Neuroinflammatory activation in sensory and motor regions of the cortex is related to sensorimotor function in individuals with low back pain maintained by nociplastic mechanisms: A preliminary proof-of-concept study.

BACKGROUND: Chronic pain involves communication between neural and immune systems. Recent data suggest localization of glial (brain immune cells) activation to the sensorimotor regions of the brain cortex (S1/M1) in chronic low back pain (LBP). As glia perform diverse functions that impact neural function, activation might contribute to sensorimotor changes, particularly in LBP maintained by increased nervous system sensitivity (i.e., nociplastic pain). This preliminary proof-of-concept study aimed to: (i) compare evidence of neuroinflammatory activation in S1/M1 between individuals with and without LBP (and between nociceptive and nociplastic LBP phenotypes), and (ii) evaluate relationships between neuroinflammatory activation and sensorimotor function. METHODS: Simultaneous PET-fMRI measured neuroinflammatory activation in functionally defined S1/M1 in pain-free individuals (n = 8) and individuals with chronic LBP (n = 9; nociceptive: n = 4, nociplastic: n = 5). Regions of S1/M1 related to the back were identified using fMRI during motor tasks and thermal stimuli. Sensorimotor measures included single and paired-pulse transcranial magnetic stimulation (TMS) and quantitative sensory testing (QST). Sleep, depression, disability and pain questionnaires were administered. RESULTS: Neuroinflammatory activation was greater in the lower back cortical representation of S1/M1 of the nociplastic LBP group than both nociceptive LBP and pain-free groups. Neuroinflammatory activation in S1/M1 was positively correlated with sensitivity to hot (r = 0.52) and cold (r = 0.55) pain stimuli, poor sleep, depression, disability and BMI, and negatively correlated with intracortical facilitation (r = -0.41). CONCLUSION: This preliminary proof-of-concept study suggests that neuroinflammation in back regions of S1/M1 in individuals with nociplastic LBP could plausibly explain some characteristic features of this LBP phenotype. SIGNIFICANCE STATEMENT: Neuroinflammatory activation localized to sensorimotor areas of the brain in individuals with nociplastic pain might contribute to changes in sensory and motor function and aspects of central sensitization. If cause-effect relationships are established in longitudinal studies, this may direct development of therapies that target neuroinflammatory activation.

The effect of skilled motor training on corticomotor control of back muscles in different presentations of low back pain.

Transcranial magnetic stimulation (TMS) has revealed differences in the motor cortex (M1) between people with and without low back pain (LBP). There is potential to reverse these changes using motor skill training, but it remains unclear whether changes can be induced in people with LBP or whether this differs between LBP presentations. This study (1) compared TMS measures of M1 (single and paired-pulse) and performance of a motor task (lumbopelvic tilting) between individuals with LBP of predominant nociceptive (n = 9) or nociplastic presentation (n = 9) and pain-free individuals (n = 16); (2) compared these measures pre- and post-training; and (3) explored correlations between TMS measures, motor performance, and clinical features. TMS measures did not differ between groups at baseline. The nociplastic group undershot the target in the motor task. Despite improved motor performance for all groups, only MEP amplitudes increased across the recruitment curve and only for the pain-free and nociplastic groups. TMS measures did not correlate with motor performance or clinical features. Some elements of motor task performance and changes in corticomotor excitability differed between LBP groups. Absence of changes in intra-cortical TMS measures suggests regions other than M1 are likely to be involved in skill learning of back muscles.

The Association between Early Opioids Prescribing and the Length of Disability in Acute Lower Back Pain: A Systematic Review and Narrative Synthesis.

