Unilateral L4-dorsal root ganglion stimulation evokes pain relief in chronic neuropathic postsurgical knee pain and changes of inflammatory markers: part II whole transcriptome profiling.

BACKGROUND: In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRGSTIM), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways. METHODS: Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRGSTIM using PANTHER™ pathway enrichment analysis tool. RESULTS: Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRGSTIM. Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated. CONCLUSIONS: In our sub-group analysis of L4-DRGSTIM treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267.

Selective L4 Dorsal Root Ganglion Stimulation Evokes Pain Relief and Changes of Inflammatory Markers: Part I Profiling of Saliva and Serum Molecular Patterns.

OBJECTIVES: Complex regional pain syndrome (CRPS) and associated comorbidities have been linked to a pro-inflammatory state driven by different mediators. Targeted dorsal root ganglion stimulation (DRGSTIM ) suppressed pain levels and improved functional capacity in intractable CRPS. However, clinical trials assessing the impact of DRG stimulation on the neuroimmune axis are lacking. METHODS: This study enrolled 24 subjects (12 refractory CRPS patients plus suitably matched healthy controls) and performed immunoassays of inflammatory mediators in saliva and serum along with score-based assessments of pain, mood, and sleep quality at baseline and after three months of selective L4-DRGSTIM . RESULTS: After three-month L4-DRGSTIM CRPS associated pain significantly decreased. In addition, disturbed sleep and mood improved post-DRGSTIM , although statistically not significant. Significantly increased serum values of pro-inflammatory markers were detected pre- and post L4-DRGSTIM for high-mobility group box 1, tumor-necrosis factor α, interleukin (IL) 6, and leptin. IL-1ß was significantly elevated pre-L4 DRGSTIM , but not posttreatment. Elevated anti-inflammatory IL-10 significantly decreased after three months in serum, while saliva oxytocin concentrations increased in CRPS subjects after L4-DRGSTIM (p = 0.65). No severe implantation and stimulation associated adverse events were recorded. CONCLUSIONS: Selective L4-DRGSTIM improved neuropathic pain and functional impairment in CRPS as previously reported. CRPS patients displayed a pro-inflammatory molecular pattern in serum. Serum anti-inflammatory IL-10 significantly declined, while saliva oxytocin nonsignificantly increased after L4-DRGSTIM . An evidence-based relational interpretation of our study is limited due to the uncontrolled study design. However, molecular profiling of biofluids (saliva, serum) represents a novel and experimental field in applied neuromodulation, which warrant further investigations to unveil mechanisms of neuroimmune modulation.

Evaluating Dorsal Root Ganglion Stimulation in a Prospective Dutch Cohort.

OBJECTIVES: Dorsal root ganglion (DRG) stimulation is a recent neuromodulation option that has delivered safe, effective pain relief for a number of etiologies. This prospective observational study was intended to establish the effectiveness of this treatment in a typical real-world clinical context. MATERIALS AND METHODS: Participants with chronic, intractable pain of the trunk or lower limbs were recruited from multiple pain clinics in the Netherlands. Subjects were trialed and implanted with DRG stimulation systems. Pain, function, mood, and quality of life, ratings were collected through 12 months postimplant. RESULTS: Of the 66 subjects enrolled, failed back surgery syndrome, peripheral nerve injury, and complex regional pain syndrome formed the largest etiologies. Permanent implants were placed in 86.2% subjects (56/65). After 12 months of treatment, average pain ratings in subjects' primary area of pain decreased from 8.0 cm at baseline to 4.1 cm, and 49% of subjects had ≥50% reduction in pain (visual analog scale). In addition, functional capacity was increased, and mood and quality of life improved. No confirmed lead migrations were observed, and there was a low rate of infection. CONCLUSIONS: DRG stimulation significantly reduced the severity of subjects' pain and enabled participatory changes that improved quality of life through 12-months postimplant.

Retrospective Case Series on the Treatment of Painful Diabetic Peripheral Neuropathy With Dorsal Root Ganglion Stimulation.

