Systemic low-grade C-reactive protein is associated with proximal symptom spread in carpal tunnel syndrome.

Introduction: Neuropathic pain is a highly prevalent condition associated with persistent disability. Some patients with neuropathic pain experience symptom spread outside neuroanatomical boundaries; these patients report more severe sensory symptoms and greater disability. However, the mechanisms behind such symptom spread are not fully understood. Objective: We used pre-surgical carpal tunnel syndrome (CTS) as a human model system of neuropathic pain to identify differences in the concentration of serologic inflammatory mediators between patients with CTS with territorial symptoms and those with proximal symptom spread to either the elbow or shoulder/neck. Methods: We performed a post-hoc analysis, comparing levels of serologic inflammatory mediators in a discovery cohort among 3 symptoms spread profiles (n = 55; n = 25 no spread, n = 21 spread to elbow, n = 9 spread to shoulder/neck). We then de-novo analysed the significantly dysregulated mediators in an independent validation cohort (n = 72; n = 34 no spread, n = 16 spread to elbow, n = 22 spread to shoulder/neck). Results: The discovery cohort revealed higher serum concentrations of C-reactive protein (CRP) and interleukin-6 in patients with any symptom spread proximal to the wrist; interferon-γ was higher in patients with symptom spread to the elbow compared with those without proximal spread. The validation study replicated the association of higher CRP concentrations in patients with proximal spread to the elbow (no spread: median [interquartile range] 2.5 [5.4]; spread to elbow 6.2 [4.6]; spread to shoulder/neck 2.6 [3.7], P = 0.006). No other markers replicated in the validation cohort. Conclusions: Our findings suggest that proximal symptom spread in the context of neuropathic symptoms is associated with low-grade inflammation.

Reliability of a clinical sensory test battery in patients with spine-related leg and arm pain.

BACKGROUND: The current standard to evaluate the presence of somatosensory dysfunctions is quantitative sensory testing, but its clinical utility remains limited. Low-cost and time-efficient clinical sensory testing (CST) batteries have thus been developed. Recent studies show moderate to substantial reliability in populations with neuropathic pain. This study evaluates the inter- and intra-tester reliability of people with spine-related leg and arm pain, representing mixed pain mechanisms. METHODS: Fifty-three patients with spine-related leg (n = 41) and arm pain (n = 12) attended three CST sessions. The CST battery consisted of eleven tests, determining loss and gain of sensory nerve function. CST was performed by the same investigator twice and by an additional investigator to determine inter- and intra-tester reliability. Fleiss' (inter-tester) and Cohen's (intra-tester) kappa were calculated for dichotomized and intraclass correlation coefficients (ICC) for continuous outcomes. RESULTS: Fleiss' kappa varied among modalities from fair to substantial (κ = 0.23-0.66). Cold, warm, and vibration detection thresholds and cold and pressure pain thresholds reached kappa >0.4 (moderate to substantial reliability). Cohen's kappa ranged from moderate to substantial (κ = 0.45-0.66). The reliability of the windup ratio was poor (ICC <0.18). CONCLUSION: CST modalities with moderate to substantial inter-tester reliability could be of benefit as a screening tool. The moderate to substantial intra-tester reliability for all sensory modalities (except windup ratio) supports their potential use in clinical practice and research to monitor somatosensory changes over time in patients with spine-related limb pain of mixed pain mechanisms. SIGNIFICANCE: We already know that most modalities of clinical sensory test (CST) batteries achieve moderate to substantial inter- and intra-tester reliability in populations with neuropathic pain. This study evaluates the reliability of a CST battery in populations with mixed pain mechanisms. We found inter-tester reliability varied from poor to substantial for sensory modalities, questioning the value of some CST modalities. The CST battery showed moderate to substantial intra-tester reliability, suggesting its usefulness to monitor sensory changes over time in this cohort.

Higher densities of T-lymphocytes in the subsynovial connective tissue of people with carpal tunnel syndrome.

