The Cytidine N-Acetyltransferase NAT10 Promotes Thalamus Hemorrhage-Induced Central Poststroke Pain by Stabilizing Fn14 Expression in Thalamic Neurons.

The recognition of RNA N4-acetylcytidine (ac4C) modification as a significant type of gene regulation is growing; nevertheless, whether ac4C modification or the N-acetyltransferase 10 protein (NAT10, the only ac4C "writer" that is presently known) participates in thalamus hemorrhage (TH)-induced central poststroke pain (CPSP) is unknown. Here, we observed NAT10 was primarily located in the neuronal nuclei of the thalamus of mice, with Fn14 and p65. An increase of NAT10 mRNA and protein expression levels in the ipsilateral thalamus was observed from days 1 to 14 after TH. Inhibition of NAT10 by several different approaches attenuated Fn14 and p65 upregulation of TH mice, as well as tissue injury in the thalamus on the ipsilateral side, and the development and maintenance of contralateral nociceptive hypersensitivities. NAT10 overexpression increased Fn14 and p65 expression and elicited nociceptive hypersensitivities in naïve mice. Our findings suggest that ac4C modification and NAT10 participate in TH-induced CPSP by activating the NF-κB pathway through upregulating Fn14 in thalamic neurons. NAT10 could serve as a promising new target for CPSP treatment.

Management of Central Poststroke Pain: Systematic Review and Meta-analysis.

Central poststroke pain (CPSP) is a neuropathic pain condition prevalent in 8 to 35% of stroke patients. This systematic review and meta-analysis aimed to provide insight into the effectiveness of available pharmacological, physical, psychological, and neuromodulation interventions in reducing pain in CPSP patients (PROSPERO Registration: CRD42022371835). Secondary outcomes included mood, sleep, global impression of change, and physical responses. Data extraction included participant demographics, stroke etiology, pain characteristics, pain reduction scores, and secondary outcome metrics. Forty-two original studies were included, with a total of 1,451 participants. No studies providing psychological therapy to CPSP patients were identified. Twelve studies met requirements for a random-effects meta-analyses that found pharmacological therapy to have a small effect on mean pain score (SMD = -.36, 96.0% confidence interval [-.68, -.03]), physical interventions did not show a significant effect (SMD = -.55 [-1.28, .18]), and neuromodulation treatments had a moderate effect (SMD = -.64 [-1.08, -.19]). Fourteen studies were included in proportional meta-analysis with pharmacological studies having a moderate effect (58.3% mean pain reduction [-36.51, -80.15]) and neuromodulation studies a small effect (31.1% mean pain reduction [-43.45, -18.76]). Sixteen studies were included in the narrative review, the findings from which largely supported meta-analysis results. Duloxetine, amitriptyline, and repetitive transcranial magnetic stimulation had the most robust evidence for their effectiveness in alleviating CPSP-induced pain. Further multicenter placebo-controlled research is needed to ascertain the effectiveness of physical therapies, such as acupuncture and virtual reality, and invasive and noninvasive neuromodulation treatments. PERSPECTIVE: This article presents a top-down and bottom-up overview of evidence for the effectiveness of different pharmacological, physical, and neuromodulation treatments of CPSP. This review could provide clinicians with a comprehensive understanding of the effectiveness and tolerability of different treatment types.

The role of spinal neurons targeted by corticospinal neurons in central poststroke neuropathic pain.

