Genome wide association joint analysis reveals 99 risk loci for pain susceptibility and pleiotropic relationships with psychiatric, metabolic, and immunological traits.

Chronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system, and is coincident with a growing opioid crisis. While numerous genome-wide association studies have been reported for specific pain-related traits, many of these studies were underpowered, and the genetic relationship among these traits remains poorly understood. Here, we conducted a joint analysis of genome-wide association study summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, 65 of which overlap loci identified in earlier studies. The remaining 34 loci are novel. We applied leave-one-trait-out meta-analyses to evaluate the influence of each trait on the joint analysis, which suggested that loci fall into four categories: loci associated with nearly all pain-related traits; loci primarily associated with a single trait; loci associated with multiple forms of skeletomuscular pain; and loci associated with headache-related pain. Overall, 664 genes were mapped to the 99 loci by genomic proximity, eQTLs, and chromatin interaction and ~15% of these genes showed differential expression in individuals with acute or chronic pain compared to healthy controls. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Genetic correlation and two-sample Mendelian randomization indicated that psychiatric, metabolic, and immunological traits mediate some of these effects.

Can non-invasive brain stimulation modulate peak alpha frequency in the human brain? A systematic review and meta-analysis.

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.

The reliability and validity of rapid transcranial magnetic stimulation mapping for muscles under active contraction.

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.

Patient lived experiences of functioning and disability following lumbar discectomy: a secondary analysis of qualitative data.

BACKGROUND: Knowledge of patient lived experiences of functioning and disability is limited. This study aims to address the gap in the literature by exploring patient lived experiences of functioning and disability following lumbar discectomy. METHOD: A secondary analysis, reported in line with the Standards for Reporting Qualitative Research, was conducted of qualitative data exploring patient journeys following lumbar discectomy surgery (DiscJourn). Adult patients (≥ 16 years) undergoing elective or emergency primary lumbar discectomy were recruited from one National Health Service secondary care centre in the UK. Semi-structured interviews were conducted at 1-3 weeks and 1-year post surgery. Participants who completed both semi-structured interviews were eligible for the secondary analysis. Transcripts from the semi-structured interviews were analysed using interpretative phenomenological analysis (IPA). IPA involved two independent reviewers identifying themes for individual data sets followed by an iterative process involving the wider research team to identify overarching themes that represented the whole date set. Subthemes generated from the IPA were mapped against the International Classification of Functioning, Disability and Health (ICF) framework at the level of chapters, in order to ascertain the ICF's utility in capturing experiences of functioning and disability. Strategies to enhance trustworthiness of data analysis included blind coding, peer examination and debrief, declaration of pre-conceived beliefs and active reflexivity throughout the study. RESULTS: Nine participants met the eligibility criteria and their interview transcripts were analysed. Patient lived experiences of functioning and disability were captured by three overarching themes: Immediate impact following surgery, Multiple roads to recovery over 1 year, and Functioning influenced by personal loci of control. Each theme consisted of three subthemes which were subsequently mapped onto the ICF. Three subthemes mapped to the ICF's body component, 1 to activity and participation and 3 to environment. Two subthemes themes did not map onto the ICF. CONCLUSION: Findings provide valuable insights into patient experiences of functioning and disability following lumbar discectomy. Convergence in experiences of functioning and disability were identified immediately following surgery. Divergence in such experiences were identified with regards to the roads to recovery over 1 year and the individuals' locus of control. Findings build on the body of literature exploring patients functioning and disability following discectomy and make recommendations for future research and clinical practice.

Epigenetic Landscapes of Pain: DNA Methylation Dynamics in Chronic Pain.

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.

Knee osteoarthritis patient perspectives of their care in an australian private physiotherapy setting: a qualitative exploratory interview study.

