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Excitability of the motor cortex can be suppressed during muscle pain. Yet the mechanisms are largely unknown. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were examined as possible candidate mechanisms to underpin this change. SICI and ICF were investigated in 11 healthy individuals before, during and after infusion of hypertonic saline into right first dorsal interosseous (FDI). Using paired-pulse transcranial magnetic stimulation (TMS), interstimulus intervals of 2, 3, and 13 ms were investigated. Pain intensity and quality were recorded using a 10-cm visual analogue scale and the McGill Pain Questionnaire. Resting motor threshold and motor-evoked potentials (MEPs) to single TMS stimuli were recorded before and after pain. Electromyographic recordings were made from right FDI and abductor digiti minimi. Participants reported an average pain intensity of 5.8 (1.6) cm. MEP amplitudes decreased in both muscles. Compared with the pre-pain condition, SICI was increased following pain, but not during. ICF was decreased both during and after pain when compared with the pre-pain condition. These findings suggest that muscle pain differentially modulates SICI and ICF. Although the functional relevance is unknown, we hypothesize decreased facilitation and increased inhibition may contribute to the restriction of movement of a painful body part. PERSPECTIVE: This article provides evidence for decreased intracortical facilitation and increased short interval intracortical inhibition in response to muscle pain. This finding is relevant to clinicians as a mechanism which may underlie restricted movement in acute and chronic pain. [ABSTRACT FROM AUTHOR]

Background: Cortical plasticity underlies the brain's ability to compensate and adapt after neurological and musculoskeletal injury. However, increasing evidence demonstrates that plasticity can also be maladaptive, contributing to functional impairment in a variety of conditions. Transcranial direct current stimulation (tDCS) is an emerging brain stimulation technique with the potential to alter cortical plasticity and prime the brain to enhance learning. If the potential of this technique can be harnessed, tDCS may provide a novel therapeutic approach in physiotherapy practice. Objectives: This review aims to provide an overview of the mechanisms, stimulation parameters and clinical applications of tDCS. Major findings: tDCS is an emerging and novel technique. Evidence at this early stage is promising with reductions in pain scores and improvements in motor function noted across a range of conditions. However, further research is needed before clinical efficacy and safety can be determined. Conclusions: tDCS is a powerful, non-invasive brain stimulation technique with the potential to improve outcomes in neurological and musculoskeletal conditions. Further research is needed using large sample sizes, long-term follow-up and a range of patient populations before the technique is available for clinical use. However, tDCS may be useful as a standalone therapy or as an adjunct to other physiotherapy treatments in the future. [ABSTRACT FROM AUTHOR]

Objectives: Because of its importance for patient safety and treatment efficacy, the volume and methodological quality of the evidence available on the accuracy of therapeutic ultrasound equipment is examined with respect to power output and timing function. Evidence for a causal relationship between ultrasound inaccuracy and machine age, brand, frequency of use and intensity settings is also examined. Methods: A systematic literature search was performed to identify observational studies examining levels of ultrasound machine inaccuracy. Methodological quality was examined using the Sheffield University hierarchy of evidence and a modified version of the McMaster University critical appraisal tool. Data was pooled using the descriptive statistics (mean, standard deviation, percentage) available in each study. Results: Eighteen studies out of 47 were retained for review. Methodological scores ranged from 2 to 155 (maximum 20). Two thirds of ultrasound machines (646%; SD 232; range 14-100%) were found to produce an inaccurate power input. The average percentage of timers found to be inaccurate was 301 and 226% at 5 and 10 min, respectively. The only variable correlated with level of machine inaccuracy was that of machine age. Discussion: The current review indicates that a significant proportion of ultrasound machines produce inaccurate power outputs or have an inaccurate timing function. This finding has implications for both clinical practice and therapeutic ultrasound research. [ABSTRACT FROM AUTHOR]

Background: Whole body vibration (WBV) is a new therapeutic tool used to improve muscle strength, power and postural control in various healthy and pathological populations. Aim: The aim of this systematic review was to summarise and evaluate the available literature on the effectiveness of WBV in neurological conditions. Method: A systematic review of the literature was performed to identify randomised controlled trials (RCTs) examining the effect of WBV on common neurological conditions. The methodological quality of the studies was systematically assessed using the PEDro rating scale. Reported outcomes were assessed for differences between the experimental and control groups and effect sizes were calculated. Results: Five RCTs and two pseudo RCTs were included. Methodological scores ranged from 1 to 9 (maximum 11) with a mean score of 571 (SD 269). There is weak to moderate evidence for positive effects on postural control, mobility, motor function and strength following the single application of WBV in neurological populations. A paucity of available literature into repeated WBV training prevents the drawing of firm conclusions regarding long-term treatment effectiveness. Conclusion: Despite being a new technique, there is early evidence that WBV applied to neurological populations has positive effects on postural control, mobility, motor function and strength. Further studies into the effectiveness of WBV in neurological populations are warranted. [ABSTRACT FROM AUTHOR]

