Siobhan M. Schabrun

Alpha-band oscillatory activity, assessed using electroencephalography (EEG), is among the most widely studied neurophysiological markers of pain. However, the literature has focused predominantly on resting-state measures, leaving unclear whether pain also alters evoked alpha-band dynamics, measured via cortical perturbation using transcranial magnetic stimulation (TMS). Here, we examined whether prolonged pain alters TMS-evoked alpha event-related spectral perturbation (ERSP) and intertrial coherence (ITC), reflecting cortical reactivity and phase consistency, and whether 10-Hz repetitive TMS (rTMS) modulates these responses. We performed a secondary analysis on 2 previous experiments, which used nerve growth factor (NGF) injection to induce prolonged elbow muscle pain. In experiment 1, participants underwent primary motor cortex (M1) TMS-EEG at baseline (day 0) pre-NGF injection and day 2 (peak pain) and day 7 (pain resolution) post-injection. In experiment 2, M1-TMS-EEG was assessed on day 0 before NGF injection and again on day 4 after injection, with active or sham 10-Hz rTMS delivered to M1 between these assessments. In experiment 1, M1 TMS-EEG showed reductions in alpha ERSP ( P = 0.014) and alpha ITC ( P = 0.041) from day 0 to day 2. In experiment 2, active rTMS produced a more positive pre-to-post change in alpha ERSP ( P = 0.006) relative to sham but did not alter alpha ITC ( P = 0.804). Our findings suggest that prolonged experimental pain is associated with diminished evoked alpha oscillatory activity, whereas high-frequency rTMS modulates this activity in the positive direction. These findings suggest that perturbation-evoked alpha metrics warrant further investigation as candidate biomarkers of pain state and response to neuromodulation.

This study examined whether psychological factors mediate the relationship between acute low back pain and future disability. We conducted a secondary causal mediation analysis of the UPWaRD longitudinal cohort (N = 120 adults with acute low back pain of < 6 weeks' duration; ACTRN12619000002189; protocol: https://osf.io/q8wf6/). Baseline pain intensity (11-point numerical rating scale) was the exposure, psychological factors measured at 3 months were the mediators (depression, anxiety, stress, pain catastrophizing, pain self-efficacy), and low back pain–related disability (Roland Morris Disability Questionnaire) assessed at 6 months was the outcome. Directed acyclic graphs informed confounder adjustment. Natural effect models estimated total, direct, and indirect effects with corresponding 95% confidence intervals. Missing data were addressed using multiple imputation and mediational E-values assessed sensitivity to unmeasured confounding. Higher baseline pain intensity was associated with greater disability at 6 months (B = 0.68, 95% CI 0.23-1.14). Pain self-efficacy was the only individual psychological factor showing evidence consistent with mediation, with an indirect effect of 0.16 (95% CI 0.04-0.35), accounting for 22% of the total effect (95% CI 7%-42%). The mediational E-value for the total natural indirect effect of pain self-efficacy on the risk ratio scale was 1.21, indicating that this finding may be sensitive to unmeasured confounding. Psychological factors, particularly self-efficacy, partly explain the transition from acute low back pain to future disability. Enhancing pain self-efficacy may represent an important early intervention target, although most variance remains unexplained.

Background: Chronic pain affects over 30% of the global population and remains a major public health issue due to limited treatment efficacy and the need for mechanism-based, personalized approaches. Motor behavior is theorized to play a role in pain persistence through altered movement patterns, muscle recruitment, and proprioception. While motor behavior is linked to chronic pain, empirical evidence on underlying mechanisms, particularly cortical dynamics, remains scarce. Objective: This study aimed to investigate longitudinal changes in cortical sensorimotor excitability and their relationship with maladaptive motor behaviors. Methods: This prospective longitudinal study will follow 150 healthy participants, aged 18‐65 years, recruited from the community, experiencing experimentally induced muscle pain across 4 visits (day 0, day +2, day +4, and 5 days after pain resolution). Pain will be induced using intramuscular injections of nerve growth factor into the extensor carpi radialis brevis muscle. The primary outcome is motor variability assessed during multidimensional wrist movement tasks, and quantified using root-mean-square deviation and muscle synergies (derived from electromyographic recordings of 4 forearm muscles). Secondary outcomes include cortical mechanisms (electroencephalographic peak alpha frequency, transcranial magnetic stimulation mapping, short-interval intracortical inhibition, and intracortical facilitation), sensorimotor integration (evoked potential), cognitive control (multisource interference task), and endogenous pain modulation (conditioned pain modulation). Self-report questionnaires will assess pain intensity and disability (Patient-Rated Tennis Elbow Evaluation, McGill Pain Questionnaire–Short Form, and Likert Muscle Soreness Scale) as well as psychological factors such as fear of movement, pain-related beliefs, and coping strategies (Tampa Scale for Kinesiophobia, Pain Beliefs Questionnaire, and Coping Strategies Questionnaire–Revised). This sample size provides 80% power at 5% significance to detect a medium effect size across 23 predictor variables, with Bonferroni correction and 10% loss-to-follow-up allowance. Data will be analyzed using 2-level growth curve modeling to characterize interindividual differences in motor behavior, cortical dynamics, and pain processing trajectories. Results: All study procedures have been approved by the Western University Health Science Research Ethics Board (review reference 2025-125757-103291). Funding was provided by the Canadian Institutes of Health Research under grant number 517783 for the period 2024‐2029. Recruitment for the study began in April 2025, and all data collection is expected to be completed by 2028. As of April 2026, we have enrolled 26 participants. Results are expected to be published at the end of 2028. Conclusions: The findings will advance understanding of motor behavior in pain and lay the foundation for personalized therapies, moving beyond current generic treatments that offer limited benefits.

