome using spinal cord stimulation in The Hospital of Lithuanian University of Health Sciences (LSMU) Kauno klinikos.

Abstract: Elevated spinal extracellular γ-aminobutyric acid (GABA) levels have been described during spinal cord stimulation (SCS)-induced analgesia in experimental chronic peripheral neuropathy. Interestingly, these increased GABA levels strongly exceeded the time frame of SCS-induced analgesia. In line with the former, pharmacologically-enhanced extracellular GABA levels by GABAB receptor agonists in combination with SCS in non-responders to SCS solely could convert these non-responders into responders. However, similar treatment with GABAA receptor agonists and SCS is known to be less efficient. Since K+ Cl− cotransporter 2 (KCC2) functionality strongly determines proper GABAA receptor-mediated inhibition, both decreased numbers of GABAA receptors as well as reduced KCC2 protein expression might play a pivotal role in this loss of GABAA receptor-mediated inhibition in non-responders. Here, we explored the mechanisms underlying both changes in extracellular GABA levels and impaired GABAA receptor-mediated inhibition after 30min of SCS in rats suffering from partial sciatic nerve ligation (PSNL). Immediately after cessation of SCS, a decreased spinal intracellular dorsal horn GABA-immunoreactivity was observed in responders when compared to non-responders or sham SCS rats. One hour later however, GABA-immunoreactivity was already increased to similar levels as those observed in non-responder or sham SCS rats. These changes did not coincide with alterations in the number of GABA-immunoreactive cells. C-Fos/GABA double-fluorescence clearly confirmed a SCS-induced activation of GABA-immunoreactive cells in responders immediately after SCS. Differences in spinal dorsal horn GABAA receptor-immunoreactivity and KCC2 protein levels were absent between all SCS groups. However, KCC2 protein levels were significantly decreased compared to sham PSNL animals. In conclusion, reduced intracellular GABA levels are only present during the time frame of SCS in responders and strongly point to a SCS-mediated on/off GABAergic release mechanism. Furthermore, a KCC2-dependent impaired GABAA receptor-mediated inhibition seems to be present both in responders and non-responders to SCS due to similar KCC2 and GABAA receptor levels. [Copyright &y& Elsevier]

Abstract: The effect of Spinal Cord Stimulation (SCS) in chronic neuropathic pain is inversely related to the severity of mechanical allodynia and the underlying mechanisms are poorly understood. To understand these mechanisms further we aimed to develop a model of SCS in a neuropathic mouse. Further, the CatWalk analysis, which is claimed to be an improved test for mechanical allodynia and therapeutic intervention, was used to analyze the effect of SCS on mechanical allodynia. Male C57BL/6 mice (N =31) underwent partial ligation of the sciatic nerve. After 14days an electrode was implanted and the effect of SCS (N =22) on mechanical allodynia was tested. Unligated mice (N =8) also received SCS. Behavioral analysis was performed using von Frey filaments and the CatWalk system. The withdrawal threshold showed a significant decrease which remained over time. Changes in CatWalk parameters were observed after 2days, but tended to diminish during the next 14days. Thirty minutes of SCS resulted in a 100% response and return to pre-neuropathy levels of the withdrawal threshold. The effect of SCS on the withdrawal threshold was comparable for the most severe and milder allodynic animals. SCS did not affect any of the CatWalk parameters in all mice. In conclusion, we developed a model of SCS in a chronic neuropathic pain C57BL/6 mouse. The CatWalk gait analysis does not result in the detection of behavioral changes to SCS in mice with chronic neuropathic pain and control animals. This model allows future molecular-genetic studies on the mechanisms of SCS in chronic neuropathic pain. [Copyright &y& Elsevier]