BACKGROUND: Central poststroke pain (CPSP) is one of the primary sequelae following stroke, yet its underlying mechanisms are poorly understood. METHODS: By lesioning the lateral thalamic nuclei, we first established a CPSP model that exhibits mechanical and thermal hypersensitivity. Innocuous mechanical stimuli following the thalamic lesion evoked robust neural activation in somatosensory corticospinal neurons (CSNs), as well as in the deep dorsal horn, where low threshold mechanosensory afferents terminate. In this study, we used viral-based mapping and intersectional functional manipulations to decipher the role of somatosensory CSNs and their spinal targets in the CPSP pathophysiology. RESULTS: We first mapped the post-synaptic spinal targets of lumbar innervating CSNs using an anterograde trans-synaptic AAV1-based strategy and showed these spinal interneurons were activated by innocuous tactile stimuli post-thalamic lesion. Functionally, tetanus toxin-based chronic inactivation of spinal neurons targeted by CSNs prevented the development of CPSP. Consistently, transient chemogenetic silencing of these neurons alleviated established mechanical pain hypersensitivity and innocuous tactile stimuli evoked aversion linked to the CPSP. In contrast, chemogenetic activation of these neurons was insufficient to induce robust mechanical allodynia typically observed in the CPSP. CONCLUSION: The CSNs and their spinal targets are required but insufficient for the establishment of CPSP hypersensitivity. Our study provided novel insights into the neural mechanisms underlying CPSP and potential therapeutic interventions to treat refractory central neuropathic pain conditions.

Successful relief of central poststroke pain with BurstDR spinal cord stimulation: A case series.

Background: Central poststroke pain (CPSP) is a commonly undertreated condition that can negatively impact a patient's quality of life. The efficacy of spinal cord stimulation (SCS) for the treatment of CPSP is not established due to limited studies. Case Description: Here, two patients, ages 42 and 75, sustained strokes resulting in CPSP. After failed medical management, both underwent placement of paddle-lead SCS systems utilizing BurstDR stimulation that successfully resulted in pain resolution. Conclusion: Two patients with CPSP were successfully treated with paddle lead SCS with BurstDR programming.

Interleukin-18 in chronic pain: Focus on pathogenic mechanisms and potential therapeutic targets.

Chronic pain has been proven to be an independent disease, other than an accompanying symptom of certain diseases. Interleukin-18 (IL-18), a pro-inflammatory cytokine with pleiotropic biological effects, participates in immune modulation, inflammatory response, tumor growth, as well as the process of chronic pain. Compelling evidence suggests that IL-18 is upregulated in the occurrence of chronic pain. Antagonism or inhibition of IL-18 expression can alleviate the occurrence and development of chronic pain. And IL-18 is located in microglia, while IL-18R is mostly located in astrocytes in the spinal cord. This indicates that the interaction between microglia and astrocytes mediated by the IL-18/IL-18R axis is involved in the occurrence of chronic pain. In this review, we described the role and mechanism of IL-18 in different types of chronic pain. This review provides strong evidence that IL-18 is a potential therapeutic target in pain management.

Combination of single-nucleus and bulk RNA-seq reveals the molecular mechanism of thalamus haemorrhage-induced central poststroke pain.

Central poststroke pain (CPSP) induced by thalamic haemorrhage (TH) can be continuous or intermittent and is accompanied by paresthesia, which seriously affects patient quality of life. Advanced insights into CPSP mechanisms and therapeutic strategies require a deeper understanding of the molecular processes of the thalamus. Here, using single-nucleus RNA sequencing (snRNA-seq), we sequenced the transcriptomes of 32332 brain cells, which revealed a total of four major cell types within the four thalamic samples from mice. Compared with the control group, the experimental group possessed the higher sensitivity to mechanical, thermal, and cold stimuli, and increased microglia numbers and decreased neuron numbers. We analysed a collection of differentially expressed genes and neuronal marker genes obtained from bulk RNA sequencing (bulk RNA-seq) data and found that Apoe, Abca1, and Hexb were key genes verified by immunofluorescence (IF). Immune infiltration analysis found that these key genes were closely related to macrophages, T cells, related chemokines, immune stimulators and receptors. Gene Ontology (GO) enrichment analysis also showed that the key genes were enriched in biological processes such as protein export from nucleus and protein sumoylation. In summary, using large-scale snRNA-seq, we have defined the transcriptional and cellular diversity in the brain after TH. Our identification of discrete cell types and differentially expressed genes within the thalamus can facilitate the development of new CPSP therapeutics.

