Peripheral Nervous System Pain Modulation.

The percutaneous technique of electrode insertion in the vicinity of the greater occipital nerves to treat occipital neuralgia was first described in the 1990s by Weiner and Reed. This subsequently stimulated awareness of peripheral nerve stimulation (PNS). The more recent advent emergence of a minimally invasive percutaneous approach by way of using ultrasound has further increased the interest in PNS as a viable alternative to more invasive techniques. PNS has become more popular recently and is increasingly used to treat various pain conditions. Its foundation is fundamentally based on the gate control theory, although the precise mechanism underlying its analgesic effect is still indefinite. Studies have demonstrated the peripheral and central analgesic mechanisms of PNS by modulating the inflammatory pathways, the autonomic nervous system, the endogenous pain inhibition pathways, and the involvement of the cortical and subcortical areas. Peripheral nerve stimulation exhibits its neuromodulatory effect both peripherally and centrally. Further understanding of the modulation of PNS mechanisms can help guide stimulation approaches and parameters to optimize the use of PNS. his chapter aims to review the background and mechanisms of PNS modulation. PNS is becoming one of the most diverse therapies in neuromodulation due to rapid evolution and expansion. It is an attractive option for clinicians due to the simplicity and versatility of procedures that can be combined with other neuromodulation treatments or used alone. It has a distinct role in the modulation of functional conditions.

Microvascular decompression for trigeminal neuralgia: A retrospective analysis of long-term outcomes and prognostic factors / Descompresión microvascular en la neuralgia del trigémino: análisis retrospectivo de los resultados a largo plazo e identificación de factores pronósticos

Introduction: Microvascular decompression is considered to be the most effective and onlyetiological surgical treatment for classical trigeminal neuralgia, relieving the neurovascularcompression found in up to 95% of cases. This study aims to report the long-term outcomesand to identify prognostic factors in a series of patients with trigeminal neuralgia treated bymicrovascular decompression. Methods: A retrospective observational study of 152 consecutive patients operated bymicrovascular decompression with at least six months of follow-up. The surgical results, includ-ing pain relief according to the Barrow Neurological Institute pain scale, complications and themedical treatment during the follow-up period were reviewed. Binary regression analysis wasperformed to identify factors associated with a good long-term outcome. Results: A total of 152 patients with a mean age of 60 years and a mean follow-up of 43 monthswere included. At the final follow-up visit, 83% of the patients had achieved significant reliefof the pain and 63% could reduce the absolute drug doses by 50% or more. The most frequentcomplications were wound infection (4.5%) and CSF fistula (7%). Being over 70 years of age andhaving paroxysmal pain were associated with a long-term pain relief.(AU)

Introducción: La descompresión microvascular se considera el tratamiento quirúrgico etiológico más eficaz de la neuralgia clásica del trigémino, dirigido a aliviar la compresión neurovascular identificada hasta en un 95% de casos. Este estudio tiene como objetivo analizar los resultados quirúrgicos y la evolución a largo plazo de una serie de pacientes con neuralgia del trigémino tratados mediante descompresión microvascular, así como identificar factores pronósticos. Métodos: Estudio observacional retrospectivo de 152 pacientes consecutivos sometidos a descompresión microvascular y con un seguimiento posquirúrgico mínimo de seis meses. Analizamos los resultados quirúrgicos, clasificando el grado de dolor según la escala del Instituto Neurológico de Barrow, las complicaciones y el tratamiento médico requerido durante el período de seguimiento. Realizamos un análisis de regresión binaria para identificar factores asociados con un buen resultado a largo plazo. Resultados: Incluimos 152 pacientes con una edad media de 60 años y un seguimiento medio de 43 meses. En la última visita de seguimiento, el 83% de los pacientes había logrado un alivio significativo del dolor y el 63% pudo reducir la dosis absoluta de fármacos para la neuralgia en un 50% o más. Las complicaciones más frecuentes fueron infección de la herida (4,5%) y fístula de LCR (7%). La edad superior a 70 años y el dolor de predominio paroxístico se asociaron con un mejor pronóstico. Conclusiones: Nuestros resultados apoyan que la descompresión microvascular es una terapia efectiva y segura en pacientes con neuralgia del trigémino. La cirugía temprana puede ser beneficiosa en pacientes refractarios al tratamiento farmacológico.(AU)

Efficacy of conditioned autologous serum therapy (Orthokine®) on the dorsal root ganglion in patients with chronic radiculalgia: study protocol for a prospective randomized placebo-controlled double-blind clinical trial (RADISAC trial).

