Computational modeling of dorsal root ganglion stimulation using an Injectrode.

Objective.Minimally invasive neuromodulation therapies like the Injectrode, which is composed of a tightly wound polymer-coated Platinum/Iridium microcoil, offer a low-risk approach for administering electrical stimulation to the dorsal root ganglion (DRG). This flexible electrode is aimed to conform to the DRG. The stimulation occurs through a transcutaneous electrical stimulation (TES) patch, which subsequently transmits the stimulation to the Injectrode via a subcutaneous metal collector. However, it is important to note that the effectiveness of stimulation through TES relies on the specific geometrical configurations of the Injectrode-collector-patch system. Hence, there is a need to investigate which design parameters influence the activation of targeted neural structures.Approach.We employed a hybrid computational modeling approach to analyze the impact of Injectrode system design parameters on charge delivery and neural response to stimulation. We constructed multiple finite element method models of DRG stimulation, followed by the implementation of multi-compartment models of DRG neurons. By calculating potential distribution during monopolar stimulation, we simulated neural responses using various parameters based on prior acute experiments. Additionally, we developed a canonical monopolar stimulation and full-scale model of bipolar bilateral L5 DRG stimulation, allowing us to investigate how design parameters like Injectrode size and orientation influenced neural activation thresholds.Main results.Our findings were in accordance with acute experimental measurements and indicate that the minimally invasive Injectrode system predominantly engages large-diameter afferents (Aß-fibers). These activation thresholds were contingent upon the surface area of the Injectrode. As the charge density decreased due to increasing surface area, there was a corresponding expansion in the stimulation amplitude range before triggering any pain-related mechanoreceptor (Aδ-fibers) activity.Significance.The Injectrode demonstrates potential as a viable technology for minimally invasive stimulation of the DRG. Our findings indicate that utilizing a larger surface area Injectrode enhances the therapeutic margin, effectively distinguishing the desired Aßactivation from the undesired Aδ-fiber activation.

Use of a Sheath and Stylet for a Difficult Dorsal Root Ganglion Stimulation Lead Extraction: A Case Report.

Dorsal root ganglion stimulation (DRG-S) is a relatively new neuromodulation technique that has shown promising results in the treatment of chronic pain conditions. We present a case of a difficult lead extraction during the explantation of a DRG-S device. The lead was unable to be removed despite multiple attempts until a sheath and stylet were used to facilitate extraction. As DRG-S utilization becomes more widespread, DRG-S device explantation will inevitably become more common. The technique described in this report may be beneficial in certain cases of difficult DRG-S lead extraction.

Cancer-mediated axonal guidance of sensory neurons in a microelectrode-based innervation MPS.

Despite recent advances in the field of microphysiological systems (MPSs), availability of models capable of mimicking the interactions between the nervous system and innervated tissues is still limited. This represents a significant challenge in identifying the underlying processes of various pathological conditions, including neuropathic, cardiovascular and metabolic disorders. In this novel study, we introduce a compartmentalized three-dimensional (3D) coculture system that enables physiologically relevant tissue innervation while recording neuronal excitability. By integrating custom microelectrode arrays into tailored glass chips microfabricated via selective laser-etching, we developed an entirely novel class of innervation MPSs (INV-MPS). This INV-MPS allows for manipulation, visualization, and electrophysiological analysis of individual axons innervating complex 3D tissues. Here, we focused on sensory innervation of 3D tumor tissue as a model case study since cancer-induced pain represents a major unmet medical need. The system was compared with existing nociception models and successfully replicated axonal chemoattraction mediated by nerve growth factor (NGF). Remarkably, in the absence of NGF, 3D cancer spheroids cocultured in the adjacent compartment induced sensory neurons to consistently cross the separating barrier and establish fine innervation. Moreover, we observed that crossing sensory fibers could be chemically excited by distal application of known pain-inducing agonists only when cocultured with cancer cells. To our knowledge, this is the first system showcasing morphological and electrophysiological analysis of 3D-innervated tumor tissuein vitro, paving the way for a plethora of studies into innervation-related diseases and improving our understanding of underlying pathophysiology.