Background: Biomarkers would greatly assist chronic pain management. The present study aimed to undertake analytical validation of a sensorimotor cortical biomarker signature for pain consisting of two measures: sensorimotor peak alpha frequency (PAF) and corticomotor excitability (CME), using a human model of prolonged temporomandibular pain (masseter intramuscular injection of nerve growth factor [NGF])., Methods: 150 participants received an injection of NGF to the right masseter muscle on Days 0 and 2, inducing prolonged pain lasting up to 4 weeks. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Days 0, 2 and 5. We determined the predictive accuracy of the PAF/CME biomarker signature using a nested control-test scheme: machine learning models were run on a training set (n = 100), where PAF and CME were predictors and pain sensitivity was the outcome. The winning classifier was assessed on a test set (n = 50) comparing the predicted pain labels against the true labels., Results: The winning classifier was logistic regression, with an outstanding area under the curve (AUC=1.00). The locked model assessed on the test set had excellent performance (AUC=0.88). Results were reproduced across a range of methodological parameters. Moreover, inclusion of sex and pain catastrophizing as covariates did not improve model performance, suggesting the model including biomarkers only was more robust. PAF and CME biomarkers showed good-excellent test-retest reliability., Conclusions: This study provides evidence for a sensorimotor cortical biomarker signature for pain sensitivity. The combination of accuracy, reproducibility, and reliability, suggests the PAF/CME biomarker signature has substantial potential for clinical translation.

Background: Cervicogenic headaches (CGH) are common following concussion and whiplash injuries and significantly reduce patient quality of life. Conservative therapies such as ET (ET) and physiotherapy combined with injection-based therapies are cornerstones of treatment for CGH but have shown limited efficacy. Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has shown promise in treating other chronic pain conditions. The primary aim of this trial is to evaluate the feasibility and safety of tDCS when combined with ET for the treatment of CGH., Methods: Adults (aged 18-65), blinded to treatment arm, will be randomized into one of two groups: active tDCS followed by ET or sham tDCS followed by ET. Transcranial direct current stimulation will be applied over M1 three times per week for 6-weeks and ET will be performed daily. The primary outcomes of this trial will be the feasibility and safety of the intervention. Feasibility will be defined as greater than 30 % recruitment, 70 % protocol adherence, and 80 % retention rate. Safety will be defined as no severe adverse events. Secondary exploratory outcomes will assess improvement in pain, strength, function, and quality of life., Conclusions: This trial aims to demonstrate the safety and feasibility of tDCS in combination with ET for the treatment of CGH. Cervicogenic headaches can be difficult to treat contributing to significant impairments function and quality of life. Transcranial direct current stimulation is a potential novel treatment to improve health outcomes in these patients., Registration: ClinicalTrials.gov-NCT05582616., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The STarT Back Screening Tool (SBT) is recommended to provide risk-stratified care in low back pain (LBP), yet its predictive value is moderate for disability and low for pain severity. Assessment of human assumed central sensitisation (HACS) in conjunction with the SBT may improve its predictive accuracy., Objectives: To examine whether assessment of HACS in acute LBP improves the predictive accuracy of the SBT for LBP recovery at six months in people with acute non-specific LBP., Design: A prospective longitudinal study., Method: Data were drawn from the UPWaRD study. One hundred and twenty people with acute non-specific LBP were recruited from the community. Baseline measures included SBT risk status, nociceptive flexor withdrawal reflex, pressure and heat pain thresholds and conditioned pain modulation. Primary outcome was the presence of LBP (pain numeric rating scale ≥1 and Roland Morris Disability Questionnaire score ≥3) at six-month follow-up. Regression coefficients were penalised using the least absolute shrinkage and selection operator technique to select predictor variables. Internal validation was performed using ten-fold cross-validation., Results/findings: SBT risk status alone did not predict the presence of LBP at six months (area under receiver operating characteristic curve [AUC] = 0.58). Adding measures of HACS to the SBT did not improve discrimination for whether LBP was present at six months (AUC = 0.59)., Conclusions: This study confirmed the suboptimal predictive accuracy of the SBT, administered during acute LBP, for LBP recovery at six months. Assessment of HACS in acute LBP does not improve the predictive accuracy of the SBT., (Copyright © 2024. Published by Elsevier Ltd.)

