The role and treatment potential of the complement pathway in chronic pain.

The role of the complement system in pain syndromes has garnered attention on the back of preclinical and clinical evidence supporting its potential as a target for new analgesic pharmacotherapies. Of the components that make up the complement system, component 5a (C5a) and component 3a (C3a) are most strongly and consistently associated with pain. Receptors for C5a are widely found in immune resident cells (microglia, astrocytes, sensory neuron-associated macrophages (sNAMs)) in the central nervous system (CNS) as well as hematogenous immune cells (mast cells, macrophages, T-lymphocytes, etc.). When active, as is often observed in chronic pain conditions, these cells produce various inflammatory mediators including pro-inflammatory cytokines. These events can trigger nervous tissue inflammation (neuroinflammation) which coexists with and potentially maintains peripheral and central sensitization. C5a has a likely critical role in initiating this process highlighting its potential as a promising non-opioid target for treating pain. This review summarises the most up-to-date research on the role of the complement system in pain with emphasis on the C5 pathway in peripheral tissue, dorsal root ganglia (DRG) and the CNS, and explores advances in complement-targeted drug development and sex differences. A perspective on the optimal application of different C5a inhibitors for different types (e.g., neuropathic, post-surgical and chemotherapy-induced pain, osteoarthritis pain) and stages (e.g., acute, subacute, chronic) of pain is also provided to help guide future clinical trials. PERSPECTIVE: This review highlights the role and mechanisms of complement components and their receptors in physiological and pathological pain. The potential of complement-targeted therapeutics for the treatment of chronic pain is also explored with a focus on C5a inhibitors to help guide future clinical trials.

Characterization of pain-related behaviors in a rat model of acute-to-chronic low back pain: single vs. multi-level disc injury.

Introduction: Low back pain is the most common type of chronic pain. We examined pain-related behaviors across 18 weeks in rats that received injury to one or two lumbar intervertebral discs (IVD) to determine if multi-level disc injuries enhance/prolong pain. Methods: Twenty-three Sprague-Dawley adult female rats were used: 8 received disc puncture (DP) of one lumbar IVD (L5/6, DP-1); 8 received DP of two lumbar IVDs (L4/5 & L5/6, DP-2); 8 underwent sham surgery. Results: DP-2 rats showed local (low back) sensitivity to pressure at 6- and 12-weeks post-injury, and remote sensitivity to pressure (upper thighs) at 12- and 18-weeks and touch (hind paws) at 6, 12 and 18-weeks. DP-1 rats showed local and remote pressure sensitivity at 12-weeks only (and no tactile sensitivity), relative to Sham DP rats. Both DP groups showed reduced distance traveled during gait testing over multiple weeks, compared to pre-injury; only DP-2 rats showed reduced distance relative to Sham DP rats at 12-weeks. DP-2 rats displayed reduced positive interactions with a novel adult female rat at 3-weeks and hesitation and freezing during gait assays from 6-weeks onwards. At study end (18-weeks), radiological and histological analyses revealed reduced disc height and degeneration of punctured IVDs. Serum BDNF and TNFα levels were higher at 18-weeks in DP-2 rats, relative to Sham DP rats, and levels correlated positively with remote sensitivity in hind paws (tactile) and thighs (pressure). Discussion: Thus, multi-level disc injuries resulted in earlier, prolonged and greater discomfort locally and remotely, than single-level disc injury. BDNF and TNFα may have contributing roles.

Poor lumbar spine coordination in acute low back pain predicts persistent long-term pain and disability.