Multiformity of extracellular microelectrode recordings from Aδ neurons in the dorsal root ganglia: a computational modeling study.

Microelectrodes serve as a fundamental tool in electrophysiology research throughout the nervous system, providing a means of exploring neural function with a high resolution of neural firing information. We constructed a hybrid computational model using the finite element method and multicompartment cable models to explore factors that contribute to extracellular voltage waveforms that are produced by sensory pseudounipolar neurons, specifically smaller A-type neurons, and that are recorded by microelectrodes in dorsal root ganglia. The finite element method model included a dorsal root ganglion, surrounding tissues, and a planar microelectrode array. We built a multicompartment neuron model with multiple trajectories of the glomerular initial segment found in many A-type sensory neurons. Our model replicated both the somatic intracellular voltage profile of Aδ low-threshold mechanoreceptor neurons and the unique extracellular voltage waveform shapes that are observed in experimental settings. Results from this model indicated that tortuous glomerular initial segment geometries can introduce distinct multiphasic properties into a neuron's recorded waveform. Our model also demonstrated how recording location relative to specific microanatomical components of these neurons, and recording distance from these components, can contribute to additional changes in the multiphasic characteristics and peak-to-peak voltage amplitude of the waveform. This knowledge may provide context for research employing microelectrode recordings of pseudounipolar neurons in sensory ganglia, including functional mapping and closed-loop neuromodulation. Furthermore, our simulations gave insight into the neurophysiology of pseudounipolar neurons by demonstrating how the glomerular initial segment aids in increasing the resistance of the stem axon and mitigating rebounding somatic action potentials.NEW & NOTEWORTHY We built a computational model of sensory neurons in the dorsal root ganglia to investigate factors that influence the extracellular waveforms recorded by microelectrodes. Our model demonstrates how the unique structure of these neurons can lead to diverse and often multiphasic waveform profiles depending on the location of the recording contact relative to microanatomical neural components. Our model also provides insight into the neurophysiological function of axon glomeruli that are often present in these neurons.

Burst Spinal Cord Stimulation as Compared With L2 Dorsal Root Ganglion Stimulation in Pain Relief for Nonoperated Discogenic Low Back Pain: Analysis of Two Prospective Studies.

INTRODUCTION: Chronic discogenic low back pain (CD-LBP) is caused by degenerated disks marked by neural and vascular ingrowth. Spinal cord stimulation (SCS) has been shown to be effective for pain relief in patients who are not responsive to conventional treatments. Previously, the pain-relieving effect of two variations of SCS has been evaluated in CD-LBP: Burst SCS and L2 dorsal root ganglion stimulation (DRGS). The aim of this study is to compare the effectivity in pain relief and pain experience of Burst SCS with that of conventional L2 DRGS in patients with CD-LBP. MATERIALS AND METHODS: Subjects were implanted with either Burst SCS (n = 14) or L2 DRGS with conventional stimulation (n = 15). Patients completed the numeric pain rating score (NRS) for back pain and Oswestry disability index (ODI) and EuroQoL 5D (EQ-5D) questionnaires at baseline, and at three, six, and 12 months after implantation. Data were compared between time points and between groups. RESULTS: Both Burst SCS and L2 DRGS significantly decreased NRS, ODI, and EQ-5D scores as compared with baseline. L2 DRGS resulted in significantly lower NRS scores at 12 months and significantly increased EQ-5D scores at six and 12 months. CONCLUSIONS: Both L2 DRGS and Burst SCS resulted in reduction of pain and disability, and increased quality of life in patients with CD-LBP. L2 DRGS provided significantly increased pain relief and improvement in quality of life when compared with Burst SCS. CLINICAL TRIAL REGISTRATION: The clinical trial registration numbers for the study are NCT03958604 and NL54405.091.15.

Effectiveness of combined dorsal root ganglion and spinal cord stimulation: a retrospective, single-centre case series for chronic focal neuropathic pain.