Pain hypersensitivity is present in some people with acute low back pain (LBP) and thought to be involved in the development of chronic LBP. Early evidence suggests that pain hypersensitivity in acute LBP precedes poor long-term outcome. We aimed to examine whether the presence of pain hypersensitivity in acute LBP influenced recovery status at 6 months and differentiated how pain and disability changed over time. Participants with acute nonspecific LBP (<6 weeks after pain onset, N = 118) were included in this longitudinal study. Quantitative sensory testing, including pressure and heat pain thresholds, and conditioned pain modulation and questionnaires were compared at baseline and longitudinally (at 3 and 6 months) between recovered and unrecovered participants. Using k-means clustering, we identified subgroups based on baseline sensory measures alone, and in combination with psychological factors, and compared pain and disability outcomes between subgroups. Sensory measures did not differ at baseline or longitudinally between recovered (N = 50) and unrecovered (N = 68) participants. Subgrouping based on baseline sensory measures alone did not differentiate pain or disability outcomes at any timepoint. Participants with high psychological distress at baseline (N = 19) had greater disability, but not pain, at all timepoints than those with low psychological distress, regardless of the degrees of pain sensitivity. Our findings suggest that pain hypersensitivity in acute LBP does not precede poor recovery at 6 months or differentiate how pain and disability change over time. High psychological distress during acute LBP is associated with unremitting and pronounced disability, while pain severity is unaffected. PERSPECTIVE: Pain hypersensitivity is thought to be involved in the transition to chronic LBP. Contradictory to prevailing hypothesis, our findings suggest pain hypersensitivity alone in acute LBP does not precede poor recovery. High psychological distress in acute LBP has a stronger influence than pain hypersensitivity on long-term disability, but not pain outcomes., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Rapid mapping is a transcranial magnetic stimulation (TMS) mapping method which can significantly reduce data collection time compared to traditional approaches. However, its validity and reliability has only been established for upper-limb muscles during resting-state activity. Here, we determined the validity and reliability of rapid mapping for non-upper limb muscles that require active contraction during TMS: the masseter and quadriceps muscles. Eleven healthy participants attended two sessions, spaced two hours apart, each involving rapid and 'traditional' mapping of the masseter muscle and three quadriceps muscles (rectus femoris, vastus medialis, vastus lateralis). Map parameters included map volume, map area and centre of gravity (CoG) in the medial-lateral and anterior-posterior directions. Low to moderate measurement errors (%SEM eas = 10-32) were observed across muscles. Relative reliability varied from good-to-excellent (ICC = 0.63-0.99) for map volume, poor-to-excellent (ICC = 0.11-0.86) for map area, and fair-to-excellent for CoG (ICC = 0.25-0.8) across muscles. There was Bayesian evidence of equivalence (BF's > 3) in most map outcomes between rapid and traditional maps across all muscles, supporting the validity of the rapid mapping method. Overall, rapid TMS mapping produced similar estimates of map parameters to the traditional method, however the reliability results were mixed. As mapping of non-upper limb muscles is relatively challenging, rapid mapping is a promising substitute for traditional mapping, however further work is required to refine this method., (© 2024. The Author(s).)

Peak alpha frequency (PAF), the dominant oscillatory frequency within the alpha range (8-12 Hz), is associated with cognitive function and several neurological conditions, including chronic pain. Manipulating PAF could offer valuable insight into the relationship between PAF and various functions and conditions, potentially providing new treatment avenues. This systematic review aimed to comprehensively synthesise effects of non-invasive brain stimulation (NIBS) on PAF speed. Relevant studies assessing PAF pre- and post-NIBS in healthy adults were identified through systematic searches of electronic databases (Embase, PubMed, PsychINFO, Scopus, The Cochrane Library) and trial registers. The Cochrane risk-of-bias tool was employed for assessing study quality. Quantitative analysis was conducted through pairwise meta-analysis when possible; otherwise, qualitative synthesis was performed. The review protocol was registered with PROSPERO (CRD42020190512) and the Open Science Framework (https://osf.io/2yaxz/). Eleven NIBS studies were included, all with a low risk-of-bias, comprising seven transcranial alternating current stimulation (tACS), three repetitive transcranial magnetic stimulation (rTMS), and one transcranial direct current stimulation (tDCS) study. Meta-analysis of active tACS conditions (eight conditions from five studies) revealed no significant effects on PAF (mean difference [MD] = -0.12, 95% CI = -0.32 to 0.08, p = 0.24). Qualitative synthesis provided no evidence that tDCS altered PAF and moderate evidence for transient increases in PAF with 10 Hz rTMS. However, it is crucial to note that small sample sizes were used, there was substantial variation in stimulation protocols, and most studies did not specifically target PAF alteration. Further studies are needed to determine NIBS's potential for modulating PAF., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Transcranial magnetic stimulation (TMS) is commonly delivered at an intensity defined by the resting motor threshold (rMT), which is thought to represent cortical excitability, even if the TMS target area falls outside of the motor cortex. This approach rests on the assumption that cortical excitability, as measured through the motor cortex, represents a 'global' measure of excitability. Another common approach to measure cortical excitability relies on the phosphene threshold (PT), measured through the visual cortex of the brain. However, it remains unclear whether either estimate can serve as a singular measure to infer cortical excitability across different brain regions. If PT and rMT can indeed be used to infer cortical excitability across brain regions, they should be correlated. To test this, we systematically identified previous studies that measured PT and rMT to calculate an overall correlation between the two estimates. Our results, based on 16 effect sizes from eight studies, indicated that PT and rMT are correlated (ρ = 0.4), and thus one measure could potentially serve as a measure to infer cortical excitability across brain regions. Three exploratory meta-analyses revealed that the strength of the correlation is affected by different methodologies, and that PT intensities are higher than rMT. Evidence for a PT-rMT correlation remained robust across all analyses. Further research is necessary for an in-depth understanding of how cortical excitability is reflected through TMS., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS prior to pain onset might protect against a future episode of prolonged pain. The present study aimed to determine i) whether 5 consecutive days of rTMS delivered prior to experimentally-induced prolonged jaw pain could reduce future pain intensity and ii) whether any effects of rTMS on pain were mediated by changes in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from Day 0-4, forty healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. PAF and CME were assessed on Day 0 (before rTMS) and Day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor (NGF) in the right masseter muscle after the final rTMS session. From Days 5-25, participants completed twice-daily electronic dairies including pain on chewing and yawning (primary outcomes), as well as pain during other activities (e.g. talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Although active rTMS increased PAF, the effects of rTMS on pain were not mediated by changes in PAF or CME. This study is the first to show that rTMS delivered prior to pain onset can protect against future pain and associated functional impairment. Thus, rTMS may hold promise as a prophylactic intervention for persistent pain., Competing Interests: Conflict of Interest: The authors have no conflicts of interests to declare.