PURPOSE: Sitting balance on an unstable surface requires coordinated out-of-phase lumbar spine and provides sufficient challenge to expose quality of spine control. We investigated whether the quality of spine coordination to maintain balance in acute low back pain (LBP) predicts recovery at 6 months. METHODS: Participants in an acute LBP episode (n = 94) underwent assessment of sitting balance on an unstable surface. Seat, hip and spine (lower lumbar, lumbar, upper lumbar, thoracic) angular motion and force plate data were recorded. Coordination between the seat and hip/spine segments to maintain balance was quantified in the frequency domain to evaluate coordination (coherence) and relative timing (phase angle: in-phase [segments move together]; out-of-phase [segments move opposite]). Center of pressure (CoP) and upper thorax motion assessed overall balance performance. Hip and spine coordination with the seat were compared between those who did not recover (increased/unchanged pain/disability), partially recovered (reduced pain/disability) or recovered (no pain and disability) at 6 months. RESULTS: In both planes, coherence between the seat and lower lumbar spine was lower (and in-phase-unhelpful for balance) at baseline in those who did not recover than those who recovered. Coherence between the seat and hip was higher in partially recovered in both planes, suggesting compensation by the hip. LBP groups had equal overall balance performance (CoP, upper thorax motion), but non-recovery groups used a less optimal strategy that might have consequences for long-term spine health. CONCLUSION: These longitudinal data revealed that individuals with compromised contribution of the lumbar spine to the balance during unstable sitting during acute LBP are less likely to recover.

Trunk postural control during unstable sitting among individuals with and without low back pain: A systematic review with an individual participant data meta-analysis.

INTRODUCTION: Sitting on an unstable surface is a common paradigm to investigate trunk postural control among individuals with low back pain (LBP), by minimizing the influence lower extremities on balance control. Outcomes of many small studies are inconsistent (e.g., some find differences between groups while others do not), potentially due to confounding factors such as age, sex, body mass index [BMI], or clinical presentations. We conducted a systematic review with an individual participant data (IPD) meta-analysis to investigate whether trunk postural control differs between those with and without LBP, and whether the difference between groups is impacted by vision and potential confounding factors. METHODS: We completed this review according to PRISMA-IPD guidelines. The literature was screened (up to 7th September 2023) from five electronic databases: MEDLINE, CINAHL, Embase, Scopus, and Web of Science Core Collection. Outcome measures were extracted that describe unstable seat movements, specifically centre of pressure or seat angle. Our main analyses included: 1) a two-stage IPD meta-analysis to assess the difference between groups and their interaction with age, sex, BMI, and vision on trunk postural control; 2) and a two-stage IPD meta-regression to determine the effects of LBP clinical features (pain intensity, disability, pain catastrophizing, and fear-avoidance beliefs) on trunk postural control. RESULTS: Forty studies (1,821 participants) were included for the descriptive analysis and 24 studies (1,050 participants) were included for the IPD analysis. IPD meta-analyses revealed three main findings: (a) trunk postural control was worse (higher root mean square displacement [RMSdispl], range, and long-term diffusion; lower mean power frequency) among individuals with than without LBP; (b) trunk postural control deteriorated more (higher RMSdispl, short- and long-term diffusion) among individuals with than without LBP when vision was removed; and (c) older age and higher BMI had greater adverse impacts on trunk postural control (higher short-term diffusion; longer time and distance coordinates of the critical point) among individuals with than without LBP. IPD meta-regressions indicated no associations between the limited LBP clinical features that could be considered and trunk postural control. CONCLUSION: Trunk postural control appears to be inferior among individuals with LBP, which was indicated by increased seat movements and some evidence of trunk stiffening. These findings are likely explained by delayed or less accurate corrective responses. SYSTEMATIC REVIEW REGISTRATION: This review has been registered in PROSPERO (registration number: CRD42021124658).

Poor sleep versus exercise: A duel to decide whether pain resolves or persists after injury.