PURPOSE: This study aimed to understand perceptions that knee osteoarthritis patients have regarding their experiences of guideline-based recommendations within their care received from physiotherapists in private practice. METHODS: A qualitative semi-structured interview study nested within a larger trial auditing care provided by physiotherapists. Recruited adults ≥ 45 years with knee osteoarthritis across nine primary care physiotherapy practices. Interview questions were anchored around the core elements recommended in guidelines for the management of knee osteoarthritis and patient perceptions of these were analysed using both content and thematic qualitative analysis approaches. Patient satisfaction with care received was asked at the time of interview. RESULTS: Twenty-six patients volunteered for the study (mean 60 years, 58% female). Analysis identified that physiotherapists focused on treating symptoms through quadriceps strengthening exercises, which patients found to be effective, though focussed less on other aspects of evidenced-based care. Patient's perceived treatment to be effective in relieving pain and enabling them to stay active and they appreciated the positive role that their physiotherapist provided in alleviating their concerns. Overall, patients were satisfied with their physiotherapy care but would have liked more specific osteoarthritis education and longer-term management. CONCLUSION: The description of the physiotherapy-related care received by people with knee osteoarthritis aligns with guideline recommendations, though mainly for strength-related exercise prescription. Despite some perceived shortfalls in care, patients do appear to be satisfied. However, improvements in patient outcomes may be possible if more elements of guideline-base care are regularly provided, including enhancing osteoarthritis education and fostering behaviour change. TRIAL REGISTRATION: ACTRN12620000188932.

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.

Development and measurement properties of the AxEL (attitude toward education and advice for low-back-pain) questionnaire.

INTRODUCTION: Clinician time and resources may be underutilised if the treatment they offer does not match patient expectations and attitudes. We developed a questionnaire (AxEL-Q) to guide clinicians toward elements of first-line care that are pertinent to their patients with low back pain. METHODS: We used guidance from the COSMIN consortium to develop the questionnaire and evaluated it in a sample of people with low back pain of any duration. Participants were recruited from the community, were over 18 years and fluent in English. Statements that represented first-line care were identified. Semantic scales were used to measure attitude towards these statements. These items were combined to develop the questionnaire draft. Construct validity was evaluated with exploratory factor analysis and hypotheses testing, comparing to the Back Beliefs Questionnaire and modified Pain Self-Efficacy Questionnaire. Reliability was evaluated and floor and ceiling effects calculated. RESULTS: We recruited 345 participants, and had complete data for analysis for 313 participants. The questionnaire draft was reduced to a 3-Factor questionnaire through exploratory factor analysis. Factor 1 comprised 9 items and evaluated Attitude toward staying active, Factor 2 comprised 4 items and evaluated Attitude toward low back pain being rarely caused by a serious health problem, Factor 3 comprised 4 items and evaluated Attitude toward not needing to know the cause of back pain to manage it effectively. There was a strong inverse association between each factor and the Back Beliefs Questionnaire and a moderate positive association with the modified Pain Self-Efficacy Questionnaire. Each independent factor demonstrated acceptable internal consistency; Cronbach α Factor 1 = 0.92, Factor 2 = 0.91, Factor 3 = 0.90 and adequate interclass correlation coefficients; Factor 1 = 0.71, Factor 2 = 0.73, Factor 3 = 0.79. CONCLUSION: This study demonstrates acceptable construct validity and reliability of the AxEL-Q, providing clinicians with an insight into the likelihood of patients following first-line care at the outset.

Aberrant plasticity in musculoskeletal pain: a failure of homeostatic control?

Aberrant synaptic plasticity is hypothesised to underpin chronic pain. Yet, synaptic plasticity regulated by homeostatic mechanisms have received limited attention in pain. We investigated homeostatic plasticity in the human primary motor cortex (M1) of 21 healthy individuals in response to experimentally induced muscle pain for several days. Experimental pain was induced by injecting nerve growth factor into the muscle belly of the right extensor carpi radialis brevis muscle. Pain and disability were monitored until day 21. Homeostatic plasticity was induced on day 0, 2, 4, 6, and 14 in the left M1 using anodal transcranial direct stimulation (tDCS) applied for 7 and 5 min, separated by a 3-min rest period. Motor-evoked potentials (MEP) to transcranial magnetic stimulation assessed the homeostatic response. On days 0 and 14, MEPs increased following the first block of tDCS (p < 0.004), and decreased following the second block of tDCS (p < 0.001), consistent with a normal homeostatic response. However, on days 2 (p = 0.07) and 4 (p = 0.7), the decrease in MEPs after the second block of tDCS was attenuated, representing an impaired homeostatic response. Findings demonstrate altered homeostatic plasticity in the M1 with the greatest alteration observed after 4 days of sustained pain. This study provides longitudinal insight into homeostatic plasticity in response to the development, maintenance, and resolution of pain over the course of 14 days.

The Relationship Between Corticomotor Reorganization and Acute Pain Severity: A Randomized, Controlled Study Using Rapid Transcranial Magnetic Stimulation Mapping.