BACKGROUND: Pulsed radiofrequency (PRF) treatment on the dorsal root ganglion (DRG) has been proposed as a good option for the treatment of persistent radicular pain based on its effect of neuromodulation on neuropathic pain. Autologous conditioned serum (ACS) therapy is a conservative treatment based on the patient's own blood. The aim of this manuscript is to develop a study protocol using ACS on the DRG as a target for its molecular modulation. METHODS: We plan to conduct a randomized controlled study to compare the efficacy of PRF therapy plus ACS versus PRF therapy plus physiological saline 0.9% (PhS) on the DRG to reduce neuropathic pain in patients with persistent lower limb radiculalgia (LLR) and to contribute to the functional improvement and quality of life of these patients. Study participants will include patients who meet study the inclusion/exclusion criteria. Eligible patients will be randomized in a 1:1 ratio to one of treatment with PRF plus ACS (experimental group) or PRF plus PhS (placebo group). The study group will consist of 70 patients (35 per group) who have experienced radicular pain symptoms for ≥ 6 months' duration who have failed to respond to any therapy. Both groups will receive PRF on the DRG treatment before the injection of the sample (control or placebo). Patient assessments will occur at baseline, 1 month, 3 months, 6 months, and 12 months after therapy. The primary efficacy outcome measure is Numeric Pain Rating Scale (NPRS) responders from baseline to 12 months of follow-up using validated minimal important change (MIC) thresholds. A reduction of ≥ 2 points in NPRS is considered a clinically significant pain relief. The secondary efficacy outcome measure is the proportion of Oswestry Low Back Pain Disability Scale (ODS) responders from baseline to 12 months of follow-up in the experimental group (PRF plus ACS) versus the placebo group (PRF plus PhS). ODS responders are defined as those patients achieving the validated MIC of ≥ 10-point improvement in ODS from baseline to 12 months of follow-up as a clinically significant efficacy threshold. DISCUSSION: This prospective, double-blind, randomized placebo-controlled study will provide level I evidence of the safety and effectiveness of ACS on neuropathic symptoms in LLR patients. TRIAL REGISTRATION {2A}{2B}: EUDRACT number: 2021-005124-38. Validation date: 13 November 2021. Protocol version {3}: This manuscript presents the 2nd protocol version.

Results From a Prospective, Clinical Study (US-nPower) Evaluating a Miniature Spinal Cord Stimulator for the Management of Chronic, Intractable Pain.

BACKGROUND: Chronic, intractable, neuropathic pain is readily treatable with spinal cord stimulation (SCS). Technological advancements, including device miniaturization, are advancing the field of neuromodulation. OBJECTIVES: We report here the results of an SCS clinical trial to treat chronic, low back and leg pain, with a micro-implantable pulse generator (micro-IPG). STUDY DESIGN: This was a single-arm, prospective, multicenter, postmarket, observational study. SETTING: Patients were recruited from 15 US-based comprehensive pain centers. METHODS: This open-label clinical trial was designed to evaluate the performance of the Nalu™ Neurostimulation System (Nalu Medical, Inc., Carlsbad, CA) in the treatment of low back and leg pain. Patients, who provided informed consent and were successfully screened for study entry, were implanted with temporary trial leads. Patients went on to receive a permanent implant of the leads and micro-IPG if they demonstrated a >= 50% reduction in pain during the temporary trial period. Patient-reported outcomes (PROs), such as pain scores, functional disability, mood, patient impression of change, comfort, therapy use profile, and device ease of use, were captured. RESULTS: At baseline, the average pain Visual Analog Scale (VAS) score was 72.1 ± 17.9 in the leg and 78.0 ± 15.4 in the low back. At 90 days following permanent implant (end of study), pain scores improved by 76% (VAS 18.5 ± 18.8) in the leg and 75% (VAS 19.7 ± 20.8) in the low back. Eighty-six percent  of both leg pain and low back pain patients demonstrated a >= 50% reduction in pain at 90 days following implant. The comfort of the external wearable (Therapy Disc and Adhesive Clip) was rated 1.16 ± 1.53, on average, at 90 days on an 11-point rating scale (0 = very comfortable, 10 = very uncomfortable). All PROs demonstrated statistically significant symptomatic improvement at 90 days following implant of the micro-IPG. LIMITATIONS:   Limitations of this study include the lack of long-term results (beyond 90 days) and a relatively small sample size of 35 patients who were part of the analysis; additionally, there was no control arm or randomization as this was a single-arm study, without a comparator, designed to document the efficacy and safety of the device. Therefore, no direct comparisons to other SCS systems were possible. CONCLUSIONS: This clinical study demonstrated profound leg and low back pain relief in terms of overall pain reduction, as well as the proportion of therapy responders. The study patients reported the wearable aspects of the system to be very comfortable.