Symptoms in people with carpal tunnel syndrome (CTS) are traditionally attributed to neural tissue, but recent studies suggest that the subsynovial connective tissue (SSCT) may also play a role in CTS. The SSCT undergoes fibrotic thickening which is generally described as "non-inflammatory" based on basic histology. This study uses immunohistochemistry to determine the presence of macrophages and T-cells within SSCT and their relationship with symptoms in people with CTS. SSCT was collected from twenty people with CTS and eight controls undergoing wrist fracture surgery. Immunohistochemical quantification of CD3+ T-cells and CD68+ macrophage densities as well as CD4+/CD8+ T-cell subpopulations were compared between groups using independent t-tests. Spearman correlations were used to identify associations between immune cell densities and CTS symptom scores. The density of CD3+ T-cells was significantly higher in SSCT of people with CTS compared to controls (CTS mean 26.7 (SD 13.7); controls 6.78 (6.3), p = 0.0005) while the density of CD68+ macrophages was lower (CTS mean 9.5 (SD 6.0); controls 17.7 (8.2), p = 0.0058). Neither CD68+ nor CD3+ cell densities correlated with symptom scores. In contrast to previous assumptions, our data show that the SSCT in the carpal tunnel in both people with CTS and controls is not devoid of immune cells. Whereas the higher density of CD68+ macrophages in control participants may be associated with their early recruitment after acute fracture, CD3+ cells within the SSCT may play a role in chronic CTS.

Neanderthal introgression in SCN9A impacts mechanical pain sensitivity.

The Nav1.7 voltage-gated sodium channel plays a key role in nociception. Three functional variants in the SCN9A gene (encoding M932L, V991L, and D1908G in Nav1.7), have recently been identified as stemming from Neanderthal introgression and to associate with pain symptomatology in UK BioBank data. In 1000 genomes data, these variants are absent in Europeans but common in Latin Americans. Analysing high-density genotype data from 7594 Latin Americans, we characterized Neanderthal introgression in SCN9A. We find that tracts of introgression occur on a Native American genomic background, have an average length of ~123 kb and overlap the M932L, V991L, and D1908G coding positions. Furthermore, we measured experimentally six pain thresholds in 1623 healthy Colombians. We found that Neanderthal ancestry in SCN9A is significantly associated with a lower mechanical pain threshold after sensitization with mustard oil and evidence of additivity of effects across Nav1.7 variants. Our findings support the reported association of Neanderthal Nav1.7 variants with clinical pain, define a specific sensory modality affected by archaic introgression in SCN9A and are consistent with independent effects of the Neanderthal variants on Nav1.7 function.

Individual endogenous pain modulation profiles within a multidimensional context of people with cervicogenic headache - A retrospective exploratory study.

BACKGROUND: One in four individuals with cervicogenic headache (CeH) are unresponsive to therapy. Such therapy involves predominantly biomedical interventions targeting the upper-cervical spine. A recurring theme within musculoskeletal practice is the multidimensional nature and substantial heterogeneity of the condition. Such heterogeneity might be a reason for failure of a biomedical approach. Therefore, future studies investigating efficacy of managing CeH should ideally be based on identification, and better understanding of the heterogeneity of this population based on a comprehensive evaluation of clinically relevant contributing factors. OBJECTIVES: The objective was to map profiles of individuals with CeH based on pain modulation within a multidimensional context. DESIGN: Pain Modulation Profiles (PMPs) of 18 adults (29-51 years) with CeH were mapped retrospectively. METHOD: The PMPs consisted of a Pain-Profile (bilateral suboccipital, erector spinae, anterior tibialis pressure pain thresholds), a Psycho-Social-Lifestyle-Profile (Depression, Anxiety, Stress Scale, Headache Impact test, Pittsburgh Sleep Quality Index), or a combination of both. Individual results were compared to normative data. Two Pain-Profiles were defined: normal or altered. Psycho-Social-Lifestyle-Profiles were categorized based on the number of altered psycho-social-lifestyle factors (range 0-5). RESULTS: Mapping PMPs in individuals with CeH resulted in 50% presenting with a dominant altered Pain-Profile, 16.7% with a dominant altered Psycho-Social-Lifestyle-Profile, and 5.6% with dominant alterations in both Pain-Profile and Psycho-Social-Lifestyle-Profile. CONCLUSION: Our results indicate heterogeneity of PMPs within the CeH population. Replication of these results is needed through dynamic assessment of the Pain-Profile before evaluating if these profiles can help patient-stratification.