OBJECTIVE: To estimate the difference in confidence to become active despite low back pain in people who were exposed to one of 2 video interventions delivered on social media, compared to no intervention. DESIGN: A proof-of-concept, 3-group randomized controlled trial, in a 1:1:1 ratio. METHODS: Participants aged 18 years and over, with and without low back pain, were recruited via the social media channel Facebook, to view either a humorous video, a neutral video, or to no intervention. The videos were delivered online, explained evidence-based management for low back pain, and were designed to "go viral." The primary outcome was confidence in becoming active despite pain, measured using the Pain Self Efficacy Questionnaire (Item 10) (ranges from 0 [not at all confident] to 6 [completely confident]) immediately after watching the video. We aimed to capture the real-time impact and immediate reactions that contributed to the content's reach. RESULTS: Among 1933 randomized participants (mean [standard deviation] age: 58.9 [14.0] years, 1285 [75%] women), 1232 [70%] had low back pain and 88.8% completed the primary outcome. One thousand two hundred sixty-four participants were randomized to receive a video intervention, and 633 participants did not receive a video. On a 6-point scale, individuals exposed to either video (n = 1088) showed a mean confidence level 0.3 points higher (95% confidence interval: 0.1, 0.6) compared with no video (n = 630). CONCLUSION: Participants who viewed a brief video intervention reported a very small difference in confidence to become active despite low back pain, compared with no intervention. The difference may lack clinical relevance. J Orthop Sports Phys Ther 2024;54(6):1-8. Epub 18 April 2024. doi:10.2519/jospt.2024.12412 .

The molecular processes driving the transition from acute to chronic low back pain (LBP) remain poorly understood and are likely to be sexually dimorphic. This study aimed to explore sex differences in the serum proteomic profile of people experiencing an acute LBP episode and determine if serum protein concentrations were associated with three-month outcome. Serum samples were collected through venepuncture from 30 female and 29 male participants experiencing an acute LBP episode. Serum samples underwent trypsin digestion and fractionation using hydrophobic interaction chromatography and were then analysed using mass-spectrometry. Mass-spectrometry spectra were searched in the Swissprot database for protein identification. Sex differences in protein abundance changes were evident upon inspection of fold changes. Multivariable data analysis identified 21 serum proteins during the acute episode that correctly classified 93% of males and 23 serum proteins that correctly classified 90% of females with ongoing LBP at 3 months. Pathway analysis suggested the differentially expressed proteins during acute LBP were frequently involved in immune, inflammatory, complement, or coagulation responses. This data provides preliminary evidence that biological processes during an acute LBP episode may contribute to the resolution, or persistence, of LBP symptoms at 3 months, however, these processes differ between males and females. PERSPECTIVE: Differential expression of serum proteins was observed between male and female participants during an acute LBP episode. This preliminary work provides a foundation for future research targeting distinct immune system processes in males and females that may interfere with the transition from acute to chronic LBP., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Systematic implementation of evidence-based, clinical practice guidelines for management of knee osteoarthritis (OA) in primary care physiotherapy in Australia is embryonic. Clinical practice guidelines have been implemented in the public healthcare sector at a State-level for physiotherapists in the form of multidisciplinary programs, but the reach of physiotherapy-led OA management programs is grossly inadequate in the private sector., Objective: To provide a snapshot of the management of people with knee OA in private physiotherapy practice in an Australian setting. Primarily the aim was to determine the alignment between the treatment provided and guideline-based management. Secondary aims included the capture of both patient-reported improvement after 3-months and patient satisfaction with treatment. Whether patient-reported outcome measures (PROMS) were routinely used was also ascertained., Methods: A prospective, observational study enrolling adults >=45 years with knee OA across nine primary care physiotherapy practices. Knee injury OA Outcome Score (KOOS) and Routine Assessment Patient Index 3 (RAPID3) were collected (baseline; 3 months) by researchers along with satisfaction with treatment. Treatment details and use of PROMS were obtained from physiotherapy record audit and patient interview. The treatment provided was compared to the minimum core elements of management stipulated in OA management guidelines., Results: Twenty-six adults (58% female, mean age 60 (9) years, 54% overweight or obese) participated. 100% were prescribed ≥1 appropriate exercise(s); 42% received OA education; 12% received weight management advice. Mean improvement (95%CI) in KOOS Pain was 9.8 (3.4 to 16.1) and RAPID3 was -3.4 (-5.5 to -1.3). Satisfaction with treatment was high (8.3/10). No PROMs were used for assessment or monitoring., Conclusion: Primary care physiotherapy treatment of knee OA did not meet minimum criteria per clinical practice guidelines. However, participant improvement at three months reached minimally important change thresholds for patient-reported measures and satisfaction was high. The data provide useful insights about areas that are deficient, thus, should inform future implementation strategies designed to improve care delivery and the uptake of routine measurement of patient-reported outcomes.