OBJECTIVE: This case series retrospectively reviewed the outcomes in patients implanted with combined, synchronous dorsal root ganglion stimulation (DRGS) and spinal cord stimulation (SCS) connected to a single implantable pulse generator (IPG) in a tertiary referral neuromodulation centre in the United Kingdom. METHODS: Twenty-six patients underwent a trial of DRGS+SCS for treating focal neuropathic pain between January 2016 and December 2019, with a follow-up in February 2022. A Transgrade approach was employed for DRGS. Patients were provided with 3 possible stimulation programs: DRGS-only, SCS-only, or DRGS+SCS. Patients were assessed for pain intensity, patients' global impression of change (PGIC), preferred lead(s) and complications. RESULTS: Twenty patients were successful and went on for full implantation. The most common diagnosis was Complex Regional Pain Syndrome. After an average of 3.1 years follow-up, 1 patient was lost to follow-up, and 2 were non-responders. Of the remaining 17 patients, 16 (94%) continued to report a PGIC of 7. The average pain intensity at Baseline was 8.5 on an NRS scale of 0-10. At the last follow-up, the average NRS reduction overall was 78.9% with no statistical difference between those preferring DRGS+SCS (n = 9), SCS-only (n = 3) and DRGS-only (n = 5). The combination of DRGS+SCS was preferred by 53% at the last follow-up. There were no serious neurological complications. CONCLUSIONS: This retrospective case series demonstrates the potential effectiveness of combined DRGS+SCS with sustained analgesia observed at an average follow-up of over 3 years. Implanting combined DRGS+SCS may provide programming flexibility and therapeutic alternatives.

Bilateral T12 Dorsal Root Ganglion Stimulation for the Treatment of Low Back Pain With 20-Hz and 4-Hz Stimulation, a Retrospective Study.

OBJECTIVES: Chronic low back pain (CLBP) is one of the most common chronic pain conditions that cause both individual suffering and a burden to society. For these patients, several interventional treatment options such as surgery, blocks, radiofrequency, and spinal cord stimulation are available. Lately, dorsal root ganglion stimulation (DRG-S) also has been mentioned as an option by targeting bilateral T12 dorsal ganglia. In this study, we present the outcome of 11 patients with CLBP treated with bilateral T12 DRG-S. MATERIALS AND METHODS: Thirteen patients with CLBP with and without leg pain were treated with bilateral T12 DRG-S. Three of the patients also received a third lumbar lead owing to leg pain. Eleven of the patients had >50% pain relief during the peri- or/and postoperative testing and received a fully implantable neurostimulator. Pain intensity, general health status, quality of life, pain catastrophizing, mental status, sleeping disorder, physical activity, and patient satisfaction were followed using numeric rating scale (NRS), Patient-Reported Outcomes Measurement Information System 29 version 2.1, Pain Catastrophizing Score, Generalized Anxiety Disorder 7-item scale, Patient Health Questionnaire Depression Module, Insomnia Severity Index, and Patient Satisfaction Questionnaire at baseline before implantation and at three months and six months. The results were analyzed on the basis of six domains: pain relief, sleeping disorder, social ability, mental status, physical activity, and satisfaction. To be identified as a responder, the patients should show a significant improvement in the pain relief domain together with at least two other domains. All responders also were given the opportunity to test 4-Hz DRG-S and compare it with traditional 20-Hz stimulation. RESULTS: All 11 patients were identified as responders at six months. Five of the patients had >80% pain relief, with an average NRS score reduction of 71% for the whole group. Significant improvement could be observed in three domains for one patient, four domains for three patients, five domains for six patients, and six domains for one patient. Seven patients chose to try 4-Hz stimulation. All seven identified 4-Hz stimulation as at least as good as or better than 20-Hz stimulation and chose to continue with 4-Hz stimulation. CONCLUSIONS: Bilateral T12 DRG-S seems to be an effective treatment for chronic low back pain, with significant beneficial effect not only on pain but also on quality of life, pain catastrophizing, mental status, sleeping disorder, and physical activity. 4-Hz DRG-S gave a result comparable with or better than 20-Hz stimulation.