BACKGROUND: There is conflicting evidence with respect to whether early opioid prescribing (EOP) within the first two weeks of acute Low Back Pain (LBP) onset is associated with the length of disability (LOD). The aim of this systematic review was to examine the relationship between EOP and LOD in individuals with acute LBP. METHODS: A systematic search of Medline, EMBASE, and CINAHL was conducted. The Newcastle-Ottawa scale was used to assess the methodological quality of included studies. A narrative synthesis of findings was used owing to between-study heterogeneity. RESULTS: Six cohort studies using workers' compensation administrative data on 178,130 adults with LBP were included. Most studies were of good methodological quality. One study reported that LBP cases with EOP had higher LOD by 4 days than cases without EOP. Two studies reported that each 100 mg morphine equivalent amount (MEA) was associated with an increase in mean LOD by 0.4 day (95% confidence interval (CI): 0.3, 0.5) and 0.4 day (95% CI: 0.3, 0.4). One study showed that LBP cases with EOP had a higher hazard of continuation of time loss benefits by 1.94 (95% CI 1.86, 2.02). One study reported a dose-response relationship between MEA of EOP and LOD ranging between 5.2 days (95% CI 14.6, 25.0) for 1-140 mg MEA and 69.1 (95% CI 49.3, 89.0) for 450+ mg MEA. One study reported that LBP cases with EOP had a higher mean LOD by 3.8 days, but there was no statistically significant relationship between EOP and LOD (Hazard ratio 1.02; 95% CI 0.91, 1.13). CONCLUSIONS: The use of early opioid in the management of acute uncomplicated LBP is associated with prolonged disability duration. Further research on factors influencing inadequate adherence to evidence-based guidelines and optimal strategies to modify such factors may improve disability outcomes among patients presenting with acute LBP.

Can training of a skilled pelvic movement change corticomotor control of back muscles? Comparison of single and paired-pulse transcranial magnetic stimulation.

Evidence suggests excitability of the motor cortex (M1) changes in response to motor skill learning of the upper limb. Few studies have examined immediate changes in corticospinal excitability and intra-cortical mechanisms following motor learning in the lower back. Further, it is unknown which transcranial magnetic stimulation (TMS) paradigms are likely to reveal changes in cortical function in this region. This study aimed to (1) compare corticospinal excitability and intra-cortical mechanisms in the lower back region of M1 before and after a single session of lumbopelvic tilt motor learning task in healthy people and (2) compare these measures between two TMS coils and two methods of recruitment curve (RC) acquisition. Twenty-eight young participants (23.6 ± 4.6 years) completed a lumbopelvic tilting task involving three 5-min blocks. Single-pulse (RC from 70% to 150% of active motor threshold) and paired-pulse TMS measures (ICF, SICF and SICI) were undertaken before (using 2 coils: figure-of-8 and double cone) and after (using double cone coil only) training. RCs were also acquired using a traditional and rapid method. A significant increase in corticospinal excitability was found after training as measured by RC intensities, but this was not related to the RC slope. No significant differences were found for paired-pulse measures after training. Finally, there was good agreement between RC parameters when measured with the two different TMS coils or different acquisition methods (traditional vs. rapid). Changes in corticospinal excitability after a single session of lumbopelvic motor learning task are seen, but these changes are not explained by changes in intra-cortical mechanisms.

Effects of different modalities of afferent stimuli of the lumbo-sacral area on control of lumbar paravertebral muscles.

Somatosensory feedback to the central nervous system is essential to plan, perform and refine spine motor control. However, the influence of somatosensory afferent input from the trunk on the motor output to trunk muscles has received little attention. The objective was to compare the effects of distinct modalities of afferent stimulation on the net motoneuron and corticomotor excitability of paravertebral muscles. Fourteen individuals were recruited. Modulation of corticospinal excitability (motor-evoked potential [MEP]) of paravertebral muscles was measured when afferent stimuli (cutaneous noxious and non-noxious, muscle contraction) were delivered to the trunk at 10 intervals prior to transcranial magnetic stimulation. Each peripheral stimulation was applied alone, and subsequent electromyography (EMG) modulation was measured to control for net motoneuron excitability. MEP modulation and MEP/EMG ratio were used as measures of corticospinal excitability with and without control of net motoneuron excitability, respectively. MEP and EMG modulation were smaller after evoked muscle contraction than after cutaneous noxious and non-noxious stimuli. MEP/EMG ratio was not different between stimulation types. Both MEP and EMG amplitudes were reduced after evoked muscle contraction, but not when expressed as MEP/EMG ratio. Noxious and non-noxious stimulation had limited impact on all variables. Distinct modalities of peripheral afferent stimulation of the lumbo-sacral area differently modulated responses of paravertebral muscles, but without an influence on corticospinal excitability with control of net motoneuron excitability. Muscle stimulation reduced paravertebral activity and was best explained by spinal mechanisms. The impact of afferent stimulation on back muscles differs from the effects reported for limb muscles.

