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Abstract: Predicting the development of chronic low back pain (LBP) at the time of an acute episode remains challenging. The Understanding persistent Pain Where it ResiDes study aimed to identify neurobiological and psychological risk factors for chronic LBP. Individuals with acute LBP (N = 120) participated in a prospective cohort study with 6-month follow-up. Candidate predictors were selected from the neurobiological (eg, sensorimotor cortical excitability assessed by sensory and motor-evoked potentials and brain-derived neurotrophic factor genotype), psychological (eg, depression and anxiety), symptom-related (eg, LBP history), and demographic domains. Analyses involved multivariable linear regression models with pain intensity or disability degree as continuous variables. Secondary analyses involved a multivariable logistic model with the presence of LBP at 6 months (thresholding pain intensity and disability degree) as a dichotomous variable. Lower sensory cortex and corticomotor excitability, higher baseline pain intensity, higher depression, stress, and pain catastrophizing were the strongest predictors ( R2 = 0.47) of pain intensity at 6 months. Older age and higher pain catastrophizing were the strongest predictors ( R2 = 0.30) of disability at 6 months. When the LBP outcome was dichotomised, sensory cortex and corticomotor excitability, brain-derived neurotrophic factor genotype, depression and anxiety, LBP history and baseline pain intensity, discriminated between those who did and did not report LBP at 6 months (C-statistic 0.91). This study identifies novel risk factors for the development of future LBP. Neurobiological risk factors, when added to a multivariable linear regression model, explained a further 15% of the variance in the 6-month pain intensity., (Copyright © 2022 International Association for the Study of Pain.)

Abstract: This observational study evaluated people's attitudes towards educational statements and tested whether this predicted intention to self-manage low back pain (LBP). People with or without LBP who were older than 18 years and fluent in written English were recruited. Participants completed an online survey asking demographic questions and questions on the presence or absence of LBP, its duration, and intensity. We assessed attitude toward educational statements and conducted linear regression analyses to investigate the relationship between attitude toward each statement and intention to self-manage. We recruited 656 participants, n = 345 (53.6%), with LBP of varying duration. On average, participants had a positive attitude toward all statements except one; participants with chronic LBP had a negative attitude toward a statement relating to the cause of LBP. The effect of attitude on intention to self-manage was dependent on whether someone had LBP and for how long. For example, increased intention to self-manage was predicted by a positive attitude toward educational statements related to staying active (β = 0.22 [CI 0.11-0.33]) in participants without pain, statements about reassurance (β = 0.33 [CI 0.16-0.49]) for participants with acute or subacute LBP, and statements about the severity of back pain (β = 0.25 [CI 0.18-0.33]) for participants with chronic LBP. We noted differences in attitude toward educational messages and individuals' intention to self-manage LBP depending on pain duration. Self-management could be encouraged with specific reassurance in people with acute or subacute LBP and education about severity in people with chronic LBP., (Copyright © 2022 International Association for the Study of Pain.)