Swimming exercise attenuates mechanical hypersensitivity and mitigates peripheral nerve degeneration in rats with painful diabetic neuropathy (PDN).

BACKGROUND: This study aimed to assess the effectiveness of swimming exercise in alleviating mechanical hypersensitivity and peripheral nerve degeneration associated with a pre-clinical model of painful diabetic neuropathy (PDN). METHODS: This study is a pre-clinical study conducted using the streptozocin (STZ)-induced PDN rat model. Rats were randomly allocated to three groups: a vehicle group of non-diabetic rats (Vehicle, n = 9), a group of rats with PDN (PDN, n = 8), and a group of rats with PDN that performed a swimming exercise program (PDN-SW, n = 10). The swimming exercise program included daily 30-minute swimming exercise, 5 days per week for 4 weeks. Von Frey testing was used to monitor hindpaw mechanical sensitivity over 4 weeks. Assessment of cutaneous peripheral nerve fiber integrity was performed after the 4-week study period via immunohistochemistry for protein gene product 9.5-positive (PGP9.5+) intra-epidermal nerve fiber density (IENFD) in hind-paw skin biopsies by a blinded investigator. RESULTS: The results showed that swimming exercise mitigated but did not fully reverse mechanical hypersensitivity in rats with PDN. Immunohistochemical testing revealed that the rats in the PDN-SW group retained higher PGP9.5+ IENFD compared to the PDN group but did not reach normal levels of the Vehicle group. CONCLUSIONS: The results of this study indicate that swimming exercise can mitigate mechanical hypersensitivity and degeneration of peripheral nerve fibers in rats with experimental PDN.

Recommendations for terminology and the identification of neuropathic pain in people with spine-related leg pain. Outcomes from the NeuPSIG working group.

ABSTRACT: Pain radiating from the spine into the leg is commonly referred to as "sciatica," "Sciatica" may include various conditions such as radicular pain or painful radiculopathy. It may be associated with significant consequences for the person living with the condition, imposing a reduced quality of life and substantial direct and indirect costs. The main challenges associated with a diagnosis of "sciatica" include those related to the inconsistent use of terminology for the diagnostic labels and the identification of neuropathic pain. These challenges hinder collective clinical and scientific understanding regarding these conditions. In this position paper, we describe the outcome of a working group commissioned by the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) which was tasked with the following objectives: (1) to revise the use of terminology for classifying spine-related leg pain and (2) to propose a way forward on the identification of neuropathic pain in the context of spine-related leg pain. The panel recommended discouraging the term "sciatica" for use in clinical practice and research without further specification of what it entails. The term "spine-related leg pain" is proposed as an umbrella term to include the case definitions of somatic referred pain and radicular pain with and without radiculopathy. The panel proposed an adaptation of the neuropathic pain grading system in the context of spine-related leg pain to facilitate the identification of neuropathic pain and initiation of specific management in this patient population.

Factors predicting the transition from acute to persistent pain in people with 'sciatica': the FORECAST longitudinal prognostic factor cohort study protocol.

INTRODUCTION: Sciatica is a common condition and is associated with higher levels of pain, disability, poorer quality of life, and increased use of health resources compared with low back pain alone. Although many patients recover, a third develop persistent sciatica symptoms. It remains unclear, why some patients develop persistent sciatica as none of the traditionally considered clinical parameters (eg, symptom severity, routine MRI) are consistent prognostic factors.The FORECAST study (factors predicting the transition from acute to persistent pain in people with 'sciatica') will take a different approach by exploring mechanism-based subgroups in patients with sciatica and investigate whether a mechanism-based approach can identify factors that predict pain persistence in patients with sciatica. METHODS AND ANALYSIS: We will perform a prospective longitudinal cohort study including 180 people with acute/subacute sciatica. N=168 healthy participants will provide normative data. A detailed set of variables will be assessed within 3 months after sciatica onset. This will include self-reported sensory and psychosocial profiles, quantitative sensory testing, blood inflammatory markers and advanced neuroimaging. We will determine outcome with the Sciatica Bothersomeness Index and a Numerical Pain Rating Scale for leg pain severity at 3 and 12 months.We will use principal component analysis followed by clustering methods to identify subgroups. Univariate associations and machine learning methods optimised for high dimensional small data sets will be used to identify the most powerful predictors and model selection/accuracy.The results will provide crucial information about the pathophysiological drivers of sciatica symptoms and may identify prognostic factors of pain persistence. ETHICS AND DISSEMINATION: The FORECAST study has received ethical approval (South Central Oxford C, 18/SC/0263). The dissemination strategy will be guided by our patient and public engagement activities and will include peer-reviewed publications, conference presentations, social media and podcasts. TRIAL REGISTRATION NUMBER: ISRCTN18170726; Pre-results.