BACKGROUND: The dorsal root ganglion (DRG) has been identified as an important neural structure in the development and maintenance of chronic pain. We present a retrospective case series of patients with refractory painful diabetic peripheral neuropathy (PDPN) that underwent electrical stimulation of the DRG and report on changes in their overall perceived pain and complication rates. METHODS: Ten diabetic males (mean age 65.2 [SD 8.8] years) with painful symptoms of the lower limbs were enrolled and trialed with up to four quadripolar percutaneous DRG stimulation leads between L2 and L5 spinal levels. Patients received a fully implantable neurostimulation system (Abbott Laboratories, Sunnyvale, CA, USA) immediately or after a successful trial period (>50% reduction in pain). Overall perceived pain was measured by visual analogue scale (VAS) at baseline, one-week postimplantation and one-, three-, six-, and twelve-month follow-up (n = 5). RESULTS: Ten patients were included in this retrospective study. Seven of these subjects received permanent stimulator implants after successful externalized or intraoperative trials. Two of those patients subsequently required explantation, due to failure to capture primary pain area (n = 1) and personal reasons (n = 1). For the five subjects that proceeded to clinical follow-ups, baseline VAS was reduced by an average of 63.90% (SD 21.39; p < 0.001) postimplantation. For four patients with available 12-month follow-up data, mean relative reduction in overall perceived pain averaged 64.16% (SD 35.8; p< 0.001). CONCLUSION: Early findings from this small retrospective case series, suggest DRG is a safe and effective neuromodulation modality to improve painful symptoms in PDPN patients. Future prospective trials are required to further investigate the use of DRG stimulation for this clinical indication.

Mechanisms of Dorsal Root Ganglion Stimulation in Pain Suppression: A Computational Modeling Analysis.

OBJECTIVE: The mechanisms of dorsal root ganglion (DRG) stimulation for chronic pain remain unclear. The objective of this work was to explore the neurophysiological effects of DRG stimulation using computational modeling. METHODS: Electrical fields produced during DRG stimulation were calculated with finite element models, and were coupled to a validated biophysical model of a C-type primary sensory neuron. Intrinsic neuronal activity was introduced as a 4 Hz afferent signal or somatic ectopic firing. The transmembrane potential was measured along the neuron to determine the effect of stimulation on intrinsic activity across stimulation parameters, cell location/orientation, and membrane properties. RESULTS: The model was validated by showing close correspondence in action potential (AP) characteristics and firing patterns when compared to experimental measurements. Subsequently, the model output demonstrated that T-junction filtering was amplified with DRG stimulation, thereby blocking afferent signaling, with cathodic stimulation at amplitudes of 2.8-5.5 × stimulation threshold and frequencies above 2 Hz. This amplified filtering was dependent on the presence of calcium and calcium-dependent small-conductance potassium channels, which produced a hyperpolarization offset in the soma, stem, and T-junction with repeated somatic APs during stimulation. Additionally, DRG stimulation suppressed somatic ectopic activity by hyperpolarizing the soma with cathodic or anodic stimulation at amplitudes of 3-11 × threshold and frequencies above 2 Hz. These effects were dependent on the stem axon being relatively close to and oriented toward a stimulating contact. CONCLUSIONS: These results align with the working hypotheses on the mechanisms of DRG stimulation, and indicate the importance of stimulation amplitude, polarity, and cell location/orientation on neuronal responses.

Stimulation of the L2-L3 Dorsal Root Ganglia Induces Effective Pain Relief in the Low Back.

INTRODUCTION: Chronic low back pain affects millions of people worldwide and can arise through a variety of clinical origins. In the case of failed back surgery syndrome (FBSS), previous surgical procedures can contribute to low back pain that is often unresponsive to intervention. Although spinal cord stimulation (SCS) can be an effective treatment modality, it does not provide sufficient pain relief for some intractable cases. Recently, alternative neuromodulation options have been developed, including dorsal root ganglion (DRG) stimulation. The objective of this report is to further investigate these clinical observations. METHODS: Twelve patients with significant chronic discogenic low back pain due to FBSS were included. All subjects underwent implantation of DRG stimulation systems that had at least 1 lead placed at L2 or L3. Subjects' pain ratings, mood, and quality of life were tracked prospectively for up to 12 months. RESULTS: More than half of subjects reported 50% or better pain relief in the low back, and the average low back pain relief was 45.5% at 12 months. Concomitant reductions in overall pain, leg pain, pain interference, mood, and quality of life were also found. DISCUSSION: For the studied population, DRG stimulation at the L2-L3 levels was effective at relieving low back pain. These reductions in pain were associated with improvements in quality of life. Thus, DRG stimulation at these levels may be effective for low back pain by recruiting both segmental and nonsegmental neural pathways that are not otherwise accessible via traditional SCS.

Dorsal root ganglion stimulation attenuates the BOLD signal response to noxious sensory input in specific brain regions: Insights into a possible mechanism for analgesia.