[Diagnostics and treatment of hourglass-like nerve constrictions and torsions in neuralgic amyotrophy]. / Diagnostik und Therapie sanduhrförmiger Nervenstrikturen und -torsionen bei neuralgischer Amyotrophie.

Neuralgic amyotrophy is a disease of the peripheral nervous system characterized by severe neuropathic pain followed by peripheral paralysis. A distinction is made between a hereditary and an idiopathic form, which is assumed to have an autoimmunological origin. Conservative medicinal treatment mainly consists of nonsteroidal anti-inflammatory drugs (NSAID), opioids and glucocorticoids; however, despite treatment, symptoms in the form of pain or paralysis persist in over 50% of cases. Inflammation can lead to strictures and torsions of peripheral nerves, which can be visualized by imaging using nerve sonography or magnetic resonance (MR) neurography and confirmed intraoperatively during surgical exploration. Based on the currently available data, patients with strictures and torsions of peripheral nerves can benefit from neurosurgical treatment.

Development of a pain self-management intervention framework for people with spinal cord injury.

BACKGROUND:  Pain is the most common reason for medical visits to primary health care practitioners. Pain self-management interventions are encouraged and there is no known self-management intervention framework available that clinicians and people with spinal cord injury (PWSCI) can use to guide treatment selection. AIM:  This study aimed to develop a pain self-management intervention framework for PWSCI. SETTING:  Online and facilitated in Gauteng, South Africa. METHODS:  A three-round modified e-Delphi method was used to reach an 80% consensus among a 21-expert panel. Fifty-nine interventions were distributed via REDCap and a final online audio meeting was held to either include or exclude interventions in the final framework. SPSS v27 was used to analyse descriptive data and content analysis was used for qualitative responses. RESULTS:  The final developed pain self-management framework consists of 56 interventions and includes interventions from multiple health professions to encompass medical, psychological, therapeutic and social interventions. Interventions are also specified for nociceptive and/or neuropathic pain and grouped according to the biopsychosocial model. CONCLUSION:  The interprofessional framework may be used as a guideline for PWSCI to alleviate pain, as well as assist health professionals in clinical decision-making, by providing them with the freedom to choose acceptable and adequate interventions that may be appropriate to treat the affected individual's pain.Contribution: Pain management is a basic need at the primary healthcare level and PWSCI need access to the broad range of interventions available to manage their pain. The framework highlights the variety of appropriate interventions to guide both health professionals and PWSCI with pain relief options.

Switching Rat Resident Macrophages from M1 to M2 Phenotype by Iba1 Silencing Has Analgesic Effects in SNL-Induced Neuropathic Pain.

Resident macrophages from dorsal root ganglia are important for the development of traumatic-induced neuropathic pain. In the first 5-7 days after a traumatic sciatic nerve injury (i.e., spinal nerve ligation (SNL), spared nerve injury (SNI), sciatic nerve transection or sciatic nerve ligation and transection), Ionized binding adapter protein 1 (Iba1) (+) resident macrophages cluster around dorsal root ganglia neurons, possibly contributing to nerve injury-induced hypersensitivity. Since infiltrating macrophages gradually recruited to the lesion site peak at about 7 days, the first few days post-lesion offer a window of opportunity when the contribution of Iba1 (+) resident macrophages to neuropathic pain pathogenesis could be investigated. Iba1 is an actin cross-linking cytoskeleton protein, specifically located only in macrophages and microglia. In this study, we explored the contribution of rat Iba1 (+) macrophages in SNL-induced neuropathic pain by using intra-ganglionic injections of naked Iba1-siRNA, delivered at the time the lesion occurred. The results show that 5 days after Iba1 silencing, Iba1 (+) resident macrophages are switched from an M1 (pro-inflammatory) phenotype to an M2 (anti-inflammatory) phenotype, which was confirmed by a significant decrease of M1 markers (CD32 and CD86), a significant increase of M2 markers (CD163 and Arginase-1), a reduced secretion of pro-inflammatory cytokines (IL-6, TNF-α and IL-1ß) and an increased release of pro-regenerative factors (BDNF, NGF and NT-3) which initiated the regrowth of adult DRG neurites and reduced SNL-induced neuropathic pain. Our data show for the first time, that it is possible to induce macrophages towards an anti-inflammatory phenotype by interacting with their cytoskeleton.