Effect of Type and Dose of Exercise on Neuropathic Pain After Experimental Sciatic Nerve Injury: A Preclinical Systematic Review and Meta-Analysis.

This preclinical systematic review aimed to determine the effectiveness of different types and doses of exercise on pain behavior and biomarkers in preclinical models of focal neuropathic pain. We searched MEDLINE, EMBASE, Web of Science, PubMed, SCOPUS, CINAHL, and Cochrane library from inception to November 2022 for preclinical studies evaluating the effect of exercise compared to control interventions on neuropathic pain behavior after experimental sciatic nerve injury. If possible, data were meta-analyzed using random effect models with inverse-variance weighting. Thirty-seven studies were included and 26 meta-analyzed. Risk of bias (SYRCLE tool) remained unclear in most studies and reporting quality (CAMARADES) was variable. Exercise reduced mechanical (standardized mean differences [SMD] .53 (95% CI .31, .74), P = .0001, I2 = 0%, n = 364), heat (.32 (.07, .57), P = .01, I2 = 0%, n = 266) and cold hypersensitivity (.51 (.03, 1.0), P = .04, I2 = 0%, n = 90) compared to control interventions. No relationship was apparent between exercise duration or intensity and antinociception. Exercise modulated biomarkers related to different systems (eg, immune system, neurotrophins). Whereas firm conclusions are prevented by the use of male animals only, variable reporting quality and unclear risk of bias in many studies, our results suggest that aerobic exercise is a promising tool in the management of focal neuropathic pain. PERSPECTIVE: This systematic review and meta-analysis demonstrates that aerobic exercise reduces neuropathic pain-related behavior in preclinical models of sciatic nerve injury. This effect is accompanied by changes in biomarkers associated with inflammation and neurotrophins among others. These results could help to develop exercise interventions for patients with neuropathic pain.

Does Your Bedside Neurological Examination for Suspected Peripheral Neuropathies Measure Up?

SYNOPSIS: Neurological testing is essential for screening and diagnosing suspected peripheral neuropathies. Detecting changes in somatosensory and motor nerve function can also have direct implications for management decisions. Nevertheless, there is considerable variation in what is included in a bedside neurological examination and how it is performed. Neurological examinations are often used as screening tools to detect neurological deficits but not used to their full potential for monitoring progress or deterioration. Here, we advocate for better use of the neurological examination within a clinical reasoning framework. Constrained by the lack of research in this field, our Viewpoint is based on neuroscientific principles. We highlight 6 challenges for clinicians when conducting neurological examinations and propose ways to overcome these challenges in clinical practice. We challenge widely held ideas about how the results of neurological examinations for peripheral neuropathies are interpreted and how the examinations are performed in practice. J Orthop Sports Phys Ther 2023;53(3):107-112. Epub: 28 October 2022. doi:10.2519/jospt.2022.11281.

How effective are physiotherapy interventions in treating people with sciatica? A systematic review and meta-analysis.