Lead migration rate in dorsal root ganglion stimulation using lead anchoring techniques: A follow-up study.

BACKGROUND: Lead anchoring has previously been shown to reduce the rate of dorsal root ganglion stimulation (DRG-S) lead migration. The aim of this study was to assess longer-term follow-up and consistency of lead migration prevention with lead anchoring in a new cohort of patients. METHODS: We performed a retrospective chart review from September 2017 to November 2022 of all patients who had DRG-S implants at our institute to identify the number of lead migrations that occurred over this period. The first cohort consisted of patients reported on in a previous publication (implanted from September 2017 through September 2020) subdivided into unanchored or anchored lead groups. The second cohort consisted of patients implanted during or after October 2020 who were not previously reported on for whom leads were anchored using silastic anchoring only. RESULTS: At the November 2022 data cutoff, in the initial cohort, 8 migrations had occurred in unanchored leads over an average follow-up of 49 months, equating to a migration rate of 9.1% per lead. Patients with anchored leads in the initial cohort experienced 2 migrations over an average follow-up of 38 months (0.7% migration rate per lead). There were no new lead migrations in these groups over the extended follow-up reported here. The migration rate in the new cohort was similar, with 1 migration over an average follow-up of 13 months (0.5% migration rate per lead). CONCLUSION: These results underscore the necessity of anchor placement during DRG-S lead implantation to prevent lead migration.

Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain.

We show here that hyperpolarization-activated current (Ih ) unexpectedly acts to inhibit the activity of dorsal root ganglion (DRG) neurons expressing WT Nav1.7, the largest inward current and primary driver of DRG neuronal firing, and hyperexcitable DRG neurons expressing a gain-of-function Nav1.7 mutation that causes inherited erythromelalgia (IEM), a human genetic model of neuropathic pain. In this study we created a kinetic model of Ih and used it, in combination with dynamic-clamp, to study Ih function in DRG neurons. We show, for the first time, that Ih increases rheobase and reduces the firing probability in small DRG neurons, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih . Our results show that Ih , due to slow gating, is not deactivated during action potentials (APs) and has a striking damping action, which reverses from depolarizing to hyperpolarizing, close to the threshold for AP generation. Moreover, we show that Ih reverses the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM. In the aggregate, our results show that Ih unexpectedly has strikingly different effects in DRG neurons as compared to previously- and well-studied cardiac cells. Within DRG neurons where Nav1.7 is present, Ih reduces depolarizing sodium current inflow due to enhancement of Nav1.7 channel fast inactivation and creates additional damping action by reversal of Ih direction from depolarizing to hyperpolarizing close to the threshold for AP generation. These actions of Ih limit the firing of DRG neurons expressing WT Nav1.7 and reverse the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM. KEY POINTS: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, the molecular determinants of hyperpolarization-activated current (Ih ) have been characterized as a 'pain pacemaker', and thus considered to be a potential molecular target for pain therapeutics. Dorsal root ganglion (DRG) neurons express Nav1.7, a channel that is not present in central neurons or cardiac tissue. Gain-of-function mutations (GOF) of Nav1.7 identified in inherited erythromelalgia (IEM), a human genetic model of neuropathic pain, produce DRG neuron hyperexcitability, which in turn produces severe pain. We found that Ih increases rheobase and reduces firing probability in small DRG neurons expressing WT Nav1.7, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih . We also demonstrate that Ih reverses the hyperexcitability of DRG neurons expressing a GOF Nav1.7 mutation (L858H) that causes IEM. Our results show that, in contrast to cardiac cells and CNS neurons, Ih acts to stabilize DRG neuron excitability and prevents excessive firing.

Unveiling adcyap1 as a protective factor linking pain and nerve regeneration through single-cell RNA sequencing of rat dorsal root ganglion neurons.