OBJECTIVE: Although acute pain has been shown to reduce corticomotor excitability, it remains unknown whether this response resolves over time or is related to symptom severity. Furthermore, acute pain research has relied upon data acquired from the cranial "hotspot," which do not provide valuable information regarding reorganization, such as changes to the distribution of a painful muscle's representation within M1. Using a novel, rapid transcranial magnetic stimulation (TMS) mapping method, this study aimed to 1) explore the temporal profile and variability of corticomotor reorganization in response to acute pain and 2) determine whether individual patterns of corticomotor reorganization are associated with differences in pain, sensitivity, and somatosensory organization. METHODS: Corticomotor (TMS maps), pain processing (pain intensity, pressure pain thresholds), and somatosensory (two-point discrimination, two-point estimation) outcomes were taken at baseline, immediately after injection (hypertonic [n = 20] or isotonic saline [n = 20]), and at pain resolution. Follow-up measures were recorded every 15 minutes until 90 minutes after injection. RESULTS: Corticomotor reorganization persisted at least 90 minutes after pain resolution. Corticomotor depression was associated with lower pain intensity than was corticomotor facilitation (r = 0.47 [P = 0.04]). These effects were not related to somatosensory reorganization or peripheral sensitization mechanisms. CONCLUSIONS: Individual patterns of corticomotor reorganization during acute pain appear to be related to symptom severity, with early corticomotor depression possibly reflecting a protective response. These findings hold important implications for the management and potential prevention of pain chronicity. However, further research is required to determine whether these adaptations relate to long-term outcomes in clinical populations.

High frequency repetitive transcranial magnetic stimulation to the left dorsolateral prefrontal cortex modulates sensorimotor cortex function in the transition to sustained muscle pain.

Based on reciprocal connections between the dorsolateral prefrontal cortex (DLPFC) and basal-ganglia regions associated with sensorimotor cortical excitability, it was hypothesized that repetitive transcranial magnetic stimulation (rTMS) of the left DLPFC would modulate sensorimotor cortical excitability induced by muscle pain. Muscle pain was provoked by injections of nerve growth factor (end of Day-0 and Day-2) into the right extensor carpi radialis brevis (ECRB) muscle in two groups of 15 healthy participants receiving 5 daily sessions (Day-0 to Day-4) of active or sham rTMS. Muscle pain scores and pressure pain thresholds (PPTs) were collected (Day-0, Day-3, Day-5). Assessment of motor cortical excitability using TMS (mapping cortical ECRB muscle representation) and somatosensory evoked potentials (SEPs) from electrical stimulation of the right radial nerve were recorded at Day-0 and Day-5. At Day-0 versus Day-5, the sham compared to active group showed: Higher muscle pain scores and reduced PPTs (P < 0.04); decreased frontal N30 SEP (P < 0.01); increased TMS map volume (P < 0.03). These results indicate that muscle pain exerts modulatory effects on the sensorimotor cortical excitability and left DLPFC rTMS has analgesic effects and modulates pain-induced sensorimotor cortical adaptations. These findings suggest an important role of prefrontal to basal-ganglia function in sensorimotor cortical excitability and pain processing.

Cerebral peak alpha frequency reflects average pain severity in a human model of sustained, musculoskeletal pain.

Heightened pain sensitivity, the amount of pain experienced in response to a noxious event, is a known risk factor for development of chronic pain. We have previously reported that pain-free, sensorimotor peak alpha frequency (PAF) is a reliable biomarker of pain sensitivity for thermal, prolonged pains lasting tens of minutes. To test whether PAF can provide information about pain sensitivity occurring over clinically relevant timescales (i.e., weeks), EEG was recorded before and while participants experienced a long-lasting pain model, repeated intramuscular injection of nerve growth factor (NGF), that produces progressively developing muscle pain for up to 21 days. We demonstrate that pain-free, sensorimotor PAF is negatively correlated with NGF pain sensitivity; increasingly slower PAF is associated with increasingly greater pain sensitivity. Furthermore, PAF remained stable following NGF injection, indicating that the presence of NGF pain for multiple weeks is not sufficient to induce the PAF slowing reported in chronic pain. In total, our results demonstrate that slower pain-free, sensorimotor PAF is associated with heightened sensitivity to a long-lasting musculoskeletal pain and also suggest that the apparent slowing of PAF in chronic pain may reflect predisease pain sensitivity.NEW & NOTEWORTHY Pain sensitivity, the intensity of pain experienced after injury, has been identified as an important risk factor in the development of chronic pain. Biomarkers of pain sensitivity have the potential to ease chronic pain burdens by preventing disease emergence. In the current study, we demonstrate that the speed of pain-free, sensorimotor peak alpha frequency recorded during resting-state EEG predicts pain sensitivity to a clinically-relevant, human model of prolonged pain that persists for weeks.