PURPOSE: Physiotherapy interventions are prescribed as first-line treatment for people with sciatica; however, their effectiveness remains controversial. The purpose of this systematic review was to establish the short-, medium- and long-term effectiveness of physiotherapy interventions compared to control interventions for people with clinically diagnosed sciatica. METHODS: This systematic review was registered on PROSPERO CRD42018103900. Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), Embase, PEDro, PubMed, Scopus and grey literature were searched from inception to January 2021 without language restrictions. Inclusion criteria were randomised controlled trials evaluating physiotherapy interventions compared to a control intervention in people with clinical or imaging diagnosis of sciatica. Primary outcome measures were pain and disability. Study selection and data extraction were performed by two independent reviewers with consensus reached by discussion or third-party arbitration if required. Risk of bias was assessed independently by two reviewers using the Cochrane Risk of Bias tool with third-party consensus if required. Meta-analyses and sensitivity analyses were performed with random effects models using Revman v5.4. Subgroup analyses were undertaken to examine the effectiveness of physiotherapy interventions compared to minimal (e.g. advice only) or substantial control interventions (e.g. surgery). RESULTS: Three thousand nine hundred and fifty eight records were identified, of which 18 trials were included, with a total number of 2699 participants. All trials had a high or unclear risk of bias. Meta-analysis of trials for the outcome of pain showed no difference in the short (SMD - 0.34 [95%CI - 1.05, 0.37] p = 0.34, I2 = 98%), medium (SMD 0.15 [95%CI - 0.09, 0.38], p = 0.22, I2 = 80%) or long term (SMD 0.09 [95%CI - 0.18, 0.36], p = 0.51, I2 = 82%). For disability there was no difference in the short (SMD - 0.00 [95%CI - 0.36, 0.35], p = 0.98, I2 = 92%, medium (SMD 0.25 [95%CI - 0.04, 0.55] p = 0.09, I2 = 87%), or long term (SMD 0.26 [95%CI - 0.16, 0.68] p = 0.22, I2 = 92%) between physiotherapy and control interventions. Subgroup analysis of studies comparing physiotherapy with minimal intervention favoured physiotherapy for pain at the long-term time points. Large confidence intervals and high heterogeneity indicate substantial uncertainly surrounding these estimates. Many trials evaluating physiotherapy intervention compared to substantial intervention did not use contemporary physiotherapy interventions. CONCLUSION: Based on currently available, mostly high risk of bias and highly heterogeneous data, there is inadequate evidence to make clinical recommendations on the effectiveness of physiotherapy interventions for people with clinically diagnosed sciatica. Future studies should aim to reduce clinical heterogeneity and to use contemporary physiotherapy interventions.

Types and Concentrations of Blood-Based Biomarkers in Adults With Peripheral Neuropathies: A Systematic Review and Meta-analysis.

Importance: Peripheral neuropathies are common conditions and can result in numbness, paresthesia, motor deficits, and pain. There is increasing evidence for the use of biomarkers as clinical indicators of the presence, severity, and prognosis of nerve lesions; however, biomarker identification has largely been focused on disorders of the central nervous system, and less is known about their role in the peripheral nervous system. Objective: To assess blood-based biomarker concentrations associated with nerve involvement in patients with peripheral neuropathy compared with control participants. Data Sources: Ovid, MEDLINE, Embase, and CINAHL were searched from inception to September 23, 2021. Study Selection: Observational studies reporting on blood biomarkers in patients diagnosed with peripheral neuropathy were included. This review was preregistered on PROSPERO and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were abstracted by 1 investigator and independently reviewed by a second. Data Extraction and Synthesis: Data were meta-analyzed when at least 2 studies reported the same biomarker with comparable methodology. Fixed-effects models were used when only 2 studies were included; random-effects models were used when more than 2 studies were included. Main Outcomes and Measures: The outcome of interest was concentration of biomarkers. Results: This review included 36 studies reporting on 4414 participants, including 2113 control participants and 2301 patients with peripheral neuropathy with 13 distinct peripheral neuropathy diagnoses. Diabetic neuropathy was the most common neuropathy diagnosis (13 studies), followed by Charcot-Marie-Tooth disease (6 studies) and Guillain-Barre syndrome (6 studies). Overall, 16 different blood-based biomarkers associated with nerve involvement were evaluated. The most used were neurofilament light chain, S100B, brain-derived neurotrophic factor, and neuron-specific enolase. Patients with peripheral neuropathy demonstrated significantly higher levels of neurofilament light chain compared with controls (standardized mean difference [SMD], 0.93 [95% CI, 0.82 to 1.05]; P < .001). There were no significant differences in levels of S100B (SMD, 1.10 [95% CI, -3.08 to 5.28]; P = .38), brain-derived neurotrophic factor (SMD, -0.52 [95% CI, -2.23 to 1.19]; P = .40), or neuron-specific enolase (SMD, -0.00 [95% CI, -1.99 to 1.98]; P = .10) in patients with peripheral neuropathy compared with control participants. Conclusions and Relevance: The findings of this systematic review and meta-analysis support the use of neurofilament light chain as a blood-based measure associated with the presence of neuronal injury in patients with peripheral neuropathy.