Modulation of Melatonin in Pain Behaviors Associated with Oxidative Stress and Neuroinflammation Responses in an Animal Model of Central Post-Stroke Pain.

Central post-stroke pain is a severe persistent pain disease that affects 12% of stroke survivors (CPSP). These patients may have a cognitive impairment, depression, and sleep apnea, which leave them open to misdiagnosis and mistreatment. However, there has been little research on whether the neurohormone melatonin can effectively reduce pain in CPSP conditions. In the present study, we labeled melatonin receptors in various brain regions of rats. Later, we established a CPSP animal model by intra-thalamic collagenase lesions. After a rehabilitation period of three weeks, melatonin was administered using different doses (i.e., 30 mg/kg, 60 mg/kg, 120 mg/kg) for the following three weeks. Mechanical allodynia, thermal hyperalgesia, and cold allodynia behavioral tests were performed. Immediately after behavioral parameters were tested, animals were sacrificed, and the thalamus and cortex were isolated for biochemical (mitochondrial complexes/enzyme assays and LPO, GSH levels) and neuroinflammatory (TNF-α, IL-1ß, IL-6) assessments. The results show that melatonin receptors were abundant in VPM/VPL regions. The thalamic lesion significantly induced pain behaviors in the mechanical, thermal planters, and cold allodynia tests. A significant decrease in mitochondrial chain complexes (C-I, II, III, IV) and enzymes (SOD, CAT, Gpx, SDH) was observed after the thalamic lesion. While there were significant increases in reactive oxygen species levels, including increases in LPO, the levels of reduced GSH were decreased in both the cortex and thalamus. Proinflammatory infiltration was noticed after the thalamic lesion, as there was a significant elevation in levels of TNF-α, IL-1ß, and IL-6. Administration of melatonin has been shown to reverse the injury effect dose-dependently. Moreover, a significant increase in C-I, IV, SOD, CAT, and Gpx levels occurred in the CPSP group. Proinflammatory cytokines were significantly reduced by melatonin treatments. Melatonin seems to mediate its actions through MT1 receptors by preserving mitochondrial homeostasis, reducing free radical generation, enhancing mitochondrial glutathione levels, safeguarding the proton potential in the mitochondrial ETC by stimulating complex I and IV activities, and protecting the neuronal damage. In summary, exogenous melatonin can ameliorate pain behaviors in CPSP. The present findings may provide a novel neuromodulatory treatment in the clinical aspects of CPSP.

Relief of Central Poststroke Pain Affecting Both the Arm and Leg on One Side by Double-independent Dual-lead Spinal Cord Stimulation Using Fast-acting Subperception Therapy Stimulation: A Case Report.

Central poststroke pain is a chronic, intractable, central neuropathic pain. Spinal cord stimulation is a neuromodulation therapy for chronic neuropathic pain. The conventional stimulation method induces a sense of paresthesia. Fast-acting subperception therapy is one of the latest new stimulation methods without paresthesia. A case of achieving pain relief of central poststroke pain affecting both the arm and leg on one side by double-independent dual-lead spinal cord stimulation using fast-acting subperception therapy stimulation is presented. A 67-year-old woman had central poststroke pain due to a right thalamic hemorrhage. The numerical rating scale scores of the left arm and leg were 6 and 7, respectively. Using dual-lead stimulation at the Th 9-11 levels, a spinal cord stimulation trial was performed. Fast-acting subperception therapy stimulation achieved pain reduction in the left leg from 7 to 3. Therefore, a pulse generator was implanted, and the pain relief continued for 6 months. Then, two additional leads were implanted at the C 3-5 levels, and pain in the arm decreased from 6 to 4. Independent setting and adjustments of the dual-lead stimulation were required because the thresholds of paresthesia perception were significantly different. To achieve pain relief in both the arm and leg, double-independent dual-lead stimulation placed at cervical and thoracic levels is an effective treatment. Fast-acting subperception therapy stimulation may be effective for central poststroke pain, especially in cases where the paresthesia is perceived as uncomfortable or the conventional stimulation itself is ineffective.