Objectives: Explore the moderating effects of psychological or social variables on associations between biomarkers of inflammation/stress and clinical reports of pain., Methods: This is a cross-sectional exploratory study. Data were drawn from the Systematic Merging of Biology, Mental Health and Environment (SYMBIOME) longitudinal study (clinicaltrials.gov ID no. NCT02711085). Eligible participants were adults who presented to an Urgent Care Centre in Ontario, Canada within 3 weeks of a noncatastrophic musculoskeletal trauma (no surgery or hospitalization). A questionnaire package was given that included the Brief Pain Inventory (capturing pain severity and pain interference) and relevant person-level variables. Blood samples were also drawn for serum analysis of 8 target biomarkers (brain-derived neurotrophic factor, transforming growth factor beta 1 [TGF-β1], c-reactive protein, tumor necrosis factor-α, interleukin [IL]-1β, IL-6, IL-10, and cortisol)., Results: Employment before trauma (employed for pay/not employed for pay) fully moderated the association between tumor necrosis factor-α and pain severity (∆R2=4.4%). Pre-existing psychopathology (yes/no) fully moderated the association between TGF-β1 and pain severity (∆R2=8.0%). Sex (male/female) fully moderated the association between c-reactive protein and pain severity (∆R2=6.3%). A pre-existing pain condition (yes/no) was significantly associated with worse pain interference (R2=7.2%), and partially moderated the effect of IL-1β on pain interference (∆R2=6.9%). Higher peritraumatic life stress significantly explained 8.9% of variance in pain interference alone, and partially moderated the effect of TGF-β1 on interference (∆R2=4.4%)., Discussion: Simple bivariate associations between blood-based markers and clinical symptoms are unlikely to reveal meaningful relationships. However, when stratified by existing person-level or "metadata" variables, an association may exist for at least 1 clinically relevant subgroup., Competing Interests: J.C.M. was supported by a Canadian Institutes of Health Research (Ottawa, ON) Chair in Gender, Work and Health and the Dr James Roth Chair in Musculoskeletal Measurement and Knowledge Translation. J.M.E. was supported by the National Institutes of Health (NIH), Bethesda, MD through Grant Numbers R01HD079076 and R03HD094577: Eunice Kennedy Shriver National Institute of Child Health & Human Development, Rockville, MD; National Center for Medical Rehabilitation Research, Rockville, MD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. J.M.E. reports payment for lectures/workshops on assessment and management of the patient with pain that is outside the submitted work. S.M.S. receives salary support from The National Health and Medical Research Council of Australia, Canberra, ACT through grant number 1105040. D.M.W. was supported by a Canadian Pain Society Early Career Investigator Award, an Ontario Ministry of Research and Innovation Early Researcher Award, and funding from the Strategy for Patient-Oriented Research (SPOR) program for chronic pain jointly funded by the Canadian Institutes of Health Research, Ottawa, ON, Canada and matching industry partners. D.M.W. reports payment for lectures/workshops on assessment and management of the patient with pain that is irrespective of the submitted work. All funders were arm’s length and funds were managed by institutional research accounting with no influence on the interpretation or reporting of results. The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) is increasingly being investigated as a means of alleviating chronic pain. However, rTMS interventions are typically initiated once pain has already become chronic and maladaptive patterns of neural activity are likely to have been established. A critical question is whether M1 rTMS applied soon after pain onset can prevent the development of maladaptive neural activity and promote recovery. This study investigated the effect of 5 consecutive days of excitatory M1 rTMS on pain, functional limitation, mechanical hyperalgesia, descending inhibitory pain control, and M1 organisation in the transition from acute to sustained pain. Thirty healthy participants attended 8 sessions over a 16-day period. On days 0, 2, and 4, nerve growth factor was injected into the right forearm to induce progressively developing muscle soreness and mechanical hyperalgesia. Active or sham excitatory rTMS was delivered on days 4 to 8. Clinical and neurophysiological outcomes were recorded on days 0, 2, 4, 6, 8, 11, and 14. Active rTMS promoted recovery of muscle soreness, pain, and mechanical hyperalgesia when compared with sham rTMS (all between-group P < 0.05). Corticomotor excitability and descending inhibitory pain control did not differ between groups. These findings suggest that active excitatory M1 rTMS promotes recovery of muscle soreness, pain, and mechanical hyperalgesia in the transition from acute to sustained experimental pain. The analgesic effects of M1 rTMS do not seem to be modulated by descending inhibitory pain control or local changes in corticomotor excitability.

Musculoskeletal pain is associated with altered motor control that, despite short-term benefit, is hypothesised to have long-term consequences, contributing to the development of chronic pain. However, data on how motor control is altered when pain is sustained beyond a transient event are scarce. Here, we investigated motor adaptation, and its relationship with corticomotor excitability, in the transition to sustained muscle pain. Twenty-eight healthy individuals were injected with nerve growth factor into the right extensor carpi radialis brevis muscle on days 0 and 2. Motor adaptation and corticomotor excitability were assessed on day -2, before injection on days 0 and 2, and again on days 4 and 14. Motor adaptation was quantified during a radial-ulnar movement as kinematic variability of wrist flexion-extension and pronation-supination, and as electromyographic (EMG) variability of extensor carpi radialis brevis activity. Pain, muscle soreness, and functional limitation were assessed from days 0 to 14. Pain, muscle soreness, and functional limitation were evident at days 2 and 4 (P < 0.001). Electromyographic variability reduced at days 4 and 14 (P < 0.04), with no change in kinematic variability (P = 0.9). However, data revealed variation in EMG and kinematic variability between individuals: some displayed increased motor variability, whereas others a decrease. Individuals who displayed an increase in EMG variability after 4 days of pain also displayed an increase in corticomotor excitability (r = 0.43, P = 0.034). These findings suggest individual adaptation of the motor system in the transition to sustained pain that could have implications for clinical musculoskeletal pain disorders.