A Single Injection of rAAV-shmTOR in Peripheral Nerve Persistently Attenuates Nerve Injury-Induced Mechanical Allodynia.

Activation of mammalian target of rapamycin (mTOR) has been known as one of the contributing factors in nociceptive sensitization after peripheral injury. Its activation followed by the phosphorylation of downstream effectors causes hyperexcitability of primary sensory neurons in the dorsal root ganglion. We investigated whether a single injection of rAAV-shmTOR would effectively downregulate both complexes of mTOR in the long-term and glial activation as well. Male SD rats were categorized into shmTOR (n = 29), shCON (n = 23), SNI (n = 13), and Normal (n = 8) groups. Treatment groups were injected with rAAV-shmTOR or rAAV-shCON, respectively. DRG tissues and sciatic nerve were harvested for Western blot and immunohistochemical analyses. Peripheral sensitization was gradually attenuated in the shmTOR group, and it reached a peak on PID 21. Western blot analysis showed that both p-mTORC1 and p-mTORC2 were downregulated in the DRG compared to shCON and SNI groups. We also found decreased expression of phosphorylated p38 and microglial activation in the DRG. We first attempted a therapeutic strategy for neuropathic pain with a low dose of AAV injection by interfering with the mTOR signaling pathway, suggesting its potential application in pain treatment.

The relationship between neuropathic pain and the outcomes of minimally invasive pain management in rotator cuff ruptures.

This study aimed to investigate how the presence of neuropathic pain related to partial rotator cuff tears affects the short-term results of subacromial injection and suprascapular nerve blockade therapy in patients with chronic shoulder pain. In this prospective observational study, shoulder pain via verbal numeric pain rating (VNPR, 0-10) and functional status through simple shoulder test (SST) were evaluated before and second week after procedure. After dividing as neuropathic pain and non-neuropathic pain groups, pre-procedural and follow-up scores concerning pain intensity, functional status, and whether there were those of patients with minimal clinically important change (MCIC) in areas of pain and function were evaluated. Between the groups including 140 patients, while there was no statistical difference in baseline pain intensity and functional status (P = .14,.11, respectively), outcomes of those without neuropathic pain were favored at the follow-up (P = .02,.01, respectively). Given baseline pain scores, the reduction (%) was significantly lower in neuropathic pain group (P = .03). There was no significant difference in patients with MCIC in pain intensity and functional status between the groups (P = .08,.59, respectively). An improvement was determined in pain intensity and functional status at the follow-up in both groups (P < .001). The improvement in pain intensity and functional status is poorer in patients with partial rotator cuff rupture-related neuropathic pain than in those without neuropathic pain. However neuropathic pain has no negative effect on the response to treatment.

Effects of acupuncture therapy in diabetic neuropathic pain: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of acupuncture in relieving diabetic neuropathic pain and to establish a more reliable and efficient foundation for acupuncture practice in diabetes care. METHODS: The Chinese National Knowledge Infrastructure, Wanfang database, Chongqing Weipu, Chinese Biomedical Literature Database, PubMed, Embase, and Cochrane Library were all searched for a randomized controlled trial research of acupuncture for DNP. Two researchers independently performed literature screening, quality evaluation, and data extraction. After selecting studies and extracting data, we conducted the data analysis using RevMan 5.4 and Stata 14.0. The quality was assessed using the Cochrane Risk of Bias Assessment Tool. RESULTS: An extensive review of 19 studies involving 1276 patients up to April 29, 2023, found that acupuncture was successful in improving pain intensity [MD= -1.09; 95% CI (-1.28, -0.89), P < 0.00001], clinical efficacy indicating pain changes [RR= 1.22; 95% CI (1.15, 1.29), P < 0.00001], and clinical neuropathy [MD= -1.55; 95% CI ( -3.00, -0.09), P = 0.04] in DNP patients. Quality of life was also improved, with few side effects reported. CONCLUSION: According to this meta-analysis, acupuncture therapy significantly improved the clinical efficacy of pain intensity, pain changes, and clinical neuropathy in patients with DNP, improved the quality of life of patients to a certain extent, and had lower side effects. This discovery provides evidence-based and practical recommendations for the treatment of DNP patients.

