Dr Wei-Ju Chang

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 whether (1) 5 consecutive days of rTMS delivered prior to experimentally induced prolonged jaw pain has a prophylactic effect on future pain intensity and (2) whether these effects were accompanied by increases in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from day 0 to 4, 40 healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. Peak alpha frequency 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 in the right masseter muscle after the final rTMS session. From days 5 to 25, participants completed twice-daily electronic diaries including pain on chewing and yawning (primary outcomes), as well as pain during other activities (eg, 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. Furthermore, active rTMS led to an increase in PAF. This is the first study to show that rTMS delivered prior to prolonged pain onset can protect against future pain. Our findings suggest that rTMS may hold promise as a prophylactic intervention for pain.

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.

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.

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.

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 (%SEMeas = 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.

Despite chronic low back pain (LBP) being considered a biopsychosocial condition for diagnosis and management, few studies have investigated neurobiological risk factors thought to underpin the transition from acute to chronic LBP. The aim of this research is to describe the methodology, compare baseline characteristics between acute LBP participants and pain-free controls, and compare LBP participants with or without completed follow-up. One hundred and twenty individuals experiencing acute LBP and 57 pain-free controls were recruited to participate in the Understanding persistent Pain Where it ResiDes (UPWaRD) study. Neurobiological, psychological, and sociodemographic data were collected at baseline, and at 3 and 6 months. Ninety-five participants (79%) provided outcome data at 3-month follow-up and 96 participants (80%) at 6 months. Compared to controls, LBP participants in the UPWaRD cohort were older, had a higher BMI, a higher prevalence of comorbidities, and higher medication usage. Higher depression, anxiety and stress, lower pain self-efficacy, and higher pain catastrophising during acute LBP were correlated with higher 6-month pain and disability. This cohort provides novel and significant opportunities to increase understanding of neurobiological risk factors of LBP. Future findings endeavour to provide new targets for treatment and prevention of chronic LBP. Additional priorities include exploring epigenetic and proteomic biomarkers of poor LBP outcome.

Theta burst stimulation (TBS) over the primary motor cortex (M1) is an emerging technique that may have utility in the treatment of musculoskeletal pain. However, previous work exploring the analgesic effects of noninvasive brain stimulation has been limited largely to the arm or hand, despite 80% of acute musculoskeletal injuries occurring in the lower limb. This is a pertinent point, given the functional and neurophysiological differences between upper and lower limb musculature, as well as evidence suggesting that reorganization of corticomotor pathways is region-specific. This study investigated the effect of excitatory TBS on pain, function, and corticomotor organization during experimentally induced lower limb pain. Twenty-eight healthy participants attended 2 experimental sessions. On Day 0, participants completed 10 sets of 10 maximal eccentric contractions of the right hamstring muscles to induce delayed onset muscle soreness. Four consecutive blocks of either active or sham TBS were delivered on Day 2. Measures of mechanical sensitivity, pain (muscle soreness, pain intensity, pain area) function (single-leg hop distance, maximum voluntary isometric contraction, lower extremity functional scale), and corticomotor organization were recorded before and after TBS on Day 2. Pain and function were also assessed daily from Days 2 to 10. Active TBS reduced mechanical sensitivity compared to sham stimulation (P = .01). Corticomotor organization did not differ between groups, suggesting that improvements in mechanical sensitivity were not mediated by changes in M1. Subjective reports of pain intensity and function did not change following active TBS, contrasting previous reports in studies of the upper limb. Perspective: M1 TBS reduces mechanical sensitivity associated with experimentally induced hamstring pain. Though further work is needed, these findings may hold important implications for those seeking to expedite recovery or reduce muscle sensitivity following hamstring injury.

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.