The application of non-invasive brain stimulation (NIBS) often relies on proxy estimates of cortical excitability (CE), such as the resting motor threshold (rMT), measured through transcranial magnetic stimulation (TMS). However, estimating the rMT is not always possible, as it requires an intact corticospinal pathway for neural signals to travel from the cortex to the periphery. To broaden the application of NIBS there is a need for additional CE measures. In three experiments combining TMS, transcranial direct current stimulation (tDCS), and eye-tracking, we measured TMS-induced pupil dilations as a potential CE proxy. We present Bayesian evidence (Experiment 1: BF > 9; Experiment 2: BF > 46; Experiment 3: BFs > 6) that TMS-induced pupil dilations serve as an objective CE proxy, with larger pupil size reflecting higher CE. We also show that these effects are not due to auditory, muscle, or sensory confounds. The introduction of this novel measure paves the way for a deeper understanding of CE by enabling objective NIBS measures beyond the motor cortex. Moving away from the reliance on the motor cortex would allow NIBS research and therapy to become more inclusive, allowing access to populations that are affected by damage along the corticospinal pathway.

Introduction: Sensory cortex activity differs between acute and chronic low back pain (LBP) with decreased activity in acute LBP but increased activity in chronic LBP. However, it is unknown how and when sensory cortex activity changes during the transition from acute to chronic LBP and whether fluctuations in sensory cortex activity are associated with pain sensitivity. Objectives: To examine (1) the trajectory of changes in sensory cortex activity over a period of six months from the onset of acute LBP; (2) the assoication between sesnory cortex activity and pain pain sensitivity. Methods: In a prospective cohort study (N = 120), sensory evoked potentials (SEPs) were recorded using electroencephalography within 6 weeks of LBP onset (baseline) and at 3- and 6-month follow-up. Pain sensitivity was assessed using quantitative sensory testing (QST). Results: At baseline, individuals who developed chronic pain at 6-month follow-up exhibited less nonnoxious sensory processing (smaller area of N ₈₀ , N ₁₅₀ , and P ₂₆₀ SEP components) compared with those who recovered. In individuals who recovered, SEP measures did not change over time. In individuals who developed chronic pain, N ₈₀ and N ₁₅₀ SEP area increased between baseline and 3 months, while P ₂₆₀ SEP area increased between baseline and 6 months, reaching values consistent with those of recovered individuals. Sensory evoked potential measures showed no relationship with QST, except for a larger P ₂₆₀ SEP area correlating with higher 6-month heat pain threshold at the site of LBP. Conclusions: Nonnoxious sensory processing in acute LBP was less in those who developed chronic pain than those who recovered. Nonnoxious sensory processing increased over time in those who developed chronic pain but was unchanged in those who recovered. In the transition from acute to chronic LBP, nonnoxious sensory processing in the sensory cortex was not associated with pain sensitivity.

The glutathione shunt is one of the most important contributors to the cellular redox state, with implications across cancer, chronic diseases, diseases of ageing, and autoimmune diseases, including inflammatory bowel disease (IBD). Traditionally, the redox state is gauged by the ratio of the surrogate metabolites GSH and GSSG. However, this presents methodological challenges and offers a constrained illustration of metabolites without a systems-level understanding of redox dynamics, failing to elucidate variations across an entire biochemical network. Targeted proteomics can fill this void. Here, we describe an in-parallel metabolomic and proteomic targeted method to encompass measurements directly related to the shunt. Samples are simultaneously prepared to extract the substrate building blocks, cysteine, cystine, methionine, glutamic acid, and kynurenine; and the proteins, SLC7A11 (xCT), Glutamate Cysteine Ligase (GSH1), Glutathione Synthetase (GSH2), Glutathione Peroxidase (GPx), and Glutathione Reductase (GSHR) for targeted mass spectrometry. We demonstrate the method by targeted analysis of proteins in plasma, serum, nasal swab, and saliva and apply the multi-omic method to assess changes in the glutathione shunt in the serum of patients diagnosed with IBD. This allows for a broader narrative to establish context at which the glutathione shunt is operating.