Clinical significance of small nerve fiber involvement in the early diagnosis and treatment of patients with Fabry disease.

INTRODUCTION: Peripheral nervous system is early involved in Fabry disease (FD) and preferentially the small nerve fibers, causing the characteristic neuropathic pain crises usually beginning in childhood. Early detection of this likely underdiagnosed disease is an important approach because causal therapies are available. METHODS: We conducted a case-series study to investigate the small nerve fiber involvement in FD and its contribution to the diagnosis of the disease but also to the timely effective therapy administration. We used specific structured scales of symptoms and signs to detect peripheral neuropathy, as well as suitable functional and structural tests to diagnose the small fiber neuropathy (SFN). RESULTS: Twenty-seven consecutive patients (14 men, mean age 44.62 ± 10.70 years) with suspected FD were included in this study. Most of the patients presented symptoms of small nerve fiber involvement, which were accompanied by abnormal test results, fulfilling the criteria for SFN. The detection of SFN in our patients allowed the completion of the FD diagnostic criteria and thus the initiation of therapy. In five patients the SFN diagnosis determined the administration of therapy, whereas in two others it might be considered. CONCLUSION: Our results further suggest the importance of early diagnosis of peripheral neuropathy, especially of small nerve fiber involvement, in patients with suspected FD as it contributes crucially not only to the diagnosis but also to the timely effective initiation of FD therapy.

Chronic Pain Syndromes: Chronic Neuropathic Pain.

Neuropathic pain affects 7% to 10% of the population and has major effects on quality of life. It is defined as pain caused by a lesion or disease of the somatosensory nervous system and may be central or peripheral. Diagnostic testing may yield inconclusive or inconsistent results, so physicians often rely on clinical judgment based on the history and physical examination findings. Questionnaires and scoring systems can aid in diagnosis. Neuropathic pain is differentiated from other types of chronic pain by abnormal sensory symptoms, such as shooting pain, burning pain, or numbness. It is difficult to manage and can be accompanied by mood and sleep disturbances. Referral for psychotherapy may be useful for these patients. Nonpharmacotherapy options include mindfulness training, transcutaneous electrical nerve stimulation, and massage. Acupuncture also may be effective, but the data are mixed. Topical drugs (eg, lidocaine, capsaicin), gabapentinoids, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors are considered first-line drugs. Tramadol is considered a second-line drug, but may considered first-line for certain patients. For persistent pain, physicians can consider referring patients to a pain specialist for nerve blocks or other procedural interventions. Opioids may be considered for refractory pain, but their additional benefit has been shown to be modest compared with those of other treatments.

Content and Quality of Mobile Apps for the Monitoring of Musculoskeletal or Neuropathic Pain in Australia: Systematic Evaluation.

Background: Mobile apps offer a potential mechanism for people with persistent pain to monitor pain levels conveniently within their own environment and for clinicians to remotely monitor their patients' pain. However, the quality of currently available apps and the usefulness of included features from a clinical perspective are not known. Objective: The aim of this study was to examine the content and quality of currently available smartphone apps designed for monitoring the intensity or presence of musculoskeletal or neuropathic pain. Methods: A systematic search was performed in the Australian Apple and Google Play stores. Apps were included if they were designed to monitor the intensity or presence of musculoskeletal or neuropathic pain and were available in the English language within the Australian app stores. Data pertaining to the intended use of the app and clinical population were extracted by using a custom-designed data extraction form, and app quality was assessed by using the 23-item Mobile App Rating Scale. Results: Of the 2190 apps screened, 49 met the inclusion criteria. Apps were primarily designed for adult users (36/49, 73%) with nonspecific musculoskeletal or neuropathic pain conditions, arthritis, and joint pain. All apps monitored pain intensity, with almost half (23/49, 47%) also specifying pain location. Overall, the mean quality scores from the Mobile App Rating Scale ranged from 1.5 to 4.4 (out of 5.0). Between 20% (10/49) and 22% (11/49) of apps involved clinicians, consumers, or both in their development, and 20% (10/49) had published literature related to the development or use of the app in clinical scenarios. Although 71% (35/49) had data sharing features, only 5 apps enabled client-clinician communication through the app. Conclusions: The overall quality of mobile apps that are currently available for monitoring pain intensity is acceptable. Presently, mobile apps for remote pain monitoring lack functionality for clinicians to view data between consults. Both users and clinicians should be aware of the limitations of these apps and make informed choices in using or recommending apps that best suit the clinical need.