Corticomotor excitability reduction induced by experimental pain remains unaffected by performing a working memory task as compared to staying at rest.

Experimental pain inhibits primary motor cortex (M1) excitability. Attenuating pain-related inhibition of M1 excitability may be useful during rehabilitation in individuals with pain. One strategy to attenuate M1 excitability is to influence prefrontal and premotor cortex activity. Working memory tasks, e.g. the two-back task (TBT), engage prefrontal and premotor cortices and may influence M1 excitability. We hypothesized that performing the TBT during pain would influence pain-related changes in M1 excitability. Participants (n = 28) received rigorous training in the TBT before baseline testing. Experimental pain was induced by injecting hypertonic saline into the first dorsal interosseous (FDI) muscle. Participants rated pain intensity on a 0-10 numerical rating scale (NRS) every second min until pain-resolved (PR) during the performance of the TBT (n = 14) or during REST (n = 14). In the TBT, letters were presented pseudo-randomly, and accuracy and reaction time to identified letters corresponding to letters shown two times back were recorded. M1 excitability was assessed using transcranial magnetic stimulation. Motor-evoked potentials (MEPs) were recorded at baseline, and at PR, PR + 10, PR + 20, and PR + 30 min. Four minutes after hypertonic saline injection, the pain NRS scores were higher in the TBT group than the REST group (p = 0.009). No time × group interaction was found for MEPs (p = 0.73), but a main effect of time (p < 0.0005) revealed a reduction of MEPs at PR up until PR + 30 (p < 0.008). The TBT accuracy improved at PR + 30 in both groups (p = 0.019). In conclusion, the pain-induced reduction in corticomotor excitability was unaffected by performing a working memory task, despite greater pain in the TBT group.

Association Between Clinical Tests Related to Motor Control Dysfunction and Changes in Pain and Disability After Lumbar Stabilization Exercises in Individuals With Chronic Low Back Pain.

OBJECTIVE: To investigate whether clinical tests used to detect motor control dysfunction can predict improvements in pain and disability in patients with chronic nonspecific low back pain (LBP) who have undergone an 8-week lumbar stabilization exercise program. STUDY DESIGN: A prospective cohort study. SETTING: Outpatient physical therapy university clinic. PARTICIPANTS: Seventy people with chronic nonspecific LBP were recruited, and 64 completed the exercise program (N=64). INTERVENTIONS: The lumbar stabilization program was provided twice a week for 8 weeks. MAIN OUTCOME MEASURES: Pain intensity (11-point numerical rating scale) and disability (Roland Morris Disability Questionnaire) and clinical tests, such as the Deep Muscle Contraction (DMC) scale, Clinical Test of Thoracolumbar Dissociation (CTTD), and Passive Lumbar Extension (PLE) test. Univariate and multivariate linear regression models were used in the prediction analysis. RESULTS: Mean changes in pain intensity and disability following the 8-week stabilization program were -3.8 (95% confidence interval [CI], -3.2 to -4.4) and -7.4 (95% CI, -6.3 to -8.5), respectively. Clinical test scores taken at baseline did not predict changes in pain and disability at 8-week follow-up. CONCLUSION: Our findings revealed that the DMC scale, CTTD, PLE test, clinical tests used to assess motor control dysfunction, do not predict improvements in pain and disability in patients with chronic nonspecific LBP following an 8-week lumbar stabilization exercise program.

Electrical Stimulation of Back Muscles Does Not Prime the Corticospinal Pathway.