Features and methods to discriminate between mechanism-based categories of pain experienced in the musculoskeletal system: a Delphi expert consensus study.

ABSTRACT: Classification of musculoskeletal pain based on underlying pain mechanisms (nociceptive, neuropathic, and nociplastic pain) is challenging. In the absence of a gold standard, verification of features that could aid in discrimination between these mechanisms in clinical practice and research depends on expert consensus. This Delphi expert consensus study aimed to: (1) identify features and assessment findings that are unique to a pain mechanism category or shared between no more than 2 categories and (2) develop a ranked list of candidate features that could potentially discriminate between pain mechanisms. A group of international experts were recruited based on their expertise in the field of pain. The Delphi process involved 2 rounds: round 1 assessed expert opinion on features that are unique to a pain mechanism category or shared between 2 (based on a 40% agreement threshold); and round 2 reviewed features that failed to reach consensus, evaluated additional features, and considered wording changes. Forty-nine international experts representing a wide range of disciplines participated. Consensus was reached for 196 of 292 features presented to the panel (clinical examination-134 features, quantitative sensory testing-34, imaging and diagnostic testing-14, and pain-type questionnaires-14). From the 196 features, consensus was reached for 76 features as unique to nociceptive (17), neuropathic (37), or nociplastic (22) pain mechanisms and 120 features as shared between pairs of pain mechanism categories (78 for neuropathic and nociplastic pain). This consensus study generated a list of potential candidate features that are likely to aid in discrimination between types of musculoskeletal pain.

The association between early MRI and length of disability in acute lower back pain: a systematic review and narrative synthesis.

BACKGROUND: Clinical guideline recommendations are against early magnetic resonance imaging (eMRI) within the first 4 to 6 weeks of conservative management of acute low back pain (LBP) without "clinical suspicion" of serious underlying conditions (red flags). There is some limited evidence that a significant proportion of patients with LBP receive eMRI non- indicated by clinical guidelines, which could be associated with increased length of disability (LOD). The aim of this systematic review was to investigate whether eMRI for acute LBP without red flags is associated with increased LOD. The LOD was defined as the number of disability days (absence from work). METHODS: Medline, EMBASE, and CINAHL bibliographic databases were searched from inception until June 5, 2021. Two reviewers independently assessed the methodological quality of included studies using the Newcastle-Ottawa scale and extracted data for the review. The search identified 324 records, in which seven studies met the inclusion criteria. Three of the included studies used the same study population. Owing to between-study heterogeneity, a narrative synthesis of results was used. RESULTS: All included studies were of good methodological quality and consistently reported that patients with acute LBP without red flags who received eMRI had increased LOD compared to those who did not receive eMRI. Three retrospective cohort studies reported that the eMRI groups had a higher mean LOD than the no eMRI groups ranging from 9.4 days (95% CI 8.5, 10.2) to 13.7 days (95% CI 13.0, 14.5) at the end of 1-year follow-up period. The remaining studies reported that the eMRI groups had a higher hazard ratio of work disability ranging between 1.75 (95% CI 1.23, 2.50) and 3.57 (95% CI 2.33, 5.56) as compared to the no eMRI groups. CONCLUSION: eMRI is associated with increased LOD in patients with acute LBP without red flags. Identifying reasons for performing non-indicated eMRI and addressing them with quality improvement interventions may improve adherence to clinical guidelines and improve disability outcomes among patients with LBP.

Methods to discriminate between mechanism-based categories of pain experienced in the musculoskeletal system: a systematic review.