Site matters: Central neuropathic pain characteristics and somatosensory findings after brain and spinal cord lesions.

BACKGROUND: It is unknown if different etiologies or lesion topographies influence central neuropathic pain (CNP) clinical manifestation. METHODS: We explored the symptom-somatosensory profile relationships in CNP patients with different types of lesions to the central nervous system to gain insight into CNP mechanisms. We compared the CNP profile through pain descriptors, standardized bedside examination, and quantitative sensory test in two different etiologies with segregated lesion locations: the brain, central poststroke pain (CPSP, n = 39), and the spinal cord central pain due to spinal cord injury (CPSCI, n = 40) in neuromyelitis optica. RESULTS: Results are expressed as median (25th to 75th percentiles). CPSP presented higher evoked and paroxysmal pain scores compared to CPSCI (p < 0.001), and lower cold thermal limen (5.6°C [0.0-12.9]) compared to CPSCI (20.0°C [4.2-22.9]; p = 0.004). CPSCI also had higher mechanical pain thresholds (784.5 mN [255.0-1078.0]) compared to CPSP (235.2 mN [81.4-1078.0], p = 0.006) and higher mechanical detection threshold compared to control areas (2.7 [1.5-6.2] vs. 1.0 [1.0-3.3], p = 0.007). Evoked pain scores negatively correlated with mechanical pain thresholds (r = -0.38, p < 0.001) and wind-up ratio (r = -0.57, p < 0.001). CONCLUSIONS: CNP of different etiologies may present different pain descriptors and somatosensory profiles, which is likely due to injury site differences within the neuroaxis. This information may help better design phenotype mechanism correlations and impact trial designs for the main etiologies of CNP, namely stroke and spinal cord lesions. This study provides evidence that topography may influence pain symptoms and sensory profile. The findings suggest that CNP mechanisms might vary according to pain etiology or lesion topography, impacting future mechanism-based treatment choices.

Deep Brain Stimulation of the Central Lateral and Ventral Posterior Thalamus for Central Poststroke Pain Syndrome: Preliminary Experience.

OBJECTIVE: The beneficial effects of thalamic deep brain stimulation (DBS) at various target sites in treating chronic central neuropathic pain (CPSP) remain unclear. This study aimed to evaluate the effectiveness of DBS at a previously untested target site in the central lateral (CL) thalamus, together with classical sensory thalamic stimulation (ventral posterior [VP] complex). MATERIALS AND METHODS: We performed a monocentric retrospective study of a consecutive series of six patients with CPSP who underwent combined DBS lead implantation of the CL and VP. Patient-reported outcome measures were recorded before and after surgery using the numeric rating scale (NRS), short-form McGill pain questionnaire (sf-MPQ), EuroQol 5-D quality-of-life questionnaire, and Beck Depression Inventory. DBS leads were reconstructed and projected onto a three-dimensional stereotactic atlas. RESULTS: NRS-but not sf-MPQ-rated pain intensity-was significantly reduced throughout the follow-up period of 12 months compared with baseline (p = 0.005, and p = 0.06 respectively, Friedman test). At the last available follow-up (12 to 30 months), three patients described a more than 50% reduction. Two of the three long-term responders were stimulated in the CL (1000 Hz, 90 µs, 3.5-5.0 mA), whereas the third preferred VP complex stimulation (50 Hz, 200 µs, 0.7-1.2 mA). No persistent procedure- or stimulation-associated side effects were noted. CONCLUSIONS: These preliminary findings suggest that DBS of the CL might constitute a promising alternative target in cases in which classical VP complex stimulation does not yield satisfactory postoperative pain reduction. The results need to be confirmed in larger, prospective series of patients.