BACKGROUND: Severe peripheral nerve injury (PNI) often leads to significant movement disorders and intractable pain. Therefore, promoting nerve regeneration while avoiding neuropathic pain is crucial for the clinical treatment of PNI patients. However, established animal models for peripheral neuropathy fail to accurately recapitulate the clinical features of PNI. Additionally, researchers usually investigate neuropathic pain and axonal regeneration separately, leaving the intrinsic relationship between the development of neuropathic pain and nerve regeneration after PNI unclear. To explore the underlying connections between pain and regeneration after PNI and provide potential molecular targets, we performed single-cell RNA sequencing and functional verification in an established rat model, allowing simultaneous study of the neuropathic pain and axonal regeneration after PNI. RESULTS: First, a novel rat model named spared nerve crush (SNC) was created. In this model, two branches of the sciatic nerve were crushed, but the epineurium remained unsevered. This model successfully recapitulated both neuropathic pain and axonal regeneration after PNI, allowing for the study of the intrinsic link between these two crucial biological processes. Dorsal root ganglions (DRGs) from SNC and naïve rats at various time points after SNC were collected for single-cell RNA sequencing (scRNA-seq). After matching all scRNA-seq data to the 7 known DRG types, we discovered that the PEP1 and PEP3 DRG neuron subtypes increased in crushed and uncrushed DRG separately after SNC. Using experimental design scRNA-seq processing (EDSSP), we identified Adcyap1 as a potential gene contributing to both pain and nerve regeneration. Indeed, repeated intrathecal administration of PACAP38 mitigated pain and facilitated axonal regeneration, while Adcyap1 siRNA or PACAP6-38, an antagonist of PAC1R (a receptor of PACAP38) led to both mechanical hyperalgesia and delayed DRG axon regeneration in SNC rats. Moreover, these effects can be reversed by repeated intrathecal administration of PACAP38 in the acute phase but not the late phase after PNI, resulting in alleviated pain and promoted axonal regeneration. CONCLUSIONS: Our study reveals that Adcyap1 is an intrinsic protective factor linking neuropathic pain and axonal regeneration following PNI. This finding provides new potential targets and strategies for early therapeutic intervention of PNI.

Oligodendrocyte precursor cells stop sensory axons regenerating into the spinal cord.

Primary somatosensory axons stop regenerating as they re-enter the spinal cord, resulting in incurable sensory loss. What arrests them has remained unclear. We previously showed that axons stop by forming synaptic contacts with unknown non-neuronal cells. Here, we identified these cells in adult mice as oligodendrocyte precursor cells (OPCs). We also found that only a few axons stop regenerating by forming dystrophic endings, exclusively at the CNS:peripheral nervous system (PNS) borderline where OPCs are absent. Most axons stop in contact with a dense network of OPC processes. Live imaging, immuno-electron microscopy (immuno-EM), and OPC-dorsal root ganglia (DRG) co-culture additionally suggest that axons are rapidly immobilized by forming synapses with OPCs. Genetic OPC ablation enables many axons to continue regenerating deep into the spinal cord. We propose that sensory axons stop regenerating by encountering OPCs that induce presynaptic differentiation. Our findings identify OPCs as a major regenerative barrier that prevents intraspinal restoration of sensory circuits following spinal root injury.

Core patient-reported outcome measures for chronic pain patients treated with spinal cord stimulation or dorsal root ganglia stimulation.