Background: Electroencephalographic (EEG) neurofeedback has been utilized to regulate abnormal brain activity associated with chronic pain. Methods: In this systematic review, we synthesized the evidence from randomized controlled trials (RCTs) to evaluate the effect of EEG neurofeedback on chronic pain using random effects meta-analyses. Additionally, we performed a narrative review to explore the results of non-randomized studies. The quality of included studies was assessed using Cochrane risk of bias tools, and the GRADE system was used to rate the certainty of evidence. Results: Ten RCTs and 13 non-randomized studies were included. The primary meta-analysis on nine eligible RCTs indicated that although there is low confidence, EEG neurofeedback may have a clinically meaningful effect on pain intensity in short-term. Removing the studies with high risk of bias from the primary meta-analysis resulted in moderate confidence that there remained a clinically meaningful effect on pain intensity. We could not draw any conclusion from the findings of non-randomized studies, as they were mostly non-comparative trials or explorative case series. However, the extracted data indicated that the neurofeedback protocols in both RCTs and non-randomized studies mainly involved the conventional EEG neurofeedback approach, which targeted reinforcing either alpha or sensorimotor rhythms and suppressing theta and/or beta bands on one brain region at a time. A posthoc analysis of RCTs utilizing the conventional approach resulted in a clinically meaningful effect estimate for pain intensity. Conclusion: Although there is promising evidence on the analgesic effect of EEG neurofeedback, further studies with larger sample sizes and higher quality of evidence are required.

Determining the mechanistic causes of complex biopsychosocial health conditions such as low back pain (LBP) is challenging, and research is scarce. Cross-sectional studies demonstrate altered excitability and organization of the somatosensory and motor cortex in people with acute and chronic LBP, however, no study has explored these mechanisms longitudinally or attempted to draw causal inferences. Using sensory evoked potential area measurements and transcranial magnetic stimulation derived map volume we analyzed somatosensory and motor cortex excitability in 120 adults experiencing acute LBP. Following multivariable regression modelling with adjustment for confounding, we identified lower primary (OR = 2.08, 95% CI = 1.22¿3.57) and secondary (OR = 2.56, 95% CI = 1.37¿4.76) somatosensory cortex excitability significantly increased the odds of developing chronic pain at 6-month follow-up. Corticomotor excitability in the acute stage of LBP was associated with higher pain intensity at 6-month follow-up (B = -0.15, 95% CI: -0.28 to -0.02) but this association did not remain after confounder adjustment. These data provide evidence that low somatosensory cortex excitability in the acute stage of LBP is a cause of chronic pain. Perspective: This prospective longitudinal cohort study design identified low sensorimotor cortex excitability during the acute stage of LBP in people who developed chronic pain. Interventions that target this proposed mechanism may be relevant to the prevention of chronic 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.

Sensorimotor cortical activity is altered in both the immediate acute and chronic stages of musculoskeletal pain. However, these changes are opposite, with decreased cortical activity reported in experimentally induced acute pain (lasting minutes to hours), and increased cortical activity in chronic, clinical pain (lasting >6 months). It is unknown whether sensorimotor cortical activity is altered in acute, clinical musculoskeletal pain (lasting <4 weeks). In 36 individuals with acute, nonspecific, clinical low back pain (LBP) and 36 age- and sex-matched, pain-free controls, we investigated the processing of non-noxious afferent inputs using sensory evoked potentials (SEPs), as well as corticomotor excitability and organization of the primary motor cortex using transcranial magnetic stimulation. Processing of non-noxious sensory inputs was lower (smaller area of the N80¿N150¿P260 SEP complex) in acute LBP (F1,70 = 45.28, P < .01). The examination of specific SEP components revealed a smaller area of the N150 and P260 SEP components in acute LBP, although interindividual variability was high. Motor cortical map volume was lower in acute LBP (F1,70 = 5.61, P = .02). These findings demonstrate that acute LBP is characterized by lower sensorimotor cortical activity at the group level. However, individual variation was high, suggesting individual adaptation of cortical plasticity in acute pain. Perspective: This is the first study to examine sensorimotor cortical activity in the acute stage of clinical LBP. This information is critical for understanding the neurophysiology of acute LBP.