The power of integrating data: advancing pain research using meta-analysis.

Publications related to pain research have increased significantly in recent years. The abundance of new evidence creates challenges staying up to date with the latest information. A comprehensive understanding of the literature is important for both clinicians and investigators involved in pain research. One commonly used method to combine and analyse data in health care research is meta-analysis. The primary aim of a meta-analysis is to quantitatively synthesise the results of multiple studies focused on the same research question. Meta-analysis is a powerful tool that can be used to advance pain research. However, there are inherent challenges when combining data from multiple sources. There are also numerous models and statistical considerations when undertaking a meta-analysis. This review aims to discuss the planning and preparation for completing a meta-analysis, review commonly used meta-analysis models, and evaluate the clinical implications of meta-analysis in pain research.

Does the efficacy of neurodynamic treatments depend on the presence and type of criteria used to define neural mechanosensitivity in spinally-referred leg pain? A systematic review and meta-analysis.

Background: It remains unclear whether definite neural mechanosensitivity (NM) is required for neural mobilisations to be beneficial in people with spinally referred leg pain. Objective: To determine whether the efficacy of neural mobilisations in patients with spinally referred leg pain depends on the presence and type of criteria used to define NM. Method: PubMed, CINAHL, Cochrane Central Register of Controlled Trials, PEDro and Science Direct were searched from 1980 to March 2020. Randomised controlled trials evaluating the efficacy of neural mobilisations on pain and disability in spinally referred leg pain were included. Studies were grouped according to the certainty of NM into NMdefinite, NMunclear, NMuntested and NMabsent. Effects on pain and disability and subgroup differences were examined. Results: We identified 21 studies in 914 patients (3 NMdefinite, 16 NMunclear, 2 NMuntested, 0 NMabsent). Meta-analysis revealed medium to large effect sizes on pain for neurodynamic compared to control interventions in NMdefinite and NMunclear groups. For disability, neurodynamic interventions had medium to large effects in NMunclear but not NMdefinite groups. NMuntested studies could not be pooled. Conclusion: The nonexistence of studies in patients with negative neurodynamic tests prevents inferences whether neural mobilisations are effective in the absence of NM. The criteria used to define NM may not impact substantially on the efficacy of neural mobilisations. The mostly high risk of bias and heterogeneity prevents firm conclusions. Clinical implications: Neural mobilisations seem beneficial to reduce pain and disability in spinally referred leg pain independent of the criteria used to interpret neurodynamic tests.

Effects of Neural Mobilization on Sensory Dysfunction and Peripheral Nerve Degeneration in Rats With Painful Diabetic Neuropathy.

OBJECTIVE: This study aims to evaluate the effectiveness of neural mobilization (NM) in the management of sensory dysfunction and nerve degeneration related to experimental painful diabetic neuropathy (PDN). METHODS: This is a pre-clinical animal study performed in the streptozocin-induced diabetic rat model. Three groups were included: a treatment group of rats with PDN receiving NM under anesthesia (PDN-NM, n = 10), a sham treatment group of rats with PDN that received only anesthesia (PDN-Sham, n = 9), and a vehicle control group with nondiabetic animals (Vehicle, n = 10). Rats in the PDN-NM and PDN-Sham groups received 1 treatment session on days 10, 12, and 14 after streptozocin injection, with a 48-hour rest period between sessions. Behavioral tests were performed using von Frey and Plantar tests. Evaluation for peripheral nerve degeneration was performed through measuring protein gene product 9.5-positive intra-epidermal nerve fiber density in hind-paw skin biopsies. All measurements were performed by a blinded investigator. RESULTS: The behavioral tests showed that a single NM session could reduce hyperalgesia, which was maintained for 48 hours. The second treatment session further improved this treatment effect, and the third session maintained it. These results suggest that it requires multiple treatment sessions to produce and maintain hypoalgesic effects. Skin biopsy analysis showed that the protein gene product 9.5-positive intra-epidermal nerve fiber density was higher on the experimental side of the PDN-NM group compared with the PDN-Sham group, suggesting NM may mitigate the degeneration of peripheral nerves. CONCLUSION: This study demonstrated that NM may be an effective method to manage experimentally induced PDN, potentially through mitigation of nerve degeneration. Further studies are needed to develop standardized protocols for clinical use. IMPACT: These findings provide neurophysiological evidence for the use of NM in PDN and can form the basis for the development of physical therapy-based programs in clinics.