BACKGROUND: Neurostimulation is a highly effective therapy for the treatment of chronic Intractable pain, however, due to the complexity of pain, measuring a subject's long-term response to the therapy remains difficult. Frequent measurement of patient-reported outcomes (PROs) to reflect multiple aspects of subjects' pain is a crucial step in determining therapy outcomes. However, collecting full-length PROs is burdensome for both patients and clinicians. The objective of this work is to identify the reduced set of questions from multiple validated PROs that can accurately characterize chronic pain patients' responses to neurostimulation therapies. METHODS: Validated PROs were used to capture pain, physical function and disability, as well as psychometric, satisfaction, and global health metrics. PROs were collected from 509 patients implanted with Spinal Cord Stimulation (SCS) or Dorsal Root Ganglia (DRG) neurostimulators enrolled in the prospective, international, post-market REALITY study (NCT03876054, Registration Date: March 15, 2019). A combination of linear regression, Pearson's correlation, and factor analysis were used to eliminate highly correlated questions and find the minimal meaningful set of questions within the predefined domains of each scale. RESULTS: The shortened versions of the questionnaires presented almost identical accuracy for classifying the therapy outcomes as compared to the validated full-length versions. In addition, principal component analysis was performed on all the PROs and showed a robust clustering of pain intensity, psychological factors, physical function, and sleep across multiple PROs. A selected set of questions captured from multiple PROs can provide adequate information for measuring neurostimulation therapy outcomes. CONCLUSIONS: PROs are important subjective measures to evaluate the physiological and psychological aspects of pain. However, these measures are cumbersome to collect. These shorter and more targeted PROs could result in better patient engagement, and enhanced and more frequent data collection processes for digital health platforms that minimize patient burden while increasing therapeutic benefits for chronic pain patients.

Dorsal root ganglion stimulation for chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common consequence of cancer treatment that can be persistent and difficult to manage. Dorsal root ganglion stimulation (DRG-S) is a recently introduced but understudied treatment modality. This study explored the effect of DRG-S on pain and symptom burden associated with CIPN. METHODS: Patients with CIPN who underwent a DRG-S trial between January 2017 and August 2022 were identified through chart review after IRB approval was obtained. Demographic data, procedure details, pre-and postoperative scores, including the Numerical Rating Scale (NRS) and Edmonton Symptom Assessment System (ESAS), and duration of follow-up were recorded. Statistical analysis included descriptive statistics and paired t-tests to compare pre-and postoperative scores. RESULTS: Nine patients with an even mix of solid and hematologic malignancies underwent DRG-S trial and had a statistically significant decrease in NRS scores, with a mean reduction of 2.3 in their average pain (p = 0.014), 2.6 in worst pain (p = 0.023), and 2.1 in least pain (p = 0.018). Eight patients (88.9%) underwent permanent DRG-S implantation. Mean NRS scores remained lower than preoperative baselines through the first year of follow-up. Statistically significant reductions were noted at 3 months in average (2.1, p = 0.006) and least pain scores (1.9, p = 0.045), which further decreased after 6-12 months (average: 3.6, p = 0.049; least: 3.4, p = 0.023). Only the pain component of ESAS scores showed a significant reduction with DRG-S (2.0, p = 0.021). All patients endorsed improved sensation, 75% decreased their pain medication usage, and 37.5% reported complete pain relief by 2 years. CONCLUSION: Dorsal root ganglion stimulation can be an effective treatment for pain related to CIPN and deserves further investigation.

Engineering a multicompartment in vitro model for dorsal root ganglia phenotypic assessment.

Despite the significant global prevalence of chronic pain, current methods to identify pain therapeutics often fail translation to the clinic. Phenotypic screening platforms rely on modeling and assessing key pathologies relevant to chronic pain, improving predictive capability. Patients with chronic pain often present with sensitization of primary sensory neurons (that extend from dorsal root ganglia [DRG]). During neuronal sensitization, painful nociceptors display lowered stimulation thresholds. To model neuronal excitability, it is necessary to maintain three key anatomical features of DRGs to have a physiologically relevant platform: (1) isolation between DRG cell bodies and neurons, (2) 3D platform to preserve cell-cell and cell-matrix interactions, and (3) presence of native non-neuronal support cells, including Schwann cells and satellite glial cells. Currently, no culture platforms maintain the three anatomical features of DRGs. Herein, we demonstrate an engineered 3D multicompartment device that isolates DRG cell bodies and neurites and maintains native support cells. We observed neurite growth into isolated compartments from the DRG using two formulations of collagen, hyaluronic acid, and laminin-based hydrogels. Further, we characterized the rheological, gelation and diffusivity properties of the two hydrogel formulations and found the mechanical properties mimic native neuronal tissue. Importantly, we successfully limited fluidic diffusion between the DRG and neurite compartment for up to 72 h, suggesting physiological relevance. Lastly, we developed a platform with the capability of phenotypic assessment of neuronal excitability using calcium imaging. Ultimately, our culture platform can screen neuronal excitability, providing a more translational and predictive system to identify novel pain therapeutics to treat chronic pain.