Targeted dorsal root ganglion (DRG) electrical stimulation (i.e. ganglionic field stimulation - GFS) is an emerging therapeutic approach to alleviate chronic pain. Here we describe blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) responses to noxious hind-limb stimulation in a rat model that replicates clinical GFS using an electrode implanted adjacent to the DRG. Acute noxious sensory stimulation in the absence of GFS caused robust BOLD fMRI response in brain regions previously associated with sensory and pain-related response, such as primary/secondary somatosensory cortex, retrosplenial granular cortex, thalamus, caudate putamen, nucleus accumbens, globus pallidus, and amygdala. These regions differentially demonstrated either positive or negative correlation to the acute noxious stimulation paradigm, in agreement with previous rat fMRI studies. Therapeutic-level GFS significantly attenuated the global BOLD response to noxious stimulation in these regions. This BOLD signal attenuation persisted for 20minutes after the GFS was discontinued. Control experiments in sham-operated animals showed that the attenuation was not due to the effect of repetitive noxious stimulation. Additional control experiments also revealed minimal BOLD fMRI response to GFS at therapeutic intensity when presented in a standard block-design paradigm. High intensity GFS produced a BOLD signal map similar to acute noxious stimulation when presented in a block-design. These findings are the first to identify the specific brain region responses to neuromodulation at the DRG level and suggest possible mechanisms for GFS-induced treatment of chronic pain.

Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial.

Animal and human studies indicate that electrical stimulation of dorsal root ganglion (DRG) neurons may modulate neuropathic pain signals. ACCURATE, a pivotal, prospective, multicenter, randomized comparative effectiveness trial, was conducted in 152 subjects diagnosed with complex regional pain syndrome or causalgia in the lower extremities. Subjects received neurostimulation of the DRG or dorsal column (spinal cord stimulation, SCS). The primary end point was a composite of safety and efficacy at 3 months, and subjects were assessed through 12 months for long-term outcomes and adverse events. The predefined primary composite end point of treatment success was met for subjects with a permanent implant who reported 50% or greater decrease in visual analog scale score from preimplant baseline and who did not report any stimulation-related neurological deficits. No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving ≥50% pain relief and treatment success was greater in the DRG arm (81.2%) than in the SCS arm (55.7%, P < 0.001) at 3 months. Device-related and serious adverse events were not different between the 2 groups. Dorsal root ganglion stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (P < 0.001) and reduced extraneous stimulation in nonpainful areas (P = 0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities. As the largest prospective, randomized comparative effectiveness trial to date, the results show that DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS.

Dorsal Root Ganglion (DRG) Stimulation in the Treatment of Phantom Limb Pain (PLP).

OBJECTIVES: Phantom limb pain (PLP) is a neuropathic condition in which pain is perceived as arising from an amputated limb. PLP is distinct from, although associated with, pain in the residual limb and nonpainful phantom sensations of the missing limb. Its treatment is extremely challenging; pharmaceutical options, while commonly employed, may be insufficient or intolerable. Neuromodulatory interventions such as spinal cord stimulation have generated mixed results and may be limited by poor somatotopic specificity. It was theorized that dorsal root ganglion (DRG) neuromodulation may be more effective. MATERIALS AND METHODS: Patients trialed a DRG neurostimulation system for their PLP and were subsequently implanted if results were positive. Retrospective chart review was completed, including pain ratings on a 100-mm visual analogue scale (VAS) and patient-reported outcomes. RESULTS: Across eight patients, the average baseline pain rating was 85.5 mm. At follow-up (mean of 14.4 months), pain was rated at 43.5 mm. Subjective ratings of quality of life and functional capacity improved. Some patients reduced or eliminated pain medications. Patients reported precise concordance of the paresthesia with painful regions, including in their phantom limbs; in one case, stimulation eliminated PLP as well as nonpainful phantom sensations. Three patients experienced a diminution of pain relief, despite good initial outcomes. CONCLUSIONS: DRG neuromodulation may be an effective tool in treating this pain etiology. Clinical outcomes in this report support recent converging evidence suggesting that the DRG may be the site of PLP generation and/or maintenance. Further research is warranted to elucidate mechanisms and optimal treatment pathways.

A systematic review: current and future directions of dorsal root ganglion therapeutics to treat chronic pain.