Chronic Pain Considerations in Patients with Cardiovascular Disease.

Cardiovascular disease affects close to half of the United States population and many of these patients will develop chronic pain syndromes as a result of their disease process. This article provides an overview of several pain syndromes that result, directly or indirectly, from cardiovascular disease including peripheral arterial disease, angina, thoracic outlet syndrome, postamputation pain, complex regional pain syndrome, and poststroke pain. Psychological and medical comorbidities that affect the medical decision-making process in the treatment of chronic pain associated with cardiovascular disease are also discussed.

A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial.

OBJECTIVES: Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. MATERIALS AND METHODS: This prospective, randomized, double-blind, sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control. RESULTS: We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17-20% pain relief), with no difference between M1, S2, or sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. CONCLUSIONS: S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.

Long-term follow-up of motor cortex stimulation on central poststroke pain in thalamic and extrathalamic stroke.

OBJECTIVE: To investigate the long-term effects of motor cortex stimulation (MCS) on central poststroke pain (CPSP) in patients with thalamic and extrathalamic stroke. MATERIALS AND METHODS: We retrospectively analyzed 21 cases of CPSP patients who were treated with MCS. Pain intensity was evaluated using the visual analog scale (VAS) and Neuropathic Pain Symptom Inventory (NPSI) before the operation and at follow-up assessments. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The average follow-up time was 65.43 ± 26.12 months. In the thalamus stroke group (n = 11), the mean preoperative VAS score was 8.18 ± 0.75 and the final mean follow-up VAS score was 4.0 ± 2.14. The mean total NPSI score at the last follow-up (20.45 ± 12.7) was significantly reduced relative to the pre-MCS score (30.27 ± 8.97, p < 0.001). Similarly, the mean PSQI value at the last follow-up (12.63 ± 1.91) was significantly reduced compared with the pre-MCS value (16.55 ± 1.97, p < 0.001). In the extrathalamic stroke group (n = 11), the mean preoperative VAS score was 8.2 ± 0.79 and the final mean follow-up VAS score was 6.6 ± 2.12. The mean total NPSI score before MCS was not statistically different from that at the last follow-up. There were no statistical differences in sleep quality before versus after surgery. CONCLUSION: Motor cortex stimulation has higher long-term efficacy in CPSP patients with stroke confined to the thalamus than in CPSP patients with stroke involving extrathalamic structures.

The Management of Poststroke Thalamic Pain: Update in Clinical Practice.

Poststroke thalamic pain (PS-TP), a type of central poststroke pain, has been challenged to improve the rehabilitation outcomes and quality of life after a stroke. It has been shown in 2.7-25% of stroke survivors; however, the treatment of PS-TP remains difficult, and in majority of them it often failed to manage the pain and hypersensitivity effectively, despite the different pharmacotherapies as well as invasive interventions. Central imbalance, central disinhibition, central sensitization, other thalamic adaptative changes, and local inflammatory responses have been considered as its possible pathogenesis. Allodynia and hyperalgesia, as well as the chronic sensitization of pain, are mainly targeted in the management of PS-TP. Commonly recommended first- and second-lines of pharmacological therapies, including traditional medications, e.g., antidepressants, anticonvulsants, opioid analgesics, and lamotrigine, were more effective than others. Nonpharmacological interventions, such as transcranial magnetic or direct current brain stimulations, vestibular caloric stimulation, epidural motor cortex stimulation, and deep brain stimulation, were effective in some cases/small-sized studies and can be recommended in the management of therapy-resistant PS-TP. Interestingly, the stimulation to other areas, e.g., the motor cortex, periventricular/periaqueductal gray matter, and thalamus/internal capsule, showed more effect than the stimulation to the thalamus alone. Further studies on brain or spinal stimulation are required for evidence.

miR-223 ameliorates thalamus hemorrhage-induced central poststroke pain via targeting NLRP3 in a mouse model.