Dorsal root ganglion stimulation for the treatment of chronic pelvic pain: A systematic review.

BACKGROUND: Chronic pelvic pain (CPP) is a difficult condition to treat. Due to complex pelvic innervation, dorsal column spinal cord stimulation (SCS) has not been shown to produce the same effect as dorsal root ganglion stimulation (DRGS) given emerging evidence suggesting that applying DRGS may result in favorable outcomes for individuals with CPP. The aim of this systematic review is to investigate the clinical use and effectiveness of DRGS for patients with CPP. MATERIALS AND METHODS: A systematic review of clinical studies demonstrating the use of DRGS for CPP. Searches were conducted using four electronic databases (PubMed, EMBASE, CINAHL, and Web of Science) across August and September 2022. RESULTS: A total of nine studies comprising 65 total patients with variable pelvic pain etiologies met the inclusion criteria. The majority of subjects implanted with DRGS reported >50% mean pain reduction at variable times of follow-up. Secondary outcomes reported throughout studies including quality of life (QOL) and pain medication consumption were reported to be significantly improved. CONCLUSIONS: Dorsal root ganglion stimulation for CPP continues to lack supportive evidence from well-designed, high-quality studies and recommendations from consensus committee experts. However, we present consistent evidence from level IV studies showing success with the use of DRGS for CPP in reducing pain symptoms along with reports of improved QOL through periods as short as 2 months to as long as 3 years. Because the available studies at this time are of low quality with a high risk of bias, we strongly recommend the facilitation of high-quality studies with larger sample sizes in order to better ascertain the utility of DRGS for this specific patient population. At the same time, from a clinical perspective, it may be reasonable and appropriate to evaluate patients for DRGS candidacy on a case-by-case basis, especially those patients who report CPP symptoms that are refractory to noninterventional measures and who may not be ideal candidates for other forms of neuromodulation.

Characteristics of acid-sensing ion channel currents in male rat muscle dorsal root ganglion neurons following ischemia/reperfusion.

Peripheral artery diseases (PAD) increases muscle afferent nerve-activated reflex sympathetic nervous and blood pressure responses during exercise (termed as exercise pressor reflex). However, the precise signaling pathways leading to the exaggerated autonomic responses in PAD are undetermined. Considering that limb ischemia/reperfusion (I/R) is a feature of PAD, we determined the characteristics of acid-sensing ion channel (ASIC) currents in muscle dorsal root ganglion (DRG) neurons under the conditions of hindlimb I/R and ischemia of PAD. In particular, we examined ASIC currents in two distinct subpopulations, isolectin B4 -positive, and B4 -negative (IB4+ and IB4-) muscle DRG neurons, linking to glial cell line-derived neurotrophic factor and nerve growth factor. In results, ASIC1a- and ASIC3-like currents were observed in IB4- muscle DRG neurons with a greater percentage of ASIC3-like currents. Hindimb I/R and ischemia did not alter the distribution of ASIC1a and ASIC3 currents with activation of pH 6.7 in IB4+ and IB4- muscle DRG neurons; however, I/R altered the distribution of ASIC3 currents in IB4+ muscle DRG neurons with pH 5.5, but not in IB4- neurons. In addition, I/R and ischemia amplified the density of ASIC3-like currents in IB4- muscle DRG neurons. Our results suggest that a selective subpopulation of muscle afferent nerves should be taken into consideration when ASIC signaling pathways are studied to determine the exercise pressor reflex in PAD.