Fully Implantable Neurostimulation System for Long-Term Behavioral Animal Study.

Spinal cord stimulation (SCS) is an emerging therapeutic option for patients with neuropathic pain due to spinal cord injury (SCI). Numerous studies on pain relief effects with SCS have been conducted and demonstrated promising results while the mechanisms of analgesic effect during SCS remain unclear. However, an experimental system that enables large-scale long-term animal studies is still an unmet need for those mechanistic studies. This study proposed a fully wireless neurostimulation system that can efficiently support a long-term animal study for neuropathic pain relief. The developed system consists of an implantable stimulator, an animal cage with an external charging coil, and a wireless communication interface. The proposed device has the feature of remotely controlling stimulation parameters via radio-frequency (RF) communication and wirelessly charging via magnetic induction in freely moving rats. Users can program stimulation parameters such as pulse width, intensity, and duration through an interface on a computer. The stimulator was packaged with biocompatible epoxy to ensure long-term durability under in vivo conditions. Animal experiments using SCI rats were conducted to demonstrate the functionality of the device, including long-term usability and therapeutic effects. The developed system can be tailored to individual user needs with commercially available components, thus providing a cost-effective solution for large-scale long-term animal studies on neuropathic pain relief.

Efficacy of transcutaneous auricular vagus nerve stimulation on radiotherapy-related neuropathic pain in patients with head and neck cancers (RELAX): protocol for a multicentre, randomised, double-blind, sham-controlled trial.

INTRODUCTION: Radiotherapy-related neuropathic pain (RRNP) is one of the most distressing complications after radiotherapy for head and neck cancers. Drug therapy is not sufficiently effective and has limitations in terms of dose titration period and side effects. Transcutaneous auricular vagus nerve stimulation (taVNS), which stimulates the auricular branches of the vagus nerve through electrical impulses, has been proven to have analgesic effects in certain diseases. However, it is unknown whether taVNS can relieve RRNP. METHODS AND ANALYSIS: This is a multicentre, randomised, double-blind, parallel, sham-controlled trial. We will include adult patients newly diagnosed with neuropathic pain after radiotherapy for head and neck cancers. One hundred and sixteen individuals will be recruited and randomly assigned in a 1:1 ratio to receive taVNS or sham stimulation. The interventions will last for 7 days, twice daily for 30 min each. The primary efficacy outcome is pain reduction on day 7. The secondary outcomes are changes in functional interference, psychological distress, fatigue, quality of life and serum inflammatory factors. The study may provide a new early intervention strategy for RRNP among patients with head and neck cancers. ETHICS AND DISSEMINATION: This study has been approved by the Medical Research Ethics Committee of Sun Yat-sen University (SYSKY-2022-109-01) and will be conducted in strict accordance with the Declaration of Helsinki. Ethical approvals will be obtained separately for all centres involved in the study. Study results will be published in peer-reviewed academic journals. The database of the study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: NCT05543239.

Motor cortical stimulation for the treatment of trigeminal neuropathic pain secondary to an arteriovenous malformation. A case report.

INTRODUCTION: Trigeminal neuropathic pain (TNP) is a syndrome of severe, disabling, constant facial pain arising from the trigeminal nerve or ganglion. Arteriovenous malformations (AVM) are a rare cause of TNP. The limited choices of intervention of TNP include peripheral nerve stimulation, trigeminal nucleotomy and motor cortex stimulation. CASE REPORT: We present a 56-year-old man who suffered from trigeminal neuropathic pain secondary to nerve compression due to a giant posterior fossa AVM. The pain was refractory to drug treatment. From all the therapeutic options available we declined the microvascular decompression of the trigeminal nerve due to the presence of the giant AVM, or stereotactic radiosurgery because of the AVM´s diffuse nidus. After a multidisciplinary discussion we proposed a minimally invasive, safe and reversible treatment: Motor Cortical Stimulation (MCS). We placed a 16-pole epidural electrode on the right precentral gyrus. The patient had satisfactory pain control with some supplemental medication. No complications or side effects such as seizures, sensory disturbances or infections were presented. DISCUSSION: The limited choices of intervention of TNP include peripheral nerve stimulation, trigeminal nucleotomy and MCS. Henssen et al performed a systematic review where they investigated the effectiveness of MCS and discovered that this is significantly different among different chronic neuropathic orofacial pain disorders. A visual analogue scale (VAS) measured median pain relief of 66.5% was found. CONCLUSION: MCS should be one more tool to consider in highly selected cases, when other treatments are unfeasible.