Poor sleep is thought to enhance pain via increasing peripheral and/or central sensitization. Aerobic exercise, conversely, relives pain via reducing sensitization, among other mechanisms. This raises two clinical questions: (1) does poor sleep contribute to the transition from acute-to-persistent pain, and (2) can exercise protect against this transition? This study tested these questions and explored underlying mechanisms in a controlled injury model. Twenty-nine adult female Sprague-Dawley rats performed an intensive lever-pulling task for 4 weeks to induce symptoms consistent with clinical acute-onset overuse injury. Rats were then divided into three groups and exposed for 4 weeks to either: voluntary exercise via access to a running wheel, sleep disturbance, or both. Pain-related behaviours (forepaw mechanical sensitivity, reflexive grip strength), systemic levels of brain derived neurotrophic factor (BDNF), estradiol and corticosterone, and white blood cells (WBC) were assessed pre-injury, post-injury and post-intervention. Mechanical sensitivity increased post-injury and remained elevated with sleep disturbance alone, but decreased to pre-injury levels with exercise both with and without sleep disturbance. Reflexive grip strength decreased post-injury but recovered post-intervention-more with exercise than sleep disturbance. BDNF increased with sleep disturbance alone, remained at pre-injury levels with exercise regardless of sleep, and correlated with mechanical sensitivity. WBCs and estradiol increased with exercise alone and together with sleep disturbance, respectively. Corticosterone was not impacted by injury/intervention. Findings provide preliminary evidence for a role of poor sleep in the transition from acute-to-persistent pain, and the potential for aerobic exercise to counter these effects. BDNF might have a role in these relationships.

Coordination of hip and spine in individuals with acute low back pain during unstable sitting.

BACKGROUND CONTEXT: Trunk postural control differs between individuals with and without chronic low back pain (LBP). Whether this corresponds to differences in hip/spine coordination during the early acute phase of LBP (ALBP) is unclear. PURPOSE: To compare hip/spine coordination in relation to seat movements between individuals with and without ALBP when balancing on an unstable seat and to identify coordination strategies to maintain balance using cluster analysis. STUDY DESIGN/SETTING: Cross-sectional observational study. PATIENT SAMPLE: ALBP (n=130) and pain-free (n=72) individuals. OUTCOME MEASURES: Frequency domain measures to evaluate hip/spine coordination (amplitude spectrum, phase angle, and coherence) and time-series measures to assess overall balance performance (center of pressure [CoP] reflecting the amount of seat movements, upper thorax motion as a surrogate for head motion). METHODS: Participants maintained balance while sitting on a seat fixed to a hemisphere. Seat, hip, and spine (lower lumbar, lumbar, upper lumbar, and thoracic) angular motion and force plate data were recorded. RESULTS: Overall, seat/CoP movements (amplitude spectrum and RMSdisplacement) were greater (in both planes) and sagittal coordination (coherence) between the hip or lower spine and seat movements was lower in ALBP than controls. Cluster analysis using coherence data revealed different coordination strategies to maintain balance. Separate clusters used a "lower lumbar strategy" and "hip strategy" in the sagittal plane, and a "lower and upper lumbar strategy" and "lower lumbar strategy" in the frontal plane. A cluster using a "low coherence strategy" in both planes was also identified. CONCLUSIONS: Hip and lower spine coordination was less in individuals with ALBP in conjunction with a lower quality of overall balance performance. However, interpretation of the relationship between coherence and overall balance performance was not straightforward. Clusters in both the ALBP group and the control group adopted a low coherence strategy, and this was not consistently related to poor overall balance performance. This suggests overall balance performance cannot be inferred from coherence alone and requires consideration of interaction of other different features.

Low back pain and osteoarthritis pain: a perspective of estrogen.

Low back pain (LBP) is the world's leading cause of disability and is increasing in prevalence more rapidly than any other pain condition. Intervertebral disc (IVD) degeneration and facet joint osteoarthritis (FJOA) are two common causes of LBP, and both occur more frequently in elderly women than in other populations. Moreover, osteoarthritis (OA) and OA pain, regardless of the joint, are experienced by up to twice as many women as men, and this difference is amplified during menopause. Changes in estrogen may be an important contributor to these pain states. Receptors for estrogen have been found within IVD tissue and nearby joints, highlighting the potential roles of estrogen within and surrounding the IVDs and joints. In addition, estrogen supplementation has been shown to be effective at ameliorating IVD degeneration and OA progression, indicating its potential use as a therapeutic agent for people with LBP and OA pain. This review comprehensively examines the relationship between estrogen and these pain conditions by summarizing recent preclinical and clinical findings. The potential molecular mechanisms by which estrogen may relieve LBP associated with IVD degeneration and FJOA and OA pain are discussed.

Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain.

PURPOSE: Causal mechanisms underlying systemic inflammation in spinal & widespread pain remain an intractable experimental challenge. Here we examined whether: (i) associations between blood C-reactive protein (CRP) and chronic back, neck/shoulder & widespread pain can be explained by shared underlying genetic variants; and (ii) higher CRP levels causally contribute to these conditions. METHODS: Using genome-wide association studies (GWAS) of chronic back, neck/shoulder & widespread pain (N = 6063-79,089 cases; N = 239,125 controls) and GWAS summary statistics for blood CRP (Pan-UK Biobank N = 400,094 & PAGE consortium N = 28,520), we employed cross-trait bivariate linkage disequilibrium score regression to determine genetic correlations (rG) between these chronic pain phenotypes and CRP levels (FDR < 5%). Latent causal variable (LCV) and generalised summary data-based Mendelian randomisation (GSMR) analyses examined putative causal associations between chronic pain & CRP (FDR < 5%). RESULTS: Higher CRP levels were genetically correlated with chronic back, neck/shoulder & widespread pain (rG range 0.26-0.36; P ≤ 8.07E-9; 3/6 trait pairs). Although genetic causal proportions (GCP) did not explain this finding (GCP range - 0.32-0.08; P ≥ 0.02), GSMR demonstrated putative causal effects of higher CRP levels contributing to each pain type (beta range 0.027-0.166; P ≤ 9.82E-03; 3 trait pairs) as well as neck/shoulder pain effects on CRP levels (beta [S.E.] 0.030 [0.021]; P = 6.97E-04). CONCLUSION: This genetic evidence for higher CRP levels in chronic spinal (back, neck/shoulder) & widespread pain warrants further large-scale multimodal & prospective longitudinal studies to accelerate the identification of novel translational targets and more effective therapeutic strategies.

How Do Nonsurgical Interventions Improve Pain and Physical Function in People With Osteoarthritis? A Scoping Review of Mediation Analysis Studies.

OBJECTIVE: Nonsurgical interventions are recommended for osteoarthritis (OA). However, how interventions change pain and physical function is unclear. Therefore, the objectives of this scoping review were to 1) identify what potential mediators of nonsurgical interventions on pain and physical function have been evaluated and 2) summarize the findings according to intervention, joint, and outcome. METHODS: We searched Medline, Embase, CINAHL, Cochrane Central Register of Controlled Trials, and Scopus databases. Studies were included if they conducted a mediation analysis on a randomized controlled trial evaluating a nonsurgical intervention on OA of any joint. Outcomes were pain and physical function. RESULTS: Nine knee OA studies, evaluating diet plus exercise, exercise, unloading shoes, high-expectation communication during acupuncture, and telephone-based weight loss plus exercise were identified. Except for weight loss and self-efficacy, putative mediators (knee muscle perfusion/extensor strength/adduction moment, systemic inflammatory biomarkers, physical activity, dietary intake, and pain beliefs) were evaluated by single studies. Ten mediators partially mediated intervention (diet plus exercise, exercise, high-expectation communication) effects on pain and physical function. Eight mediators were common to pain and function (reduced weight, increased knee extensor strength, and increased self-efficacy). Constant knee flexor muscle perfusion partially mediated exercise effects on pain, and knee pain relief partially mediated exercise effects on function. CONCLUSION: In knee OA, some evidence suggests that the benefits of 1) diet and exercise are mediated through changes in body weight, systemic inflammation, and self-efficacy; 2) exercise is mediated through changes in knee muscle strength and self-efficacy; and 3) high-expectation communication style is mediated through changes in self-efficacy.