The etiologic role of work-related psychological stress in the development of musculoskeletal pain disorders (MDs) has been systematically investigated. Less clear, however, is the role of perceived stress and life stressors. This review aimed to assess the evidence for an etiologic role of perceived stress and life stressors in the development of chronic MDs. Database searches were conducted to identify prospective longitudinal studies that assessed perceived stress and life stressors in individuals without, or in the first 6 weeks of, musculoskeletal pain. The primary outcome was the development of a chronic MD. Methodologic quality was investigated using an adapted version of the Quality Assessment Tool for Observational Cohort studies and Cross-Sectional studies, and the strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Seven studies were included representing data from 6 independent cohorts. There was some evidence to support the etiologic role of perceived stress and life stressors in the development of arthritis (low quality) and chronic spinal pain (low quality). The limited number of studies, the poor quality of the evidence, and the heterogeneity of stress measures used across studies suggest that further high quality prospective studies are required to clarify the role of perceived stress and life stressors in the development of chronic MDs. PROSPERO: CRD42017059949 Perspective: This review summarizes and critically appraises the evidence for the etiologic role of perceived stress and life stressors in the development of chronic MDs. The limited number of studies, the low quality of the evidence, and the heterogeneity across studies suggest that further research is needed on perceived stress and life stressors in MDs.

Chronic pain can be associated with movement abnormalities. The primary motor cortex (M1) has an essential role in the formulation and execution of movement. A number of changes in M1 function have been reported in studies of people with chronic pain. This review systematically evaluated the evidence for altered M1 structure, organization, and function in people with chronic pain of neuropathic and non-neuropathic origin. Database searches were conducted and a modified STrengthening the Reporting of OBservational studies in Epidemiology checklist was used to assess the methodological quality of included studies. Meta-analyses, including preplanned subgroup analyses on the basis of condition were performed where possible. Sixty-seven studies (2,290 participants) using various neurophysiological measures were included. There is conflicting evidence of altered M1 structure, organization, and function for neuropathic and non-neuropathic pain conditions. Meta-analyses provided evidence of increased M1 long-interval intracortical inhibition in chronic pain populations. For most measures, the evidence of M1 changes in chronic pain populations is inconclusive. Perspective: This review synthesizes the evidence of altered M1 structure, organization, and function in chronic pain populations. For most measures, M1 changes are inconsistent between studies and more research with larger samples and rigorous methodology is required to elucidate M1 changes in chronic pain populations.

A randomised, assessor- and participant-blind, sham-controlled trial was conducted to assess the safety and feasibility of adding transcranial direct current stimulation (tDCS) to quadriceps strengthening exercise in knee osteoarthritis (OA), and provide data to inform a fully powered trial. Participants were randomised to receive active tDCS+exercise (AT+EX) or sham tDCS+exercise (ST+EX) twice weekly for 8 weeks whilst completing home exercises twice per week. Feasibility, safety, patient-perceived response, pain, function, pressure pain thresholds (PPTs) and conditioned pain modulation (CPM) were assessed before and after treatment. Fifty-seven people were screened for eligibility. Thirty (52%) entered randomisation and 25 (84%) completed the trial. One episode of headache in the AT+EX group was reported. Pain reduced in both groups following treatment (AT+EX: p<0.001, partial ?2 = 0.55; ST+EX: p = 0.026, partial ?2 = 0.18) but no between-group differences were observed (p = 0.18, partial ?2 = 0.08). Function improved in the AT+EX (p = 0.01, partial ?2 = 0.22), but not the ST+EX (p = 0.16, partial ?2 = 0.08) group, between-group differences did not reach significance (p = 0.28, partial ?2 = 0.052). AT+EX produced greater improvements in PPTs than ST+EX (p<0.05) (superolateral knee: partial ?2 = 0.17; superior knee: partial ?2 = 0.3; superomedial knee: partial ?2 = 0.26). CPM only improved in the AT+EX group but no between-group difference was observed (p = 0.054, partial ?2 = 0.158). This study provides the first feasibility and safety data for the addition of tDCS to quadriceps strengthening exercise in knee OA. Our data suggest AT+EX may improve pain, function and pain mechanisms beyond that of ST+EX, and provides support for progression to a fully powered randomised controlled trial.