Systemic pro- and anti-inflammatory profiles in acute non-specific low back pain : an exploratory longitudinal study of the relationship to six-month outcome

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

Is there a causal relationship between acute stage sensorimotor cortex activity and the development of chronic low back pain? : a protocol and statistical analysis plan

Introduction: Why some people develop chronic pain following an acute episode of low back pain is unknown. Recent cross-sectional studies have suggested a relationship between aberrant sensorimotor cortex activity and pain persistence. The UPWaRD (Understanding persistent Pain Where it ResiDes) cohort study is the first prospective, longitudinal investigation of sensorimotor cortex activity in low back pain. This paper describes the development of a causal model and statistical analysis plan for investigating the causal effect of sensorimotor cortex activity on the development of chronic low back pain. Methods and analysis: Sensorimotor cortex activity was assessed within 6 weeks of low back pain onset using somatosensory evoked potentials and transcranial magnetic stimulation mapping techniques. Chronic low back pain is defined as ongoing pain (Numerical Rating score ≥1) or disability (Roland Morris Disability Questionnaire score ≥3) at 6 months follow-up. Variables that could confound the relationship between sensorimotor cortex activity and chronic low back pain were identified using a directed acyclic graph and content expertise was used to specify known causal paths. The statistical model was developed ‘a priori’ to control for confounding variables identified in the directed acyclic graph, allowing an unbiased estimate of the causal effect of sensorimotor activity in acute low back pain on the development of chronic pain. The statistical analysis plan was finalised prior to follow-up of all participants and initiation of analysis. Ethics and dissemination: Ethical approval has been obtained from Western Sydney University Human Research Ethics Committee (H10465) and from Neuroscience Research Australia (SSA: 16/002). Dissemination will occur through presentations at national and international conferences and publications in international peer-reviewed journals. Trial registration number: ACTRN12619000002189 (retrospectively registered)

The role of the brain in the transition from acute to chronic musculoskeletal pain : an investigation of neuroplastic mechanisms and novel treatments

Musculoskeletal pain is a leading health problem globally. Its prevalence and associated socioeconomic costs have increased exponentially and this trend is expected to continue in the coming decades. While all stages of musculoskeletal pain contribute to the burden of disease, the costs attributed to chronic pain (pain lasting > 3 months) are most significant. Effective treatment would substantially reduce the impact of chronic musculoskeletal pain at both the individual and societal level. Yet, the effects of current treatments are, at best, moderate for pain and function. One explanation for the limited success of current treatments is an inadequate understanding of the neurophysiological mechanisms that underpin musculoskeletal pain. Addressing the evidence gap surrounding our mechanistic understanding of musculoskeletal pain is essential to guide the development of effective treatments. Maladaptive neuroplasticity, manifesting as altered sensorimotor cortex organisation and impaired central pain processing, is the prevailing theory used to explain the development and maintenance of chronic musculoskeletal pain. Cross sectional evidence derived from individual studies suggests maladaptive neuroplasticity in the primary motor cortex (M1) is present in chronic musculoskeletal pain and is associated with symptoms of pain and movement dysfunction. Yet, a systematic evaluation of the evidence for altered M1 plasticity in chronic pain is absent. Further, no study has characterised neuroplasticity in the acute stage of clinical musculoskeletal pain. This information is critical to better understand the time course of neuroplasticity in musculoskeletal pain. Finally, few treatments exist that specifically target altered neuroplasticity in chronic musculoskeletal pain conditions. Thus, the overarching aim of this thesis was to investigate and target specific mechanisms of neuroplasticity (sensorimotor cortex organisation and central pain processing) in musculoskeletal pain. This aim was achieved through four studies. This thesis provides original and novel insight into our understanding of neuroplasticity in musculoskeletal pain and provides a foundation for the development and testing of novel interventions to reduce pain and disability. Specifically, this thesis demonstrates that: (1) evidence for M1 structural, organisational and functional changes in chronic pain conditions is inconsistent, (2) neuroplasticity in acute LBP is characterised by lower sensorimotor and cingulate cortex excitability and impaired descending inhibitory pain control when compared with pain-free individuals, although inter-individual variability is high and (3) adding tDCS to strengthening exercise may improve pain, function and pain mechanisms in knee osteoarthritis beyond that of exercise applied alone. Notably, subgroups distinguished by high or low S2 and ACC excitability may represent individual adaptation of different cortical strategies that relate to the processing of non-noxious input in acute clinical LBP and could be relevant for pain outcome. However, subgroups determined by a prior history of LBP do not differ in central pain processing in acute LBP. Future studies with larger sample sizes are needed to determine whether altered M1 plasticity is present in chronic musculoskeletal pain and to confirm findings of decreased sensorimotor cortex excitability and altered central pain processing in acute pain. Finally, a fully powered randomised controlled trial is necessary to determine the effectiveness of adding tDCS to strengthening exercise for knee osteoarthritis

Human assumed central sensitization in people with acute non-specific low back pain : a cross-sectional study of the association with brain-derived neurotrophic factor, clinical, psychological and demographic factors