Lateral epicondylalgia (LE), commonly referred to as tennis elbow, is a musculoskeletal condition characterized by pain and sensorimotor dysfunction. In some individuals with chronic unilateral LE, sensorimotor symptoms develop on the unaffected side despite no evidence of tissue damage. Altered interhemispheric inhibition (IHI) is one mechanism that could underpin this phenomenon. The aim of this cross-sectional study was to examine IHI between the primary motor cortices (M1) in individuals with chronic LE and healthy controls. In 20 individuals with chronic LE and 20 healthy participants, transcranial magnetic stimulation was used to assess 1) short and long-latency IHI from the affected (corresponding to the injured side) to the unaffected M1 and 2) corticomotor excitability of the affected and unaffected M1. Sensorimotor function was evaluated bilaterally at the extensor carpi radialis brevis muscle using pressure pain threshold, grip strength, 2-point discrimination, and temporal summation tests. Short- and long-latency IHI from the affected to the unaffected M1 and corticomotor excitability of the affected and unaffected M1 were not altered in individuals with LE compared with healthy participants. No differences in sensorimotor function were observed for the affected or unaffected extensor carpi radialis brevis muscles when individuals with LE were compared with healthy participants. IHI is not altered in individuals with chronic LE. Further studies are required to determine the mechanisms that underpin the development of bilateral sensorimotor symptoms in unilateral LE. PERSPECTIVE: IHI is unaltered from the affected M1 (corresponding to the painful muscle) to unaffected M1 in individuals with LE compared to healthy controls. The absence of bilateral sensorimotor dysfunction and low pain severity in this cohort of individuals with LE may explain this finding., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n=29), multiple sustained thermal stimuli were administered to the forearm, with the first, second, and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures, respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak ~45 ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n=10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity., Competing Interests: NC, AC, SM, PS, WC, DS, SS No competing interests declared, (© 2023, Chowdhury et al.)

Chronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system, and is coincident with a growing opioid crisis. While numerous genome-wide association studies have been reported for specific pain-related traits, many of these studies were underpowered, and the genetic relationship among these traits remains poorly understood. Here, we conducted a joint analysis of genome-wide association study summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, 65 of which overlap loci identified in earlier studies. The remaining 34 loci are novel. We applied leave-one-trait-out meta-analyses to evaluate the influence of each trait on the joint analysis, which suggested that loci fall into four categories: loci associated with nearly all pain-related traits; loci primarily associated with a single trait; loci associated with multiple forms of skeletomuscular pain; and loci associated with headache-related pain. Overall, 664 genes were mapped to the 99 loci by genomic proximity, eQTLs, and chromatin interaction and ~15% of these genes showed differential expression in individuals with acute or chronic pain compared to healthy controls. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Genetic correlation and two-sample Mendelian randomization indicated that psychiatric, metabolic, and immunological traits mediate some of these effects., Competing Interests: The authors have no conflicts of interest to declare., (Copyright: © 2023 Mocci et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: This study aimed to understand perceptions that knee osteoarthritis patients have regarding their experiences of guideline-based recommendations within their care received from physiotherapists in private practice., Methods: A qualitative semi-structured interview study nested within a larger trial auditing care provided by physiotherapists. Recruited adults ≥ 45 years with knee osteoarthritis across nine primary care physiotherapy practices. Interview questions were anchored around the core elements recommended in guidelines for the management of knee osteoarthritis and patient perceptions of these were analysed using both content and thematic qualitative analysis approaches. Patient satisfaction with care received was asked at the time of interview., Results: Twenty-six patients volunteered for the study (mean 60 years, 58% female). Analysis identified that physiotherapists focused on treating symptoms through quadriceps strengthening exercises, which patients found to be effective, though focussed less on other aspects of evidenced-based care. Patient's perceived treatment to be effective in relieving pain and enabling them to stay active and they appreciated the positive role that their physiotherapist provided in alleviating their concerns. Overall, patients were satisfied with their physiotherapy care but would have liked more specific osteoarthritis education and longer-term management., Conclusion: The description of the physiotherapy-related care received by people with knee osteoarthritis aligns with guideline recommendations, though mainly for strength-related exercise prescription. Despite some perceived shortfalls in care, patients do appear to be satisfied. However, improvements in patient outcomes may be possible if more elements of guideline-base care are regularly provided, including enhancing osteoarthritis education and fostering behaviour change., Trial Registration: ACTRN12620000188932., (© 2023. The Author(s).)