Postural control of the trunk in individuals with and without low back pain during unstable sitting: A protocol for a systematic review with an individual participant data meta-analysis.

INTRODUCTION: Postural control of the trunk is critical for performance of everyday activities and the health of spinal tissues. Although some studies report that individuals with low back pain (LBP) have poorer/compromised postural control than pain-free individuals when sitting on an unstable surface, others do not. Analyses commonly lack the statistical power to evaluate the relevance of features that could impact the performance of postural control, such as sex, age, anthropometrics, pain intensity or disability. This paper outlines a protocol for a systematic review with an individual participant data (IPD) meta-analysis that aims to synthesise the evidence and evaluate differences of postural control measures between individuals with and without LBP during unstable sitting. METHODS AND ANALYSIS: A systematic review with IPD meta-analysis will be conducted according to PRISMA-IPD guidelines. To identify relevant studies, electronic databases and the reference lists of included articles will be screened. Unstable seat movements are derived from centre of pressure (CoP) data using a force plate or angle of the seat using motion systems/sensors. The comprehensiveness of reporting and methodological quality of included studies will be assessed. Analysis will involve a descriptive analysis to synthesise the findings of all included studies and a quantitative synthesis using two-stage IPD meta-analysis of studies that include both individuals with and without LBP for which IPD set can be obtained from authors. Analyses will include consideration of confounding variables. ETHICS: Exemption from ethical approval was obtained for this review (University of Queensland, ID: 2019003026). SYSTEMATIC REVIEW REGISTRATION: PROSPERO ID: CRD42021124658.

Effects of adding aerobic physical activity to strengthening exercise on hip osteoarthritis symptoms: protocol for the PHOENIX randomised controlled trial.

BACKGROUND: Hip osteoarthritis (OA) is a leading cause of musculoskeletal pain. Exercise is a core recommended treatment. Most evidence is based on muscle-strengthening exercise, but aerobic physical activity has potential to enhance clinical benefits. The primary aim of this study is to test the hypothesis that adding aerobic physical activity to a muscle strengthening exercise leads to significantly greater reduction in hip pain and improvements in physical function, compared to a lower-limb muscle strengthening exercise program alone at 3 months. METHODS: This is a superiority, 2-group, parallel randomised controlled trial including 196 people with symptomatic hip OA from the community. Following baseline assessment, participants are randomly allocated to receive either i) aerobic physical activity and muscle strengthening exercise or; ii) muscle strengthening exercise only. Participants in both groups receive 9 consultations with a physiotherapist over 3 months. Both groups receive a progressive muscle strengthening exercise program in addition to advice about OA management. The aerobic physical activity plan includes a prescription of moderate intensity aerobic physical activity with a goal of attaining 150 min per week. Primary outcomes are self-reported hip pain assessed on an 11-point numeric rating scale (0 = 'no pain' and 10 = 'worst pain possible') and self-reported physical function (Western Ontario and McMaster Universities Osteoarthritis Index physical function subscale) at 3 months. Secondary outcomes include other measures of self-reported pain (assessed at 0, 3, 9 months), self-reported physical function (assessed at 0, 3, 9 months), performance-based physical function (assessed at 0, 3 months), joint stiffness (assessed at 0, 3, 9 months), quality of life (assessed at 0, 3, 9 months), muscle strength (assessed at 0, 3 months), and cardiorespiratory fitness (assessed at 0, 3 months). Other measures include adverse events, co-interventions, and adherence. Measures of body composition, serum inflammatory biomarkers, quantitative sensory measures, anxiety, depression, fear of movement and self-efficacy are included to explore causal mechanisms. DISCUSSION: Findings will assist to provide an evidence-based recommendation regarding the additional effect of aerobic physical activity to lower-limb muscle strengthening on hip OA pain and physical function. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry reference: ACTRN 12619001297112. Registered 20th September 2019.

Balance control in unstable sitting in individuals with an acute episode of low back pain.