Shared genetic susceptibility between trigger finger and carpal tunnel syndrome: a genome-wide association study.

Background: Trigger finger and carpal tunnel syndrome are the two most common non-traumatic connective tissue disorders of the hand. Both of these conditions frequently co-occur, often in patients with rheumatoid arthritis. However, this phenotypic association is poorly understood. Hypothesising that the co-occurrence of trigger finger and carpal tunnel syndrome might be explained by shared germline predisposition, we aimed to identify a specific genetic locus associated with both diseases. Methods: In this genome-wide association study (GWAS), we identified 2908 patients with trigger finger and 436579 controls from the UK Biobank prospective cohort. We conducted a case-control GWAS for trigger finger, followed by co-localisation analyses with carpal tunnel syndrome summary statistics. To identify putative causal variants and establish their biological relevance, we did fine-mapping analyses and expression quantitative trait loci (eQTL) analyses, using fibroblasts from healthy donors (n=79) and tenosynovium samples from patients with carpal tunnel syndrome (n=77). We conducted a Cox regression for time to trigger finger and carpal tunnel syndrome diagnosis against plasma IGF-1 concentrations in the UK Biobank cohort. Findings: Phenome-wide analyses confirmed a marked association between carpal tunnel syndrome and trigger finger in the participants from UK Biobank (odds ratio [OR] 11·97, 95% CI 11·1-13·0; p<1 × 10-300). GWAS for trigger finger identified five independent loci, including one locus, DIRC3, that was co-localised with carpal tunnel syndrome and could be fine-mapped to rs62175241 (0·76, 0·68-0·84; p=5·03 × 10-13). eQTL analyses found a fibroblast-specific association between the protective T allele of rs62175241 and increased DIRC3 and IGFBP5 expression. Increased plasma IGF-1 concentrations were associated with both carpal tunnel syndrome and trigger finger in participants from UK Biobank (hazard ratio >1·04, p<0·02). Interpretation: In this GWAS, the DIRC3 locus on chromosome 2 was significantly associated with both carpal tunnel syndrome and trigger finger, possibly explaining their co-occurrence. The disease-protective allele of rs62175241 was associated with increased expression of long non-coding RNA DIRC3 and its transcriptional target, IGBP5, an antagonist of IGF-1 signalling. These findings suggest a model in which IGF-1 is a driver of both carpal tunnel syndrome and trigger finger, and in which the DIRC3-IGFBP5 axis directly antagonises fibroblastic IGF-1 signalling. Funding: Wellcome Trust, National Institute for Health Research, Medical Research Council.

Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms.

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is "wind-up," in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.

Effect of Physiotherapeutic Interventions on Biomarkers of Neuropathic Pain: A Systematic Review of Preclinical Literature.

The purpose of this systematic review was to evaluate the effects of physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain (PNP). The search was performed in Pubmed, Web of Science, EMBASE, Cochrane, Cinhal, Psycinfo, Scopus, Medline, and Science Direct. Studies evaluating any type of physiotherapy intervention for PNP (systemic or traumatic) were included. Eighty-one articles were included in this review. The most common PNP model was chronic constriction injury, and the most frequently studied biomarkers were related to neuro-immune processes. Exercise therapy and Electro-acupuncture were the 2 most frequently studied physiotherapy interventions while acupuncture and joint mobilization were less frequently examined. Most physiotherapeutic interventions modulated the expression of biomarkers related to neuropathic pain. Whereas the results seem promising; they have to be considered with caution due to the high risk of bias of included studies and high heterogeneity of the type and anatomical localization of biomarkers reported. The review protocol is registered on PROSPERO (CRD42019142878). PERSPECTIVE: This article presents the current evidence about physiotherapeutic interventions on biomarkers of neuropathic pain in preclinical models of peripheral neuropathic pain. Existing findings are reviewed, and relevant data are provided on the effectiveness of each physiotherapeutic modality, as well as its certainty of evidence and clinical applicability.