Objectives: Pro-inflammatory molecules are thought to underpin the development of chronic low back pain (LBP). Although research has begun to explore the association between pro-inflammatory molecules in acute LBP and long-term outcome, no study has explored the role of anti-inflammatory molecules. We aimed to explore whether levels of systemic pro- and anti-inflammatory molecules 1) changed over a period of six months from the onset of acute LBP; 2) differed between people who were recovered (N = 11) and unrecovered (N = 24) from their episode of LBP at six months; 3) baseline psychological factors were related to inflammatory molecule serum concentrations at baseline, three and six months., Methods: We retrospectively included participants with acute LBP included from a larger prospective trial and examined blood samples for the measurement of pro- and anti-inflammatory molecules and measures of pain, disability, and psychological factors at baseline, three and six months., Results: The serum concentrations of pro- and anti-inflammatory molecules did not differ over time when compared between participants who recovered and those who did not recover at six-month follow-up. At three months, the unrecovered group had higher interleukin (IL)-8 and IL-10 serum concentrations than the recovered group. Baseline psychological factors were not related to inflammatory molecules at any time point., Discussion: This exploratory study showed that levels of systemic inflammatory molecules did not change over the course of LBP, irrespective of whether people were recovered or unrecovered at six months. There was no relationship between acute-stage psychological factors and systemic inflammatory molecules. Further investigation is needed to elucidate the contribution of pro- and anti-inflammatory molecules to long-term LBP outcome., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Early evidence suggests human assumed central sensitization (HACS) is present in some people with acute low back pain (LBP). Factors influencing individual variation in HACS during acute LBP have not been fully explored. We aimed to examine the evidence for HACS in acute LBP and the contribution of brain-derived neurotrophic factor (BDNF), clinical, psychological and demographic factors to HACS., Methods: Participants with acute LBP (<6 weeks after pain onset, N = 118) and pain-free controls (N = 57) from a longitudinal trial were included. Quantitative sensory testing including pressure and heat pain thresholds and conditioned pain modulation, BDNF serum concentration and genotype and questionnaires were assessed., Results: There were no signs of HACS during acute LBP at group level when compared with controls. Sensory measures did not differ when compared between controls and LBP participants with different BDNF genotypes. Two LBP subgroups with distinct sensory profiles were identified. Although one subgroup (N = 60) demonstrated features of HACS including pressure/heat pain hypersensitivity at a remote site and deficient conditioned pain modulation, pain severity and disability did not differ between the two subgroups. Variation in sensory measures (~33%) was partially explained by BDNF genotype, sex, age and psychological factors., Conclusions: This study confirms that HACS is present in some people with acute LBP, but this was not associated with pain or disability. Further, no relationship was observed between BDNF and HACS in acute LBP. More research is needed to understand factors contributing to individual variation in sensory measures in LBP., Significance: Human assumed central sensitization (HACS) is present in acute low back pain (LBP) but factors contributing to individual variation are not fully explored. This study investigated the relationship between factors such as brain derived neurotrophic factor (BDNF) and HACS in acute LBP. Our findings indicate that HACS was present in specific LBP subgroups but BDNF was unrelated to HACS. Combinations of BDNF genotype, demographic and psychological factors explained a small proportion of the variation in sensory measures during acute LBP., (© 2022 European Pain Federation - EFIC ®.)

Background: Many pain biomarkers fail to move from discovery to clinical application, attributed to poor reliability and an inability to accurately classify at-risk individuals. Preliminary evidence has shown that high pain sensitivity is associated with slow peak alpha frequency (PAF), and depression of corticomotor excitability (CME), potentially due to impairments in ascending sensory and descending motor pathway signalling respectively NEW METHOD: The present study evaluated the reliability of PAF and CME responses during sustained pain. Specifically, we determined whether, over several days of pain, a) PAF remains stable and b) individuals show two stable and distinct CME responses: facilitation and depression. Participants were given an injection of nerve growth factor (NGF) into the right masseter muscle on Day 0 and Day 2, inducing sustained pain. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Day 0, Day 2 and Day 5., Results: Using a weighted peak estimate, PAF reliability (n = 75) was in the excellent range even without standard pre-processing and ∼2 min recording length. Using a single peak estimate, PAF reliability was in the moderate-good range. For CME (n = 74), 80% of participants showed facilitation or depression of CME beyond an optimal cut-off point, with the stability of these changes in the good range., Comparison With Existing Methods: No study has assessed the reliability of PAF or feasibility of classifying individuals as facilitators/depressors, in response to sustained pain. PAF was reliable even in the presence of pain. The use of a weighted peak estimate for PAF is recommended, as excellent test-retest reliability can be obtained even when using minimal pre-processing and ∼2 min recording. We also showed that 80% of individuals exhibit either facilitation or depression of CME, with these changes being stable across sessions., Conclusions: Our study provides support for the reliability of PAF and CME as prospective cortical biomarkers. As such, our paper adds important methodological advances to the rapidly growing field of pain biomarkers., Competing Interests: Declaration of Competing Interest DAS and AJF are advisors to Empower Therapeutics. The other authors have no conflicts to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Temporomandibular disorder (TMD) is a common condition that frequently transitions to chronic symptoms. Experimental pain models that mimic the symptoms of clinical TMD may be useful in understanding the mechanisms, and sex differences, present in this disorder. Here we aimed to comprehensively characterise the nature and time-course of pain, functional impairment and hyperalgesia induced by repeated intramuscular injection of nerve growth factor (NGF) into the masseter muscle, and to investigate sex differences in the NGF-induced pain experience., Methods: 94 healthy individuals participated in a longitudinal study with 30-day follow-up. NGF was injected into the right masseter muscle on Day 0 and Day 2. Participants attended laboratory sessions to assess pain (Numerical Rating Scale; NRS), functional limitation (mouth opening distance, Jaw Functional Limitation Scale; JFLS) and mechanical sensitization (pressure pain thresholds; PPTs) on Days 0, 2 and 5 and completed twice daily electronic pain dairies from Day 0 to day 30., Results: Peak pain averaged 2.0/10 (95 % CI: 1.6-2.4) at rest and 4.3/10 (95 % CI: 3.9-4.8) on chewing. Pain-free mouth opening distance reduced from 5.0 cm (95 % CI: 4.8-5.1 cm) on Day 0 to 3.7 cm (95 % CI: 3.5-3.9 cm) on Day 5. The greatest reduction in PPTs was observed over the masseter muscle. Females experienced higher pain, greater functional impairment, and greater sensitivity to mechanical stimuli than males., Conclusion: Intramuscular injection of NGF is a useful model with which to explore the mechanisms, and sex differences, present in clinical TMD., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This project was funded by grant 1R61NS113269-01 from The National Institutes of Health to DAS, SMS and SC. DAS is an advisor to Empower Therapeutics. The other authors have no conflicts to declare., (© 2023 The Authors.)