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

[In Press] Relative and absolute reliability of somatosensory evoked potentials in response to non-noxious electrical stimulation of the paraspinal muscles in healthy participants at an interval of 3-months

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 (SDC95) 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 N150 component) and iii) perceptual threshold and stimulation intensity was not reliable over time. Conclusion: These findings suggest that the area of the N80 and P260 SEP components, and the area of the N80-N150-P260 SEP complex, can be utilised in future studies as reliable markers of cortical activity

Central pain processing does not differ between first episode and recurrent acute low back pain

BACKGROUND: One-third of individuals with acute low back pain (LBP) experience recurrent symptoms within 12 months but the underlying mechanisms are unclear. One explanation is that individuals experiencing recurrent LBP develop altered central pain processing that predisposes to symptom recurrence. We compared central pain processing between individuals experiencing their first episode of acute LBP, recurrent acute LBP, and pain-free controls. METHODS: A cross-sectional study was conducted to evaluate central pain processing in 11 individuals experiencing their first episode of acute LBP, 11 individuals with recurrent acute LBP, and 11 pain-free controls. Outcome measures included pain and disability, pressure and heat pain thresholds (PPTs and HPTs), nociceptive flexor withdraw reflex (NFR) and conditioned pain modulation (CPM). RESULTS: The NFR latency was shorter in individuals experiencing their first episode of acute LBP when compared with pain-free controls (p = 0.01). Descending inhibitory pain control measured by CPM was less efficient in both acute LBP groups when compared with pain-free controls. HPTs and PPTs did not differ between people with and without acute LBP. There were no differences between the two LBP groups for any outcome measure.CONCLUSIONS: These data demonstrate altered central pain processing in the acute stage of LBP. However, the degree of impairment did not differ between individuals with a first episode vs. recurrent acute LBP. These findings suggest that altered central pain processing in acute LBP is not related to a previous history of LBP

Legislative History: An Act Making Unified Appropriations and Allocations for the Expenditures of State Government, General Fund and Other Funds, and Changing Certain Provisions of the Law Necessary to the Proper Operations of State Government for the Fiscal Years Ending June 30, 1998 and June 30, 1999 (HP832)(LD 1137)

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Safety and feasibility of transcranial direct current stimulation (tDCS) combined with sensorimotor retraining in chronic low back pain : a protocol for a pilot randomised controlled trial

Introduction Chronic low back pain (LBP) is a common and costly health problem yet current treatments demonstrate at best, small effects. The concurrent application of treatments with synergistic clinical and mechanistic effects may improve outcomes in chronic LBP. This pilot trial aims to (1) determine the feasibility, safety and perceived patient response to a combined transcranial direct current stimulation (tDCS) and sensorimotor retraining intervention in chronic LBP and (2) provide data to support a sample size calculation for a fully powered trial should trends of effectiveness be present. Methods and analysis A pilot randomised, assessor and participant-blind, sham-controlled trial will be conducted. Eighty participants with chronic LBP will be randomly allocated to receive either (1) active tDCS + sensorimotor retraining or (2) sham tDCS + sensorimotor retraining. tDCS (active or sham) will be applied to the primary motor cortex for 20 min immediately prior to 60 min of supervised sensorimotor retraining twice per week for 10 weeks. Participants in both groups will complete home exercises three times per week. Feasibility, safety, pain, disability and pain system function will be assessed immediately before and after the 10-week intervention. Analysis of feasibility and safety will be performed using descriptive statistics. Statistical analyses will be conducted based on intention-to-treat and per protocol and will be used to determine trends for effectiveness. Ethics and dissemination Ethical approval has been gained from the institutional human research ethics committee (H10184). Written informed consent will be provided by all participants. Results from this pilot study will be submitted for publication in peer-reviewed journals. Trial registration number ACTRN1261600062448

Iron Oxide Nanoparticles Engineered Macrophage-Derived Exosomes for Targeted Pathological Angiogenesis Therapy

Engineering exosomes with nanomaterials usually leads to the damage of exosomal membrane and bioactive molecules. Here, pathological angiogenesis targeting exosomes with magnetic imaging, ferroptosis inducing, and immunotherapeutic properties is fabricated using a simple coincubation method with macrophages being the bioreactor. Extremely small iron oxide nanoparticle (ESIONPs) incorporated exosomes (ESIONPs@EXO) are acquired by sorting the secreted exosomes from M1-polarized macrophages induced by ESIONPs. ESIONPs@EXO suppress pathological angiogenesis in vitro and in vivo without toxicity. Furthermore, ESIONPs@EXO target pathological angiogenesis and exhibit an excellent T1-weighted contrast property for magnetic resonance imaging. Mechanistically, ESIONPs@EXO induce ferroptosis and exhibit immunotherapeutic ability toward pathological angiogenesis. These findings demonstrate that a pure biological method engineered ESIONPs@EXO using macrophages shows potential for targeted pathological angiogenesis therapy