OBJECTIVE: The purpose of the study was to systematically review the historical therapeutics for chronic pain care directed at the dorsal root ganglion (DRG) and to identify future trends and upcoming treatment strategies. METHODS: A literature search on bibliographic resources, including EMBASE, PubMed Cochrane Database of Systemic Reviews from literature published from 1966 to December 1, 2012 to identify studies and treatments directed at the DRG to treat chronic pain, and was limited to the English language. Case series, case reports, and preclinical work were excluded. Information on emerging technologies and pharmacologics were captured separately, as they did not meet the inclusion criteria. RESULTS: The literature review yielded three current clinical treatment strategies: ganglionectomy, conventional radiofrequency treatment of the dorsal root ganglion, and pulsed radiofrequency treatment of the DRG. Seven studies were identified utilizing ganglionectomy, 14 for conventional radiofrequency, and 16 for pulsed radiofrequency. Electrical stimulation and novel therapeutic delivery strategies have been proposed and are in development. CONCLUSIONS: Despite a robust understanding of the DRG and its importance in acute nociception, as well as the development and maintenance of chronic pain, relatively poor evidence exists regarding current therapeutic strategies. Novel therapies like electrical and pharmacologic strategies are on the horizon, and more prospective study is required to better qualify the role of the DRG in chronic pain care.

A multicenter, prospective trial to assess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain.

OBJECTIVES: This multicenter prospective trial was conducted to evaluate the clinical performance of a new neurostimulation system designed to treat chronic pain through the electrical neuromodulation of the dorsal root ganglia (DRG) neurophysiologically associated with painful regions of the limbs and/or trunk. MATERIALS AND METHODS: Thirty-two subjects were implanted with a novel neuromodulation device. Pain ratings during stimulation were followed up to six months and compared with baseline ratings. Subjects also completed two separate reversal periods in which stimulation was briefly stopped in order to establish the effects of the intervention. RESULTS: At all assessments, more than half of subjects reported pain relief of 50% or better. At six months postimplant, average overall pain ratings were 58% lower than baseline (p < 0.001), and the proportions of subjects experiencing 50% or more reduction in pain specific to back, leg, and foot regions were 57%, 70%, and 89%, respectively. When stimulation was discontinued for a short time, pain returned to baseline levels. Discrete coverage of hard-to-treat areas was obtained across a variety of anatomical pain distributions. Paresthesia intensity remained stable over time and there was no significant difference in the paresthesia intensity perceived during different body postures/positions (standing up vs. lying down). CONCLUSIONS: Results of this clinical trial demonstrate that neurostimulation of the DRG is a viable neuromodulatory technique for the treatment of chronic pain. Additionally, the capture of discrete painful areas such as the feet combined with stable paresthesia intensities across body positions suggest that this stimulation modality may allow more selective targeting of painful areas and reduce unwanted side-effects observed in traditional spinal cord stimulation (SCS).

A prospective study of dorsal root ganglion stimulation for the relief of chronic pain.

OBJECTIVE: The article aims to study the safety and effectiveness of dorsal root ganglion (DRG) stimulation with a new device in the treatment of chronic pain. DESIGN: This is a prospective, single-arm, pilot study. SETTING: Four clinical centers were used as setting for this study. PATIENTS: Ten (10) patients with chronic intractable pain of the trunk and/or limbs were included. INTERVENTION: A trial period of DRG stimulation was studied. Two to four leads, each with four electrical contacts, were inserted using a minimally invasive epidural approach and steered toward the lateral epidural space, near the DRG. Leads were attached to an external trial stimulator and stimulation therapy was provided for three to seven days. OUTCOME MEASURES: Pain reduction using a visual analog scale, subject and physician-rated improvement, adverse event (AE) rates, device programming settings, and medication utilization was evaluated at baseline and at prospective follow-up time points during stimulation. RESULTS: On average, there was a 70% reduction in pain following stimulation (p = 0.0007). Eight of the nine patients experienced a clinically meaningful (>30%) reduction in pain, and seven of the nine reduced their pain medication utilization. Pain relief in specific anatomical regions such as the leg, back, and foot was also observed. No device-related AEs were reported. CONCLUSIONS: These initial results suggest that stimulation of the DRG can reduce pain in those patients suffering from chronic pain. DRG stimulation may offer several potential benefits over other neuromodulation techniques, including the ability to target difficult-to-reach anatomies such as the low back and foot.

Corticosteroid induced psychosis in the pain management setting.