Abstract: Predicting the development of chronic low back pain (LBP) at the time of an acute episode remains challenging. The Understanding persistent Pain Where it ResiDes study aimed to identify neurobiological and psychological risk factors for chronic LBP. Individuals with acute LBP (N = 120) participated in a prospective cohort study with 6-month follow-up. Candidate predictors were selected from the neurobiological (eg, sensorimotor cortical excitability assessed by sensory and motor-evoked potentials and brain-derived neurotrophic factor genotype), psychological (eg, depression and anxiety), symptom-related (eg, LBP history), and demographic domains. Analyses involved multivariable linear regression models with pain intensity or disability degree as continuous variables. Secondary analyses involved a multivariable logistic model with the presence of LBP at 6 months (thresholding pain intensity and disability degree) as a dichotomous variable. Lower sensory cortex and corticomotor excitability, higher baseline pain intensity, higher depression, stress, and pain catastrophizing were the strongest predictors ( R2 = 0.47) of pain intensity at 6 months. Older age and higher pain catastrophizing were the strongest predictors ( R2 = 0.30) of disability at 6 months. When the LBP outcome was dichotomised, sensory cortex and corticomotor excitability, brain-derived neurotrophic factor genotype, depression and anxiety, LBP history and baseline pain intensity, discriminated between those who did and did not report LBP at 6 months (C-statistic 0.91). This study identifies novel risk factors for the development of future LBP. Neurobiological risk factors, when added to a multivariable linear regression model, explained a further 15% of the variance in the 6-month pain intensity., (Copyright © 2022 International Association for the Study of Pain.)

Background: Somatosensory evoked potentials (SEPs) are used extensively to quantify cortical activity in response to noxious and/or non-noxious sensory stimuli. However, data demonstrating the reliability of SEP measures in response to non-noxious stimulation over time are scarce., Aim: We investigated the relative and absolute reliability, and the smallest detectable change at 95% confidence (SDC 95 ) for SEPs evoked by non-noxious electrical stimulation of the paraspinal muscles in thirty-nine healthy participants at a 3-month interval., Methods: SEPs were evoked at an intensity three-times that of each participant's perceptual threshold and recorded from a single electrode placed over the primary somatosensory cortex (S1)., Results: Our analyses reveal that i) latency, as a measure of activity onset, has poor relative reliability but good absolute reliability; ii) area, as a measure of cortical activity, has good relative and absolute reliability (except for the N 150 component) and iii) perceptual threshold and stimulation intensity was not reliable over time., Conclusion: These findings suggest that the area of the N 80 and P 260 SEP components, and the area of the N 80 -N 150 -P 260 SEP complex, can be utilised in future studies as reliable markers of cortical activity.