The left dorsolateral prefrontal cortex (DLPFC) is involved in the experience and modulation of pain, and may be an important node linking pain and cognition. Repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC can reduce chronic and experimental pain. However, whether left DLPFC rTMS can influence the development of chronic pain is unknown. Using repeated intramuscular injection of nerve growth factor to induce the development of sustained muscle pain (lasting weeks), 30 healthy individuals were randomized to receive 5 consecutive daily treatments of active or sham left DLPFC rTMS, starting before the first nerve growth factor injection on day 0. Muscle soreness and pain severity were collected daily for 14 days and disability on every alternate day. Before the first and 1 day after the last rTMS session, anxiety, depression, affect, pain catastrophizing, and cognitive performance on the attention network test were assessed. Left DLPFC rTMS treatment compared with sham was associated with reduced muscle soreness, pain intensity, and painful area (P < 0.05), and a similar trend was observed for disability. These effects were most evident during the days rTMS was applied lasting up to 3 days after intervention. Depression, anxiety, pain catastrophizing, and affect were unchanged. There was a trend toward improved cognitive function with rTMS compared with sham (P = 0.057). These data indicate that repeated left DLPFC rTMS reduces the pain severity in a model of prolonged muscle pain. The findings may have implications for the development of sustained pain in clinical populations.

Study Design: Cross-sectional design., Objective: Here we aimed to determine whether motor cortical reorganization in low back pain (LBP) can be identified using noninvasive surface electromyographic (EMG) recordings of back muscles at different lumbar levels, and whether cortical reorganization is related to clinical features of LBP., Summary of Background Data: Reorganization of motor regions of the brain may contribute to altered motor control, pain, and disability in chronic LBP. However, data have been limited by the need for invasive recordings of back muscle myoelectric activity. The relationship between altered cortical organization and clinical features of LBP remains unclear., Methods: In 27 individuals with recurrent, nonspecific LBP and 23 pain-free controls, we mapped the motor cortical representation of the paraspinal muscles using transcranial magnetic stimulation in conjunction with noninvasive surface EMG recordings at L3 and L5 levels. Clinical measures of pain severity, location, and duration were made., Results: The results demonstrate a loss of discrete motor cortical organization of the paraspinal muscles in chronic LBP that can be identified using noninvasive EMG recordings. A loss of discrete cortical organization was clearer when surface electrodes were positioned at L3 rather than L5. A novel finding was that altered motor cortical organization (number of discrete peaks and map volume) was associated with the severity and location of LBP., Conclusion: These data suggest that surface EMG positioned at L3 is appropriate for the identification of changes in the motor cortex in LBP. Furthermore, our data have implications for treatment strategies that aim to restore cortical organization in LBP., Level of Evidence: 2.

Introduction: Unilateral elbow pain results in sensorimotor dysfunction that is frequently bilateral, affects local and remote upper limb muscles, and persists beyond resolution of local tendon symptoms. These characteristics suggest supraspinal involvement. Here, we investigated 1) the excitability and organization of the M1 representation of the wrist extensor muscles and 2) the relation between M1 changes and clinical outcomes in lateral epicondylalgia (LE) (n = 11) and healthy control subjects (n = 11)., Methods: Transcranial magnetic stimulation was used to map the M1 representation of the extensor carpi radialis brevis (ECRB) and extensor digitorum (ED)., Results: The cortical representations of ECRB and ED were more excitable, and the centers of gravity for the two muscles were located closer together in LE than that in healthy controls. Increased ECRB excitability and closer location of the center of gravity were associated with higher pain severity at rest and/or in the preceding 6 months. A novel finding was a reduced number of discrete peaks in the representations of ECRB and ED in participants with LE compared with that in healthy controls., Conclusions: This finding may have broad implications for the control of the wrist extensor muscles in LE. These data provide evidence that cortical organization may be maladaptive in LE and suggest that reorganization may be associated with persistence/recurrence of pain.