BACKGROUND: Low back pain (LBP) is associated with altered postural control, mostly observed at later stages in the LBP trajectory. It is unclear whether postural control differs in the acute phase of LBP. RESEARCH QUESTION: Is postural control different in the acute phase of LBP (<2 weeks) and do differences depend on pain intensity, psychological features and/or availability of vision to control posture? METHODS: Cross-sectional study design. An unstable sitting paradigm (to reduce the contribution of the legs) assessed postural control of participants with acute LBP (n = 133) and pain-free controls (n = 74). Centre of pressure (CoP) reflected seat movements. Participants balanced with eyes closed, open, or with visual feedback of the anteroposterior CoP position. Balance performance was expressed by CoP displacement and velocity, and stabilogram diffusion analysis. Generalised estimating equations (GEEs) including body mass index, sex, and safety bar touch, tested differences between groups and between balance conditions. Separate GEEs were used to model performance measures and bar touch (yes/no) including pain intensity, disability and psychological features. RESULTS: CoP displacement and critical point coordinates (time and distance where CoP diffusion rate or spread slows) were larger in LBP than pain-free controls independent of balance condition. Long-term diffusion rate was greater in LBP than controls with eyes closed. CoP velocity measures (RMS, short term diffusion rate) were not different between groups. Pain intensity and psychological features were not linearly related to balance performance in participants with acute LBP. Higher pain catastrophizing was associated with touching the safety bar. SIGNIFICANCE: Postural control differs in acute LBP than pain-free controls. Findings might be explained by altered sensory processing, lesser ability to reweight proprioceptive information and/or less accurate trunk muscle control. Although not linearly related to pain-intensity or psychological features in the acute stage, reduced balance performance could potentially have impact on LBP recovery.

Relationship between systemic inflammation and recovery over 12 months after an acute episode of low back pain.

BACKGROUND CONTEXT: Individual characteristics can influence outcomes after injury. Our previous work in individuals with early-acute low back pain (LBP) identified subgroups (clusters) with specific biopsychosocial features that recovered poorly or well by 6 months. PURPOSE: This study extends on that work by revealing the short- and long-term trajectories of recovery and systemic inflammation of these participant clusters: (1) "inflammatory & poor sleep" (Cluster 1), "high TNF & depression" (Cluster 2), "high pain & high pain-related fear" (Cluster 3), and "low pain & low pain-related fear" (Cluster 4). STUDY DESIGN/SETTING: Longitudinal cohort study. PATIENT SAMPLE: Eighty-three individuals within 2 weeks of an acute episode of LBP - grouped into their a priori-defined cluster. OUTCOME MEASURES: General participant characteristics (sex, age, body mass index, smoking history, previous LBP history); self-reported LBP (0-10 numerical rating scale, LBP-related disability (Roland-Morris Disability Questionnaire), depression (Center for Epidemiological Studies Depression Scale, pain catastrophizing (Pain Catastrophizing Scale), fear avoidance (Fear Avoidance Beliefs Questionnaire), pain self-efficacy (Pain Self-Efficacy Questionnaire), and sleep (Pittsburgh Sleep Quality Index); systemic inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], interleukin-1ß, tumor necrosis factor [TNF]). METHODS: Participants provided blood for the measurement of CRP/cytokines, and completed questionnaires related to their pain/disability, psychological and sleep status. Blood measures were repeated 3-monthly for 9 months, and pain/disability were self-reported fortnightly for 12 months. Recovery (change in pain) and CRP/cytokines were longitudinally compared between clusters using mixed-models. Associations between baseline factors and follow-up CRP/cytokines levels were assessed with multiple regression. RESULTS: Clusters 1 and 2 were associated, but oppositely, with recovery over the 12-months. Cluster 1 reported most recovery at every 3-monthly interval, whereas Cluster 2 reported least recovery. Cluster 1 had elevated CRP (and IL-6) at baseline that continued to decrease from 3 to 9 months. TNF was elevated early and persistently in Cluster 2. Baseline factors other than inflammation generally failed to predict follow-up inflammation. CONCLUSIONS: Findings support the early role of CRP (and perhaps IL-6) in control of inflammation and recovery, and a pathological role of persistent TNF overexpression, which may be perpetuated by depressive-like behaviors.