OBJECTIVES: To investigate whether peripheral electrical stimulation (PES) of back extensor muscles changes excitability of the corticospinal pathway of the stimulated muscle and synergist trunk muscles. METHODS: In 12 volunteers with no history of low back pain (LBP), intramuscular fine-wire electrodes recorded electromyography (EMG) from the deep multifidus (DM) and longissimus muscles. Surface electrodes recorded general EMG from the erector spinae and abdominal muscles. Single- and paired-pulse transcranial magnetic stimulation (TMS) paradigms tested corticospinal excitability, short-interval intracortical inhibition (SICI-2 and 3 ms), and intracortical facilitation (ICF) optimized for recordings of DM. Active motor threshold (aMT) to evoke a motor-evoked potential (MEP) in DM was determined and stimulation was applied at 120% of this intensity. PES was provided via electrodes placed over the right multifidus. The effect of 20-min PES (ramped motor activation) was studied. RESULTS: Mean aMT for DM was 42.7 ± 10% of the maximal stimulator output. No effects of PES were found on MEP amplitude (single-pulse TMS) for any trunk muscles examined. There was no evidence for changes in SICI or ICF; that is, conditioned MEP amplitude was not different between trials after PES. CONCLUSION: Results indicate that, unlike previous reports that show increased corticospinal excitability of limb muscles, PES of back muscles does not modify the corticospinal excitability. This difference in response of the motor pathway of back muscles to PES might be explained by the lesser importance of voluntary cortical drive to these muscles and the greater role of postural networks. Whether PES influences back muscle training remains unclear, yet the present results suggest that potential effects are unlikely to be explained by the effects of PES at corticospinal level with the parameters used in this study.

The Response of the Primary Motor Cortex to Neuromodulation is Altered in Chronic Low Back Pain: A Preliminary Study.

Objective: Neuromodulation is increasingly investigated for the treatment of low back pain (LBP). However, the neurophysiological effects of common neuromodulatory techniques (anodal transcranial direct current stimulation [tDCS] and peripheral electrical stimulation [PES]) have not been investigated in people with chronic LBP. Here we aimed to compare the effect of three neuromodulatory protocols (anodal tDCS, high intensity PES, and a priming protocol of combined tDCS/PES) on primary motor cortex (M1) excitability in people with and without chronic LBP. Design: Cross-sectional. Setting: University laboratory. Participants: Ten individuals with chronic LBP and 10 pain-free controls. Methods: Participants received four interventions in random order across separate sessions: 1) anodal tDCS to M1 + PES to the back muscles; 2) tDCS + sham PES; 3) sham tDCS + PES; or 4) sham tDCS + sham PES. Motor cortical excitability (map volume, discrete map peaks, and cortical silent period [CSP]) was measured before and after each intervention. Results: Anodal tDCS increased M1 excitability (increased map volume and reduced CSP) in controls but had no effect in the LBP group. PES reduced M1 excitability in both groups. The combined tDCS + PES treatment increased M1 excitability in the LBP group but had no effect in controls. Conclusions: The neurophysiological response to common neuromodulatory treatments differs between people with and without LBP. This has relevance for the design and tailoring of neuromodulation in pain. Further, if the goal of treatment is to increase M1 excitability, a priming protocol (e.g., combined tDCS + PES) may be more effective than tDCS alone.

Movement Does Not Promote Recovery of Motor Output Following Acute Experimental Muscle Pain.

Objective: To examine the effect of motor activity on the magnitude and duration of altered corticomotor output following experimental muscle pain. Design: Experimental, pre-post test. Setting: University laboratory. Subjects: Twenty healthy individuals. Methods: Participants were randomly allocated to a Rest or Movement group. The Rest group sat quietly without moving for the duration of the experiment. The Movement group repeated a unimanual pattern of five sequential keystrokes as quickly and as accurately as possible immediately following the resolution of pain. Pain was induced into the right extensor carpi radialis brevis muscle by a bolus injection of 0.5 mL hypertonic saline. Corticomotor output was assessed as motor evoked potentials in response to transcranial magnetic stimulation before, immediately after, and at 10, 20, and 30 minutes following pain resolution. Pain intensity was recorded every 30 seconds using an 11-point numerical rating scale. Results: There was no difference in peak pain intensity (P < 0.09) or duration (P < 0.2) between groups. Corticomotor output was reduced in both groups (P < 0.002) at 10 minutes (P < 0.002), 20 minutes (P < 0.02), and 30 minutes (P < 0.037) following the resolution of pain relative to baseline. There was no difference between groups at any time point. Conclusions: Performance of motor activity immediately following the resolution of acute muscle pain did not alter the magnitude or duration of corticomotor depression. Understanding corticomotor depression in the postpain period and what factors promote recovery has relevance for clinical pain syndromes where ongoing motor dysfunction, in the absence of pain, may predispose to symptom persistence or recurrence.

Test-Retest Reliability of Homeostatic Plasticity in the Human Primary Motor Cortex.