ABSTRACT: Mechanism-based classification of pain has been advocated widely to aid tailoring of interventions for individuals experiencing persistent musculoskeletal pain. Three pain mechanism categories (PMCs) are defined by the International Association for the Study of Pain: nociceptive, neuropathic, and nociplastic pain. Discrimination between them remains challenging. This study aimed to build on a framework developed to converge the diverse literature of PMCs to systematically review methods purported to discriminate between them; synthesise and thematically analyse these methods to identify the convergence and divergence of opinion; and report validation, psychometric properties, and strengths/weaknesses of these methods. The search strategy identified articles discussing methods to discriminate between mechanism-based categories of pain experienced in the musculoskeletal system. Studies that assessed the validity of methods to discriminate between categories were assessed for quality. Extraction and thematic analysis were undertaken on 184 articles. Data synthesis identified 200 methods in 5 themes: clinical examination, quantitative sensory testing, imaging, diagnostic and laboratory testing, and pain-type questionnaires. Few methods have been validated for discrimination between PMCs. There was general convergence but some disagreement regarding findings that discriminate between PMCs. A combination of features and methods, rather than a single method, was generally recommended to discriminate between PMCs. Two major limitations were identified: an overlap of findings of methods between categories due to mixed presentations and many methods considered discrimination between 2 PMCs but not others. The results of this review provide a foundation to refine methods to differentiate mechanisms for musculoskeletal pain.

Systematic Review and Synthesis of Mechanism-based Classification Systems for Pain Experienced in the Musculoskeletal System.

OBJECTIVES: Improvements in pain management might be achieved by matching treatment to underlying mechanisms for pain persistence. Many authors argue for a mechanism-based classification of pain, but the field is challenged by the wide variation in the proposed terminology, definitions, and typical characteristics. This study aimed to (1) systematically review mechanism-based classifications of pain experienced in the musculoskeletal system; (2) synthesize and thematically analyze classifications, using the International Association for the Study of Pain categories of nociceptive, neuropathic, and nociplastic as an initial foundation; and (3) identify convergence and divergence between categories, terminology, and descriptions of each mechanism-based pain classification. MATERIALS AND METHODS: Databases were searched for papers that discussed a mechanism-based classification of pain experienced in the musculoskeletal system. Terminology, definitions, underlying neurobiology/pathophysiology, aggravating/easing factors/response to treatment, and pain characteristics were extracted and synthesized on the basis of thematic analysis. RESULTS: From 224 papers, 174 terms referred to pain mechanisms categories. Data synthesis agreed with the broad classification on the basis of ongoing nociceptive input, neuropathic mechanisms, and nociplastic mechanisms (eg, central sensitization). "Mixed," "other," and the disputed categories of "sympathetic" and "psychogenic" pain were also identified. Thematic analysis revealed convergence and divergence of opinion on the definitions, underlying neurobiology, and characteristics. DISCUSSION: Some pain categories were defined consistently, and despite the extensive efforts to develop global consensus on pain definitions, disagreement still exists on how each could be defined, subdivided, and their characteristic features that could aid differentiation. These data form a foundation for reaching consensus on classification.

Corticomotor reorganization during short-term visuomotor training in the lower back: A randomized controlled study.

INTRODUCTION: Accumulating evidence suggests that motor skill training is associated with structural and functional reorganization of the primary motor cortex. However, previous studies have focussed primarily upon the upper limb, and it is unclear whether comparable reorganization occurs following training of other regions, such as the lower back. Although this holds important implications for rehabilitation, no studies have examined corticomotor adaptations following short-term motor training in the lower back. METHOD: The aims of this study were to (a) determine whether a short-term lumbopelvic tilt visuomotor task induced reorganization of the corticomotor representations of lower back muscles, (b) quantify the variability of corticomotor responses to motor training, and (c) determine whether any improvements in task performance were correlated with corticomotor reorganization. Participants were allocated randomly to perform a lumbopelvic tilt motor training task (n = 15) or a finger abduction control task involving no lumbopelvic movement (n = 15). Transcranial magnetic stimulation was used to map corticomotor representations of the lumbar erector spinae before, during, and after repeated performance of the allocated task. RESULTS: No relationship between corticomotor reorganization and improved task performance was identified. Substantial variability was observed in terms of corticomotor responses to motor training, with approximately 50% of participants showing no corticomotor reorganization despite significant improvements in task performance. CONCLUSION: These findings suggest that short-term improvements in lower back visuomotor task performance may be driven by changes in remote subcortical and/or spinal networks rather than adaptations in corticomotor pathways. However, further research using tasks of varying complexities and durations is required to confirm this hypothesis.