Does the Interaction between Local and Systemic Inflammation Provide a Link from Psychology and Lifestyle to Tissue Health in Musculoskeletal Conditions?

Musculoskeletal conditions are known to involve biological, psychological, social and, often, lifestyle elements. However, these domains are generally considered in isolation from each other. This siloed approach is unlikely to be adequate to understand the complexity of these conditions and likely explains a major component of the disappointing effects of treatment. This paper presents a hypothesis that aims to provide a foundation to understand the interaction and integration between these domains. We propose a hypothesis that provides a plausible link between psychology and lifestyle factors with tissue level effects (such as connective tissue dysregulation/accumulation) in musculoskeletal conditions that is founded on understanding the molecular basis for interaction between systemic and local inflammation. The hypothesis provides plausible and testable links between mind and body, for which empirical evidence can be found for many aspects. We present this hypothesis from the perspective of connective tissue biology and pathology (fibrosis), the role of inflammation locally (tissue level), and how this inflammation is shaped by systemic inflammation through bidirectional pathways, and various psychological and lifestyle factors via their influence on systemic inflammation. This hypothesis provides a foundation for new consideration of the development and refinement of personalized multidimensional treatments for individuals with musculoskeletal conditions.

Coordination of hip and spine to maintain equilibrium in unstable sitting revealed by spectral analysis.

Unstable sitting paradigms have been used to assess the trunk's contribution to postural control. The coordination of spine or hip with an unstable seat that underpin postural control during this task remain unclear. This study aimed to address this issue using analysis in the frequency domain. Seventy-two healthy pain-free participants maintained balance while sitting on a seat fixed to a hemisphere. Angular motion of seat, spinal regions (lower lumber, lumbar, upper lumbar, and thoracic), and hip was recorded with a three-dimensional (3-D) motion capture system. Coordination between spinal regions and hip with the seat was quantified using cross-spectral analyses. In the sagittal plane, amplitude spectrum of hip and lumbar segments were higher than other segments, coherence between these segments and the seat was high, and their motion was generally opposite in direction to the seat. In the frontal plane, amplitude spectrum of lower lumbar and lumbar segments, but not the hip, were higher than other segments, and coherently moved in the opposite direction to the seat. Segments closest to the seat made a direction-specific and greater contribution to maintenance of equilibrium than upper body segments, which were more limited during unstable sitting. Although eye closure and higher body mass index involved larger amplitude of center of pressure movement, rather than inferring poor control, this was associated with enhanced coordination between segments and seat. Understanding how hip/spine segments are coordinated with the seat is important to interpret postural strategies used to maintain equilibrium and to interpret observations for other populations (e.g., back pain).NEW & NOTEWORTHY This is the first multidirectional spectral analysis of how the hip and spine coordinate during unstable sitting and how different factors impact this coordination. Seat movement was coherently counteracted (out-of-phase) by angular motion of the hip and lower lumbar spine in the sagittal plane and by the lumbar spine in the frontal plane. Although higher BMI and balancing with eyes closed increased movement amplitude, this did not compromise coordination between segments to control balance, instead, coherence increased.

Cohort profile: why do people keep hurting their back?