Introducción: El dolor neuropático trigeminal (DNT) es un síndrome de dolor facial intenso, incapacitante y constante que surge del nervio o ganglio del trigémino. Las malformaciones arteriovenosas (MAV) son una causa rara de DNT. Las opciones terapéuticas de DNT incluyen la estimulación de los nervios periféricos, la nucleotomía del trigémino y la estimulación cortical motora. Caso clínico: Presentamos el caso de un varón de 56 años con dolor neuropático trigeminal secundario a compresión nerviosa por una MAV gigante de fosa posterior. El dolor era refractario al tratamiento farmacológico. De todas las opciones terapéuticas disponibles, desestimamos la descompresión microvascular del nervio trigémino por la presencia de la MAV gigante, o la radiocirugía estereotáctica, por ser difuso el nido de la MAV. Tras una discusión multidisciplinar propusimos un tratamiento mínimamente invasivo, seguro y reversible: Estimulación cortical motora (ECM). Colocamos un electrodo epidural en el giro precentral derecho. El paciente tuvo un control satisfactorio del dolor con medicación suplementaria. No presentó complicaciones ni efectos secundarios como convulsiones, alteraciones sensoriales o infecciones. Discusión: Las opciones limitadas de intervención de DNT incluyen estimulación nerviosa periférica, nucleotomía trigeminal y ECM. Henssen et al realizaron una revisión sistemática donde investigaron la efectividad de MCS y descubrieron que esto es significativamente diferente entre los diferentes trastornos de dolor orofacial neuropático crónico. Se encontró un promedio de alivio del dolor medida por una escala analógica visual del 66,5%. Conclusión: La ECM debería ser una herramienta más a considerar en casos estrictamente seleccionados donde otros tratamientos no son viables.

Differential Effects of Regulatory T Cells in the Meninges and Spinal Cord of Male and Female Mice with Neuropathic Pain.

Immune cells play a critical role in promoting neuroinflammation and the development of neuropathic pain. However, some subsets of immune cells are essential for pain resolution. Among them are regulatory T cells (Tregs), a specialised subpopulation of T cells that limit excessive immune responses and preserve immune homeostasis. In this study, we utilised intrathecal adoptive transfer of activated Tregs in male and female mice after peripheral nerve injury to investigate Treg migration and whether Treg-mediated suppression of pain behaviours is associated with changes in peripheral immune cell populations in lymphoid and meningeal tissues and spinal microglial and astrocyte reactivity and phenotypes. Treatment with Tregs suppressed mechanical pain hypersensitivity and improved changes in exploratory behaviours after chronic constriction injury (CCI) of the sciatic nerve in both male and female mice. The injected Treg cells were detected in the choroid plexus and the pia mater and in peripheral lymphoid organs in both male and female recipient mice. Nonetheless, Treg treatment resulted in differential changes in meningeal and lymph node immune cell profiles in male and female mice. Moreover, in male mice, adoptive transfer of Tregs ameliorated the CCI-induced increase in microglia reactivity and inflammatory phenotypic shift, increasing M2-like phenotypic markers and attenuating astrocyte reactivity and neurotoxic astrocytes. Contrastingly, in CCI female mice, Treg injection increased astrocyte reactivity and neuroprotective astrocytes. These findings show that the adoptive transfer of Tregs modulates meningeal and peripheral immunity, as well as spinal glial populations, and alleviates neuropathic pain, potentially through different mechanisms in males and females.

Positioning of epidural electrode for motor cortex stimulation in general anesthesia based on intraoperative electrophysiological monitoring to treat refractory trigeminal neuropathic pain.