Despite being a first-line treatment recommendation, there is uncertainly for how exercise helps people with chronic low back pain. We designed this study to examine how exercise might help people with chronic low back pain by following a large community sample for 1-year. Qualitative questionnaires and self-report measures were collected every 3-months for 1-year in 400 people with chronic low back pain. People were not provided any specific treatment advice as part of this study but were allowed to engage with any normal physical activity, treatment, or medication as part of their normal life. Exercise engagement was defined from inspection of participant qualitative responses, according to minimum acceptable levels of exercise that elicit symptom reduction. Multiple mediation analysis was performed to examine the effect of exercise engagement on disability through the proposed mediators (pain, fear, catastrophizing, depression, anxiety, self-efficacy). The significant effect of exercise engagement on reductions in disability at 6- and 12-months was explained through pain and catastrophizing. People with chronic low back pain who reported worsening of symptoms over the year had similar reporting of exercise throughout the 12-months to people who had improvements in disability. Exercise can reduce disability through the effect on pain and catastrophizing, but how this effect occurs (i.e., an active or passive component of exercise) is unclear., Competing Interests: Declaration of competing interest PM received funding support from the Sydney Spine and Pain Clinics during the data collection phase of this project for unrelated work, and has commenced unpaid advisory work for TBI Health (NZ) in 2021. SMS receives salary support from the National Health and Medical Research Council of Australia (1105040). The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Pain alters motor function. This is supported by studies showing reduced corticomotor excitability in response to experimental pain lasting &lt;90 minutes. Whether similar reductions in corticomotor excitability are present with pain of longer durations or whether alterations in corticomotor excitability are associated with pain severity is unknown. Here we evaluated the evidence for altered corticomotor excitability in response to experimental pain of differing durations in healthy individuals. Databases were systematically searched for eligible studies. Measures of corticomotor excitability and pain were extracted. Meta-analyses were performed to examine: (1) group-level effect of pain on corticomotor excitability, and (2) individual-level associations between corticomotor excitability and pain severity. 49 studies were included. Corticomotor excitability was reduced when pain lasted milliseconds-seconds (hedges g's = -1.26 to -1.55) and minutes-hours (g's = -0.55 to -0.9). When pain lasted minutes-hours, a greater reduction in corticomotor excitability was associated with lower pain severity (g = -0.24). For pain lasting days-weeks, there were no group level effects (g = -0.18 to 0.27). However, a greater reduction in corticomotor excitability was associated with higher pain severity (g = 0.229). In otherwise healthy individuals, suppression of corticomotor excitability may be a beneficial short-term strategy with long-term consequences. PERSPECTIVE: This systematic review synthesised the evidence for altered corticomotor excitability in response to experimentally induced pain. Reduced corticomotor excitability was associated with lower acute pain severity but higher sustained pain severity, suggesting suppression of corticomotor excitability may be a beneficial short-term adaptation with long-term consequences., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: It remains unclear to what extent Transcranial Magnetic Stimulation-evoked potentials (TEPs) reflect sensory (auditory and somatosensory) potentials as opposed to cortical excitability. The present study aimed to determine; a) the extent to which sensory potentials contaminate TEPs using a spatially-matched sham condition, and b) whether sensory potentials reflect auditory or somatosensory potentials alone, or a combination of the two., Methods: Twenty healthy participants received active or sham stimulation, with the latter consisting a sham coil click combined with scalp electrical stimulation. Two additional conditions i) electrical stimulation and ii) auditory stimulation alone, were included in a subset of 13 participants., Results: Signals from active and sham stimulation were correlated in spatial and temporal domains > 55 ms post-stimulation. Relative to auditory or electrical stimulation alone, sham stimulation resulted in a) larger potentials, b) stronger correlations with active stimulation and c) a signal that was not a linear sum of electrical and auditory stimulation alone., Conclusions: Sensory potentials can confound interpretations of TEPs at timepoints > 55 ms post-stimulation. Furthermore, TEP contamination cannot be explained by auditory or somatosensory potentials alone, but instead reflects a non-linear interaction between both., Significance: Future studies may benefit from controlling for sensory contamination using spatially-matched sham conditions, and which consist of combined auditory and somatosensory stimulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Abstract: This observational study evaluated people's attitudes towards educational statements and tested whether this predicted intention to self-manage low back pain (LBP). People with or without LBP who were older than 18 years and fluent in written English were recruited. Participants completed an online survey asking demographic questions and questions on the presence or absence of LBP, its duration, and intensity. We assessed attitude toward educational statements and conducted linear regression analyses to investigate the relationship between attitude toward each statement and intention to self-manage. We recruited 656 participants, n = 345 (53.6%), with LBP of varying duration. On average, participants had a positive attitude toward all statements except one; participants with chronic LBP had a negative attitude toward a statement relating to the cause of LBP. The effect of attitude on intention to self-manage was dependent on whether someone had LBP and for how long. For example, increased intention to self-manage was predicted by a positive attitude toward educational statements related to staying active (β = 0.22 [CI 0.11-0.33]) in participants without pain, statements about reassurance (β = 0.33 [CI 0.16-0.49]) for participants with acute or subacute LBP, and statements about the severity of back pain (β = 0.25 [CI 0.18-0.33]) for participants with chronic LBP. We noted differences in attitude toward educational messages and individuals' intention to self-manage LBP depending on pain duration. Self-management could be encouraged with specific reassurance in people with acute or subacute LBP and education about severity in people with chronic LBP., (Copyright © 2022 International Association for the Study of Pain.)

Introduction: Social media provide promising contemporary platforms for sharing public health information with a broad audience. Before implementation, testing social media campaigns that are intended to engage audiences and initiate behaviour change is necessary. This trial aims to investigate the effectiveness of a public health campaign to increase people's confidence in becoming more active despite low back pain in comparison with no intervention., Methods and Analysis: This is an online randomised controlled trial with two intervention groups and one control group in a 1:1:1 allocation. People over 18 years of age and fluent in English will be recruited via social media advertising. We developed a social media-based public health campaign to support recommendations for managing low back pain. The interventions are two videos. Participants in the control group will be asked questions about low back pain but will not view either video intervention. The primary outcome will be item 10 of the Pain Self-Efficacy Questionnaire, which asks participants to rate how confident they would feel to gradually become more active despite pain ranging from 0 (not at all confident) to 6 (completely confident). This outcome will be measured immediately in all participant groups. We will compare group mean of the three arms of the trial using univariate analyses of variance., Ethics and Dissemination: This trial has been prospectively registered with the Australian New Zealand Clinical Trials Registry. We obtained ethical approval from our institutions Human Research Ethics Committee before data collection. We will publish the results in a peer-reviewed medical journal and on institution websites., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12622000466741)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)