Homeostatic plasticity regulates synaptic activity by preventing uncontrolled increases (long-term potentiation) or decreases (long-term depression) in synaptic efficacy. Homeostatic plasticity can be induced and assessed in the human primary motor cortex (M1) using noninvasive brain stimulation. However, the reliability of this methodology has not been investigated. Here, we examined the test-retest reliability of homeostatic plasticity induced and assessed in M1 using noninvasive brain stimulation in ten, right-handed, healthy volunteers on days 0, 2, 7, and 14. Homeostatic plasticity was induced in the left M1 using two blocks of anodal transcranial direct current stimulation (tDCS) applied for 7 min and 5 min, separated by a 3 min interval. To assess homeostatic plasticity, 15 motor-evoked potentials to single-pulse transcranial magnetic stimulation were recorded at baseline, between the two blocks of anodal tDCS, and at 0 min, 10 min, and 20 min follow-up. Test-retest reliability was evaluated using intraclass correlation coefficients (ICCs). Moderate-to-good test-retest reliability was observed for the M1 homeostatic plasticity response at all follow-up time points (0 min, 10 min, and 20 min, ICC range: 0.43-0.67) at intervals up to 2 weeks. The greatest reliability was observed when the homeostatic response was assessed at 10 min follow-up (ICC > 0.61). These data suggest that M1 homeostatic plasticity can be reliably induced and assessed in healthy individuals using two blocks of anodal tDCS at intervals of 48 hours, 7 days, and 2 weeks.

"Discrete peaks" of excitability and map overlap reveal task-specific organization of primary motor cortex for control of human forearm muscles.

The primary motor cortex (M1) presents a somatotopic organization of body parts, but with overlap between muscle/movement representations. This distinct but overlapping M1 organization is believed to be important for individuated control and movement coordination, respectively. Discrete peaks of greater excitability observed within M1 might underpin organization of cortical motor control. This study aimed to examine interactions between M1 representations of synergist and antagonist forearm muscles, compare regions of greater excitability during different functional tasks, and compare characteristics of M1 representation recorded using surface and fine-wire (fw ) electrodes. Transcranial magnetic stimulation (TMS) was applied over M1 for mapping the representation of 4 forearm muscles (extensor carpi radialis brevis [ECRB], extensor digitorum communis, flexor carpi radialis, and flexor digitorum superficialis) during three tasks: rest, grip, and wrist extension in 14 participants. There are three main findings. First, discrete areas of peak excitability within the M1 representation of ECRBfw were identified during grip and wrist extension suggesting that different M1 areas are involved in different motor functions. Second, M1 representations of synergist muscles presented with greater overlap of M1 representations than muscles with mainly antagonist actions, which suggests a role in muscle coordination. Third, as larger normalized map volume and overlap were observed using surface than fine-wire electrodes, data suggest that cross-talk from adjacent muscles compromised interpretation of recordings made with surface electrodes in response to TMS. These results provide a novel understanding of the spatial organization of M1 with evidence of "functional somatotopy." This has important implications for cortical control of movement. Hum Brain Mapp 38:6118-6132, 2017. © 2017 Wiley Periodicals, Inc.

Primary Motor Cortex Organization Is Altered in Persistent Patellofemoral Pain.

OBJECTIVE: Reorganization of the primary motor cortex (M1) may be a feature of persistent patellofemoral pain (PFP), but no studies have investigated M1 organization in this condition. Here we aimed to examine the organization of the M1 representation of the quadriceps muscles in people with PFP and healthy controls. DESIGN: Using a cross-sectional design, the M1 representation of the rectus femoris, vastus lateralis, and vastus medialis was mapped using transcranial magnetic stimulation in 11 individuals with PFP and 11 controls. Measures of pain severity were also made. RESULTS: Individuals with PFP had reduced map volumes (P < 0.001) and an anterior shift in the M1 representation (P = 0.03) across all three quadriceps muscles compared with controls. Greater overlap of the M1 representation (P = 0.02) and a reduction in the number of discrete cortical peaks (P = 0.009) across all three quadriceps muscles were also observed in individuals with PFP compared with controls. There was no relationship between altered M1 organization and pain in PFP. CONCLUSIONS: These findings provide evidence of altered M1 organization in individuals with PFP compared with healthy controls. Notably, no difference in M1 organization was observed for the medial and lateral heads of the quadriceps in PFP. These data have relevance for our understanding of the pathophysiology of PFP and for the design of future treatments that aim to target M1 in this condition.