Central poststroke pain (CPSP) is a central neuropathic pain syndrome that occurs following a stroke and mainly manifests as pain and paresthesia in the body region corresponding to the brain injury area. At present, due to the lack of clinical attention given to CPSP, patients suffer from long-term pain that seriously affects their quality of life. Current literature indicates that microRNA (miR)-223 can impede inflammation and prevent collateral damage. The NLR family pyrin domain containing 3 (NLRP3) inflammasome induces IL-18 and IL-1ß secretion and maturation and participates in the inflammatory response. Previous evidence has confirmed that miR-223 can negatively regulate NLRP3 in the development of inflammatory responses. However, whether the miR-223 targeting of NLRP3 is involved in CPSP remains unclear. In the present study, the expression of miR-223 was detected by reverse transcription-quantitative PCR analysis. The expression levels of NLRP3, caspase-1, ASC, IL-18, IL-1ß, ERK1/2, p-ERK1/2 and GFAP were detected by western blot analysis. The results demonstrated that thalamic hemorrhagic stroke triggered by microinjection of collagenase Ⅳ (Coll IV) into the ventral posterior lateral (VPL) nucleus results in pain hypersensitivity. miR-223 expression level were significantly reduced in the CPSP model. The expression levels of NLRP3, caspase-1, ASC, IL-18 and IL-1ß were significantly increased in the CPSP model. The expression level of GFAP was detected to determine astrocyte activation. The results demonstrated that astrocyte activation induced by Coll IV produced a CPSP model. The p-ERK1/2 expression level was demonstrated to be significantly increased in the CPSP model. The introduction of an miR-223 agomir significantly attenuated thalamic pain and significantly decreased the levels of NLRP3, caspase-1, ASC and proinflammatory cytokines (IL-18 and IL-1ß). Furthermore, introducing a miR-223 antagomir into the VPL nucleus of naïve mice mimicked thalamic pain and significantly increased the levels of NLRP3, caspase-1, ASC and proinflammatory cytokine levels (IL-18 and IL-1ß). These results indicated that miR-223 inhibited NLRP3 inflammasome activity (caspase-1, NLRP3 and ASC), which ameliorated thalamus hemorrhage-induced CPSP in mice via NLRP3 downregulation. In conclusion, these results may determine the mechanisms underlying CPSP and facilitate development of targeted therapy for CPSP.

MicroRNA-133b-3p Targets Purinergic P2X4 Receptor to Regulate Central Poststroke Pain in Rats.

Central poststroke pain (CPSP) is a neuropathic pain syndrome that usually occurs after cerebrovascular accidents. Currently, the pathogenesis of CPSP is not fully understood. Purinergic P2X4 receptor (P2X4R) is implicated in neuropathic pain including CPSP. Herein, we demonstrated that the levels of microRNA-133b-3p (miR-133b-3p), which targets P2X4R transcripts, were significantly downregulated in the ventral posterolateral nucleus of the thalamus (VPL), cerebrospinal fluid (CSF), and plasma of CPSP rats. The expression levels of miR-133b-3p negatively correlated with the severity of allodynia. Genetic knockdown of P2X4R in the VPL protected CPSP rats against allodynia. Similarly, genetic overexpression of miR-133b-3p in the VPL reversed the allodynia established in CPSP rats via downregulation of P2X4R expression. Treatment using gabapentin in CPSP rats significantly restored the decreased miR-133b-3p expression in the VPL, CSF, and plasma and blocked allodynia in CPSP rats. The administration of an miR-133b-3p inhibitor into the VPL abolished the antiallodynic activity of gabapentin. This mechanism was associated with P2X4R expression and involved the endogenous opioid system. Human patients with CPSP showed decreased plasma levels of miR-133b-3p compared with those of control participants. Logistic regression analysis of our patient cohort showed that determining plasma levels of miR-133b-3p may be useful for CPSP diagnosis and treatment.