Recent research has linked individual peak alpha frequency (PAF) to pain sensitivity, but whether PAF alterations can influence pain remains unclear. Our study investigated the effects of nicotine on pain sensitivity and whether pain changes are mediated by PAF changes. In a randomised, double-blind, placebo-controlled experiment, 62 healthy adults (18–44 years) received either 4 mg nicotine gum (n=29) or placebo (n=33). Resting state EEG and pain ratings during prolonged heat and pressure models were collected before and after nicotine intake. The nicotine group had a decrease in heat pain ratings compared to the placebo group and increased PAF speed across the scalp from pre to post-gum, driven by changes at central-parietal and right-frontal regions. However, mediation analysis did not support the notion that PAF changes mediate nicotine’s effects on pain sensitivity. While a growing body of literature supports a link between PAF and both acute and chronic pain, further work is needed to understand the mechanisms of this link.

Physiotherapy has emerged as an important health strategy to deliver lifestyle, exercise and physical activity for people with knee osteoarthritis. However, little is known about the extent to which physiotherapists adhere to clinical practice guidelines. This study aimed to explore the perspectives and care patterns of physiotherapists in Sydney, Australia on their delivery of knee osteoarthritis care and how this aligns with the 2019 Osteoarthritis Research Society International (OARSI) guidelines. We invited thirty-three physiotherapists from nine private practices in metropolitan Sydney to partake in a semi-structured interview. The interviews were digitally recorded and transcribed verbatim. The data collected were analysed deductively using content analysis, comparing guidelines to current care patterns, while their perspectives were inductively analysed through thematic analysis. Thirty physiotherapists participated (age range 22–63 years, 17 male and 13 female). Interview responses indicated that most physiotherapists were satisfied with their care of knee osteoarthritis patients. Most physiotherapists delivered “core” guideline-based care of education and land-based exercise. Recommendations of modalities of exercise, including hydrotherapy and manual therapy, were discussed and were perceived to be beneficial despite not being “core” clinical guideline recommendations. Current treatment strategies focussed on disease severity, symptom presentation and/or patient exercise history with little emphasis on education about osteoarthritis pathophysiology and drug-based pain relief. The thematic analysis identified two over-arching themes; (1) capacity to deliver and awareness of evidence-based care and (2) perceived recommendations for future physiotherapy management. Participants identified notable areas of potential service improvement including developing stronger and more effective reimbursement models, increased consult times and improved patient access. The study provided unique insights towards physiotherapists’ current usual knee osteoarthritis care and their perceived barriers to delivering guideline-based care. Thus, informing a need for future studies to focus on developing specific and detailed guidelines if physiotherapists are to align more closely to the core guideline-based recommendations. This study was part of a larger study, with the full protocol published and registered at ClinicalTrials (ACTRN12620000188932, ACTRN12620000218998) 19/02/2020).

Objective: The objective of this scoping review is to describe the current evidence exploring integrated care for people with chronic musculoskeletal disorders. Introduction: The integrated model of care is an emerging approach to delivering person-centered care. Integrated care supports the management of people with major chronic health conditions; however, the evidence behind its use to support people with chronic musculoskeletal disorders is scant. This scoping review will synthesize how integrated care is conceptualized, delivered, and evaluated for people with chronic musculoskeletal disorders. The review will also synthesize the attributes, components, elements, goals, frequently evaluated outcomes, theories/frameworks, and facilitators and barriers to delivering this model among people with musculoskeletal disorders. Inclusion criteria: Studies conducted on the delivery and/or evaluation of integrated care for people with chronic musculoskeletal disorders in any health care setting (eg, primary, secondary, tertiary) and/or geographical location (countries, cultures) will be considered. Methods: The review will follow the JBI scoping review methodology. Databases such as MEDLINE (Ovid), CINAHL (EBSCOhost), Scopus, Embase (Ovid), PsycINFO (Ovid), the JBI EBP Database, PEDRO, Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, and Web of Science, as well as sources of gray literature, will be thoroughly searched. Papers published in all languages will be considered. Two reviewers will independently review the selected articles and extract data using a data extraction tool developed for this scoping review. The analysis will involve numerical and descriptive summaries of the selected articles and will be presented using graphs and tables, in line with Preferred Reported Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR).

Chronic pain is a prevalent condition with a multifaceted pathogenesis, where epigenetic modifications, particularly DNA methylation, might play an important role. This review delves into the intricate mechanisms by which DNA methylation and demethylation regulate genes associated with nociception and pain perception in nociceptive pathways. We explore the dynamic nature of these epigenetic processes, mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, which modulate the expression of pro- and anti-nociceptive genes. Aberrant DNA methylation profiles have been observed in patients with various chronic pain syndromes, correlating with hypersensitivity to painful stimuli, neuronal hyperexcitability, and inflammatory responses. Genome-wide analyses shed light on differentially methylated regions and genes that could serve as potential biomarkers for chronic pain in the epigenetic landscape. The transition from acute to chronic pain is marked by rapid DNA methylation reprogramming, suggesting its potential role in pain chronicity. This review highlights the importance of understanding the temporal dynamics of DNA methylation during this transition to develop targeted therapeutic interventions. Reversing pathological DNA methylation patterns through epigenetic therapies emerges as a promising strategy for pain management.