Dr Wei-Ju Chang

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.