OBJECTIVE: Low back pain (LBP) is one of the most disabling and costly conditions worldwide. It remains unclear why many individuals experience persistent and recurrent symptoms after an acute episode whereas others do not. A longitudinal cohort study was established to address this problem. We aimed to; (1) evaluate whether promising and potentially modifiable biological, psychological, social and behavioural factors, along with their possible interactions, predict LBP outcome after an acute episode; (2) compare these factors between individuals with and without acute LBP; and (3) evaluate the time-course of changes in these factors from LBP onset. This paper outlines the methodology and compares baseline characteristics between acute LBP and control, and LBP participants with and without follow-up. RESULTS: 133 individuals with acute LBP and 74 pain-free individuals participated. Bio-psycho-social and behavioural measures were collected at baseline and 3-monthly for 12 months (LBP) or 3 months (control). Pain and disability were recorded fortnightly. Baseline characteristics were mostly similar between those who did and did not return for follow-up. Initial analyses of this cohort have revealed important insights into the pathways involved in acute-to-chronic LBP. These and future findings will provide new targets for treatment and prevention of persistent and recurrent LBP.

Trunk stiffness decreases and trunk damping increases with experimental low back pain.

Movement adaptations to low back pain (LBP) are believed to protect the painful area. Increased trunk stiffness and decreased trunk damping have been shown in people with recurrent LBP. However, no study has examined these properties using external force perturbations to the trunk during acute LBP when protective adaptations might be expected to have most relevance. Adaptations to an acute painful stimulus via unilateral injection of hypertonic saline into the right longissimus muscle were assessed using a trunk force perturbation paradigm and a mass-spring-damper model to describe effective trunk dynamical properties. Equal weights (15% body weight) were connected to the front and back of the trunk via a cable. Either one was dropped at random to perturb the trunk. Effective trunk dynamical properties were estimated in fourteen males (mean (standard deviation) age 25 (6) years) assuming that trunk movement can be modelled as a second order linear system. Effective trunk dynamical properties were compared before, during and after the experimentally induced painful period. Estimates of effective trunk stiffness (K) decreased and damping (B) increased during pain compared to both before ([mean contrast, 95% CI] K: -403 [-651 to -155] Nm-1, B: 28 [9-50] Nms-1) and after (K: -324 [-58 to -591] Nm-1, B: 20 [4-33] Nms-1) the experimentally induced painful period. We interpret our results to show that, when challenged by a step force perturbation, a healthy system adapts to noxious input by controlling trunk velocity rather than trunk displacement, in contrast to observations during remission from recurrent clinical LBP.

Blocking CTGF/CCN2 reverses neural fibrosis and sensorimotor declines in a rat model of overuse-induced median mononeuropathy.

Encapsulation of median nerves is a hallmark of overuse-induced median mononeuropathy and contributes to functional declines. We tested if an antibody against CTGF/CCN2 (termed FG-3019 or Pamrevlumab) reduces established neural fibrosis and sensorimotor declines in a clinically relevant rodent model of overuse in which median mononeuropathy develops. Young adult female rats performed a high repetition high force (HRHF) lever-pulling task for 18 weeks. Rats were then euthanised at 18 weeks (HRHF untreated), or rested and systemically treated for 6 weeks with either an anti-CCN2 monoclonal antibody (HRHF-Rest/FG-3019) or IgG (HRHF-Rest/IgG), with results compared with nontask control rats. Neuropathology was evident in HRHF-untreated and HRHF-Rest/IgG rats as increased perineural collagen deposition and degraded myelin basic protein (dMBP) in median nerves, and increased substance P in lower cervical dorsal root ganglia (DRG), compared with controls. Both groups showed functional declines, specifically, decreased sensory conduction velocity in median nerves, noxious cold temperature hypersensitivity, and grip strength declines, compared with controls. There were also increases of ATF3-immunopositive nuclei in ventral horn neurons in HRHF-untreated rats, compared with controls (which showed none). FG-3019-treated rats showed no increase above control levels of perineural collagen or dMBP in median nerves, Substance P in lower cervical DRGs, or ATF3-immunopositive nuclei in ventral horns, and similar median nerve conduction velocities and thermal sensitivity, compared with controls. We hypothesize that neural fibrotic processes underpin the sensorimotor declines by compressing or impeding median nerves during movement, and that inhibiting fibrosis using an anti-CCN2 treatment reverses these effects.