BACKGROUND: Synthetic corticosteroids are commonly utilized in interventional pain management procedures. These substances have potential side-effects including psychological adverse events. OBJECTIVE: We describe a case of substance-induced psychotic disorder resulting from corticosteroids administration. DESIGN: Case Report. METHODS: We describe a 67-year-old male that, six months prior to being consulted at our center, received a cervical epidural, 4 level medial branch blocks, 4 trigger point injections and a tendon injection in the shoulder all including corticosteroids all in one treatment session. RESULTS: Approximately 7 days following the multiple injections, the patient developed psychotic episodes including racing thoughts, anger, agitation, pressured hyperverbal speech and paranoia. The symptoms spontaneously resolved in approximately 7-10 days. DISCUSSION: Although well known as a potential complication, corticosteroid induced psychosis secondary to interventional pain procedures have never been reported. We further discuss this potential side effect of utilizing corticosteroids and emphasize the need for guidelines regarding steroid utilization.

A case of spinal cord stimulation in Raynaud's Phenomenon: can subthreshold sensory stimulation have an effect?

Spinal cord stimulation is currently used to treat a variety of chronic intractable painful conditions. We report a case of severe Raynaud's phenomenon in the hands refractory to conservative treatment and responsive to diagnostic stellate ganglion block that was effectively treated with a spinal cord stimulator placed in the cervical epidural space. After capturing the affected areas with paresthesias, blood flow in the left hand and fingers significantly improved as evidenced by an increase in skin temperature, a change from cyanotic to pink appearance and concomitant reduction in pain. Moreover, the patient reported that limb ischemia and pain could be managed overnight with stimulation intensities that were below sensory perception thresholds. Thus it seems, at least in the overnight period, paresthesias were not required to maintain pain relief. This case presents a potential divergence between a requirement for paresthesias and pain relief in spinal cord stimulation therapy for the treatment of Raynaud's phenomenon. The possible role of the sympathetic nervous system in this relationship is also discussed.

Neuromodulation of the cervical spinal cord in the treatment of chronic intractable neck and upper extremity pain: a case series and review of the literature.

Electrical spinal neuromodulation in the form of spinal cord stimulation is currently used for treating chronic painful conditions such as complex regional pain syndrome, diabetic neuropathy, postherpetic neuralgia, peripheral ischemia, low back pain, and other conditions refractory to more conservative treatments. To date, there are very few published reports documenting the use of spinal cord stimulation in the treatment of head/neck and upper limb pain. This paper reports a case series of 5 consecutive patients outlining the use of spinal cord stimulation to treat upper extremity pain. All subjects had previously undergone cervical fusion surgery to treat chronic neck and upper limb pain. Patients were referred following failure of the surgery to manage their painful conditions. Spinal cord stimulators were placed in the cervical epidural space through a thoracic needle placement. Stimulation parameters were adjusted to capture as much of the painful area(s) as possible. In total, 4 out of 5 patients moved to implantation. In all cases, patients reported significant (70-90%) reductions in pain, including axial neck pain and upper extremity pain. Interestingly, 2 patients with associated headache and lower extremity pain obtained relief after paresthesia-steering reportedly covered those areas. Moreover, 2 patients reported that cervical spinal cord stimulation significantly improved axial low back pain. Patients continue to report excellent pain relief up to 9 months following implantation. This case series documents the successful treatment of neck and upper extremity pain following unsuccessful cervical spine fusion surgery. Given this initial success, prospective, controlled studies are warranted to more adequately assess the long term utility and cost effectiveness of electrical neuromodulation treatment of chronic neck and upper extremity pain.

Exercise and hypertension: a model for central neural plasticity.

1. Physical movement is accompanied by coordinated changes in respiratory and cardiovascular activity proportional to the metabolic demands of the locomotor task. Cardiorespiratory changes include increases in ventilation, blood pressure and heart rate, as well as altered regional sympathetic nerve activity and blood flow. 2. The posterior hypothalamic area, a periventricular region in the caudal-most diencephalon, has been shown to play a role in mediating the coupling of locomotion and cardiorespiratory activity. Stimulation of this brain region produces locomotor behaviour and simultaneous increases in cardiorespiratory activity that are independent of peripheral feedback from contracting muscles. Posterior hypothalamic neurons are also activated by exercise and exercise-related stimuli, such as muscle contraction. 3. In spontaneously hypertensive rats (SHR), a deficiency in the inhibitory GABA neurotransmitter system within the posterior hypothalamic area contributes to tonically elevated levels of arterial blood pressure. We previously identified a reduction in the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) within the posterior hypothalamus of SHR. 4. We have recently demonstrated that exercise can upregulate GABA-mediated caudal hypothalamic control of cardiovascular function in SHR. Similarly, exercise increases GAD gene transcript levels in the posterior hypothalamus. Thus, we have identified a model to study exercise-related central neural plasticity in GABAergic neurotransmitter function. Moreover, we suggest that exercise may increase cardiovascular health through changing central neural regulation of blood pressure.