[Research on mechanisms of acupoint sensitization in gastric ulcer mice from perspective of dorsal root ganglion neuronal excitability].

OBJECTIVE: To investigate the relationship between acupoint sensitization on the body surface and neuronal intrinsic excitability of the medium- and small-size dorsal root ganglion (DRG) neurons from the perspective of ion channel kinetics in mice with gastric ulcer. METHODS: Male C57BL/6J mice were randomly divided into control (n=32) and model groups (n=34). The gastric ulcer model was established by injection of 60% glacial acetic acid (0.2 mL/100 g) into the gastric wall muscle layer and submucosa near the pylorus in the minor curvature of the stomach. In contrast, the same dose of normal saline was injected in the same way in the control group. Six days after modeling, Evans blue (EB) solution was injected into the mouse's tail vein for observing the number and distribution of the exudation blue spots on the body surface. Histopathological changes of the gastric tissue were observed by H.E. staining. Then, whole-cell membrane currents and intrinsic excitability of medium- and small-size neurons in the spinal T9-T11 DRGs were measured by in vitro electrophysiology combining with biocytin-ABC method. RESULTS: In the control group, EB exudation blue spots were not obvious, while in the model group, the blue spots on the body surface were densely distributed in the area of spinal T9-T11 segments, the epigastric region, and the skin around "Zhongwan" (CV12) and "Huaroumen" (ST24) regions, and near the surgical incision region. Compared with the control group, the model group had a high level of eosinophilic infiltrates in the submucosa of gastric tissues, severe gastric fossa structure damage, gastric fundus gland dilation and other pathological manifestations. The number of exudation blue spots was proportional to the degree of inflammatory reaction in the stomach. In comparison with the control group, the spike discharges of type II of medium-size DRG neurons in T9-T11 segments were decreased, and the current of whole-cell membrane was increased, basic intensity was decreased (P<0.05), discharge frequency and discharge number were increased (P<0.01,P<0.000 1); while the discharges of type I small-size DRG neurons were decreased, those of type II neurons increased, the whole-cell membrane current was decreased, and discharge frequency and discharge number were decreased (P<0.01, P<0.000 1). CONCLUSION: Both the medium- and small-size DRG neurons from the spinal T9-T11 segments involve in gastric ulcer-induced acupoint sensitization via their different spike discharge activities. And intrinsic excitability of these DRG neurons can not only dynamically encode the plasticity of acupoint sensitization, but also can help us understand the neural mechanism of acupoint sensitization induced by visceral injury.

Self-renewing macrophages in dorsal root ganglia contribute to promote nerve regeneration.

Sensory neurons located in dorsal root ganglia (DRG) convey sensory information from peripheral tissue to the brain. After peripheral nerve injury, sensory neurons switch to a regenerative state to enable axon regeneration and functional recovery. This process is not cell autonomous and requires glial and immune cells. Macrophages in the DRG (DRGMacs) accumulate in response to nerve injury, but their origin and function remain unclear. Here, we mapped the fate and response of DRGMacs to nerve injury using macrophage depletion, fate-mapping, and single-cell transcriptomics. We identified three subtypes of DRGMacs after nerve injury in addition to a small population of circulating bone-marrow-derived precursors. Self-renewing macrophages, which proliferate from local resident macrophages, represent the largest population of DRGMacs. The other two subtypes include microglia-like cells and macrophage-like satellite glial cells (SGCs) (Imoonglia). We show that self-renewing DRGMacs contribute to promote axon regeneration. Using single-cell transcriptomics data and CellChat to simulate intercellular communication, we reveal that macrophages express the neuroprotective and glioprotective ligand prosaposin and communicate with SGCs via the prosaposin receptor GPR37L1. These data highlight that DRGMacs have the capacity to self-renew, similarly to microglia in the Central nervous system (CNS) and contribute to promote axon regeneration. These data also reveal the heterogeneity of DRGMacs and their potential neuro- and glioprotective roles, which may inform future therapeutic approaches to treat nerve injury.