BACKGROUND: Motor cortex stimulation (MCS) represents a treatment option for refractory trigeminal neuralgia (TGN). Usually, patients need to be awake during surgery to confirm a correct position of the epidural electrode above the motor cortex, reducing patient's comfort. METHOD: Epidural cortical mapping (ECM) and motor evoked potentials (MEPs) were intraoperatively performed for correct localization of motor cortex under general anesthesia that provided comparable results to test stimulation after letting the patient to be awake during the operation. CONCLUSION: Intraoperative ECM and MEPs facilitate a confirmation of correct MCS-electrode position above the motor cortex allowing the MCS-procedure to be performed under general anesthesia.

Effect of electrical and chemical (activation versus inactivation) stimulation of the infralimbic division of the medial prefrontal cortex in rats with chronic neuropathic pain.

Neuropathic pain (NP) represents a complex disorder with sensory, cognitive, and emotional symptoms. The medial prefrontal cortex (mPFC) takes critical regulatory roles and may change functionally and morphologically during chronic NP. There needs to be a complete understanding of the neurophysiological and psychopharmacological bases of the NP phenomenon. This study aimed to investigate the participation of the infralimbic division (IFL) of the mPFC in chronic NP, as well as the role of the N-methyl-D-aspartic acid receptor (NMDAr) in the elaboration of chronic NP. Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham-procedure ("false operated"). Electrical neurostimulation of the IFL/mPFC was performed by low-frequency stimuli (20 µA, 100 Hz) applied for 15 s by deep brain stimulation (DBS) device 21 days after CCI. Either cobalt chloride (CoCl2 at 1.0 mM/200 nL), NMDAr agonist (at 0.25, 1.0, and 2.0 nmol/200 nL) or physiological saline (200 nL) was administered into the IFL/mPFC. CoCl2 administration in the IFL cortex did not alter either mechanical or cold allodynia. DBS stimulation of the IFL cortex decreased mechanical allodynia in CCI rats. Chemical stimulation of the IFL cortex by an NMDA agonist (at 2.0 nmol) decreased mechanical allodynia. NMDA at any dose (0.25, 1.0, and 2.0 nmol) reduced the flicking/licking duration in the cold test. These findings suggest that the IFL/mPFC and the NMDAr of the neocortex are involved in attenuating chronic NP in rats.

Network model of nociceptive processing in the superficial spinal dorsal horn reveals mechanisms of hyperalgesia, allodynia, and spinal cord stimulation.

The spinal dorsal horn (DH) processes sensory information and plays a key role in transmitting nociception to supraspinal centers. Loss of DH inhibition during neuropathic pain unmasks a pathway from nonnociceptive Aß-afferent inputs to superficial dorsal horn (SDH) nociceptive-specific (NS) projection neurons, and this change may contribute to hyperalgesia and allodynia. We developed and validated a computational model of SDH neuronal circuitry that links nonnociceptive Aß-afferent inputs in lamina II/III to a NS projection neuron in lamina I via a network of excitatory interneurons. The excitatory pathway and the NS projection neuron were in turn gated by inhibitory interneurons with connections based on prior patch-clamp recordings. Changing synaptic weights in the computational model to replicate neuropathic pain states unmasked a low-threshold excitatory pathway to NS neurons similar to experimental recordings. Spinal cord stimulation (SCS) is an effective therapy for neuropathic pain, and accumulating experimental evidence indicates that NS neurons in the SDH also respond to SCS. Accounting for these responses may inform therapeutic improvements, and we quantified responses to SCS in the SDH network model and examined the role of different modes of inhibitory control in modulating NS neuron responses to SCS. We combined the SDH network model with a previously published model of the deep dorsal horn (DDH) and identified optimal stimulation frequencies across different neuropathic pain conditions. Finally, we found that SCS-generated inhibition did not completely suppress model NS activity during simulated pinch inputs, providing an explanation of why SCS does not eliminate acute pain.NEW & NOTEWORTHY Chronic pain is a severe public health problem that reduces the quality of life for those affected and exacts an enormous socio-economic burden worldwide. Spinal cord stimulation (SCS) is an effective treatment for chronic pain, but SCS efficacy has not significantly improved over time, in part because the mechanisms of action remain unclear. Most preclinical studies investigating pain and SCS mechanisms have focused on the responses of deep dorsal horn (DDH) neurons, but neural networks in the superficial dorsal horn (SDH) are also important for processing nociceptive information. This work synthesizes heterogeneous experimental recordings from the SDH into a computational model that replicates experimental responses and that can be used to quantify neuronal responses to SCS under neuropathic pain conditions.