Benefit of spinal cord stimulation for patients with central poststroke pain: a retrospective multicenter study.

OBJECTIVE: Spinal cord stimulation (SCS) has been considered an ineffective procedure for patients with central poststroke pain (CPSP). However, recent case series that included small numbers of patients reported the possible efficacy of SCS as a treatment of CPSP. This multicenter retrospective study aimed to examine the outcomes of using SCS to treat patients with CPSP and to explore factors related to outcomes. METHODS: The authors reviewed the medical records of patients with CPSP who underwent SCS to collect data regarding their background, surgical information, and outcomes of SCS at trial stimulation and last follow-up after long-term implantation in six study centers. Outcomes were evaluated with a pain score for intensity (range 0-10) and the Patient Global Impression of Changes (PGIC) scale. Factors associated with outcomes were explored with univariable and multivariable analyses. RESULTS: The authors collected data from a total of 166 patients (mean age 63.4 years; mean pain score at baseline 8.2). Of these patients, 163 underwent trial stimulation. The mean pain score decreased by 42.0%, 104 (64%) patients had ≥ 30% decrease in pain score, and 96 (59%) reported much or very much improved condition on the PGIC scale at trial stimulation. Moreover, 106 (64%) patients underwent long-term implantation of SCS devices. The mean decrease in pain score was 41.4%, 63 (59%) patients continued to show ≥ 30% decrease in pain score at last follow-up, and 60 (56%) reported much or very much improved condition on the PGIC scale at last follow-up (median [range] follow-up period 24 [24-63] months). Eleven device-related complications and 10 permanent explantations were observed. Univariable and multivariable analyses suggested that young age, less sensory disturbance, implantation of cervical leads, treatment of upper-limb pain, and extensive treated regions were associated with satisfactory outcomes at last follow-up after long-term implantation. CONCLUSIONS: These findings indicate that SCS may modestly benefit patients with CPSP. SCS has therapeutic potential for patients with intractable CPSP owing to the lower invasiveness of the SCS procedure and refractory nature of CPSP. Nevertheless, trial stimulation is necessary because of the high initial failure rate.

Analgesic Effects of Navigated Repetitive Transcranial Magnetic Stimulation in Patients With Acute Central Poststroke Pain.

INTRODUCTION: Central poststroke pain (CPSP) develops commonly after stroke, which impairs the quality of life, mood, and social functioning. Current pharmacological approaches for the treatment of CPSP are not satisfactory. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique which has been recommended for the treatment of chronic CPSP. However, few studies have evaluated the analgesic effects of rTMS in patients with acute neuropathic pain after stroke. METHODS: We evaluated the analgesic effects of rTMS applied over the upper extremity area of the motor cortex (M1) in patients with acute CPSP. Forty patients were randomized to receive either rTMS (10 Hz, 2000 stimuli) (n = 20) or a sham intervention (n = 20) for 3 weeks. The Numeric Rating Scale (NRS), Short-form McGill Pain Questionnaire-2 (SF-MPQ-2, Chinese version), Hamilton Anxiety Scale (HAM-A), Hamilton Depression Scale (HAM-D), brain-derived neurotrophic factor (BDNF) levels, and motor-evoked potentials (MEP) were analyzed at baseline, 3 days, 1 week, 2 weeks, and 3 weeks. RESULTS: Significant treatment-time interactions were found for pain intensity. Compared with the sham group, the NRS and SF-MPQ-2 scores were significantly lower on the seventh day of treatment in the rTMS group (P < 0.001, Cohen's d = 1.302) (P = 0.003, Cohen's d = 0.771), and this effect lasted until the third week (P = 0.001, Cohen's d = 0.860) (P = 0.027, Cohen's d = 0.550). The HAM-A and HAM-D scores did not change in the rTMS group when compared with the sham group (P = 0.341, Cohen's d = 0.224) (P = 0.356, Cohen's d = 0.217). The serum BDNF levels were significantly higher in the treated group (P = 0.048, Cohen's d = -0.487), and the resting motor threshold (RMT) decreased by 163.65%. CONCLUSION: Our findings indicate that rTMS applied over the upper extremity area of the motor cortex can effectively alleviate acute CPSP, possibly by influencing cortical excitability and serum BDNF secretion. TRIAL REGISTRATION: This trial is registered with Clinical Trial Registry of China: Reg. No. ChiCTR-INR-17012880.

Electrical Thalamic Stimulation in the Anterior Part of the Ventral Posterolateral Nucleus for the Treatment of Patients With Central Poststroke Pain.

OBJECTIVES: The effects of thalamic stimulation of the anterior part of the ventral posterolateral nucleus (VPLa) for central poststroke pain (CPSP) and the pain-related electrophysiological characteristics of this structure were investigated. MATERIALS AND METHODS: Nine patients with CPSP manifesting as hemibody pain were enrolled. Stereotactic thalamic VPLa stimulation was implemented, and intraoperative electrophysiological studies on hyperactive and unstable discharges (HUDs) and responses to sensory and electrical stimulation were performed in the sensory thalamus. A preoperative somatosensory-evoked potential (SEP) study was carried out in all nine patients and in eight other patients with localized pain. RESULTS: The patients were classified into two groups: a HUD-dominant group (group H, n = 5) and a sensory response-dominant group (group R, n = 4). HUDs were frequently encountered in the thalamic VPLa in the former group. The total number of HUDs and the number along the trajectory to the VPLa in group H were significantly larger than those in group R. The improvements on the pain numeric rating scale in group H were significantly higher than those in group R two years after surgery. The amplitude ratio of the SEP N20s in the ipsilateral to the contralateral side of CVD lesion in the study group was significantly lower than in the localized pain group. CONCLUSIONS: Adequate and stable pain relief with thalamic VPLa stimulation is obtainable in patients with CPSP who exhibit hyperactivity and electrical instability along the trajectory to this nucleus. Both responders and nonresponders were found to have severe dysfunction of the lemniscal system.

Lysophosphatidic acid LPA1 and LPA3 receptors play roles in the maintenance of late tissue plasminogen activator-induced central poststroke pain in mice.

We developed a mouse model for central post-stroke pain (CPSP), a centrally-originated neuropathic pain (NeuP). In this mode, mice were first injected with Rose Bengal, followed by photo-irradiation of left middle cerebral artery (MCA) to generate thrombosis. Although the MCA thrombosis was soon dissolved, the reduced blood flow remained for more than 24 h due to subsequent occlusion of microvessels. This photochemically induced thrombosis (PIT) model showed a hypersensitivity to the electrical stimulation of both sides of paw, but did not show any abnormal pain in popular thermal or mechanical nociception tests. When tissue-type plasminogen activator (tPA) was injected 6 h after the PIT stress, tPA-dependent hypersensitivity to the electrical paw stimulation and stable thermal and mechanical hyperalgesia on both sides for more than 17 or 18 days after the PIT treatment. These hyperalgesic effects were abolished in lysophosphatidic acid receptor 1 (LPA1)- and lysophosphatidic acid receptor 3 (LPA3)-deficient mice. When Ki-16425, an LPA1 and LPA3 antagonist was treated twice daily for 6 days consecutively, the thermal and mechanical hyperalgesia at day 17 and 18 were significantly reversed. The liquid chromatography-mass spectrometry (LC-MS/MS) analysis revealed that there is a significant increase in several species of LPA molecules in somatosensory S-I and medial dorsal thalamus (MD), but not in striatum or ventroposterior thalamus. All these results suggest that LPA1 and LPA3 signaling play key roles in the development and maintenance of CPSP.