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Background Increasing pre-clinical evidence suggests that aerobic exercise positively modulates neuroimmune responses following traumatic nerve injury. However, meta-analyses on neuroimmune outcomes are currently still lacking. This study aimed to synthesize the pre-clinical literature on the effects of aerobic exercise on neuroimmune responses following peripheral nerve injury. Methods MEDLINE (via Pubmed), EMBASE and Web of Science were searched. Controlled experimental studies on the effect of aerobic exercise on neuroimmune responses in animals with a traumatically induced peripheral neuropathy were considered. Study selection, risk of bias assessment and data extraction were performed independently by two reviewers. Results were analyzed using random effects models and reported as standardized mean differences. Outcome measures were reported per anatomical location and per class of neuro-immune substance. Results The literature search resulted in 14,590 records. Forty studies were included, reporting 139 comparisons of neuroimmune responses at various anatomical locations. All studies had an unclear risk of bias. Compared to non-exercised animals, meta-analyses showed the following main differences in exercised animals: (1) in the affected nerve, tumor necrosis factor-α (TNF-α) levels were lower (p = 0.003), while insulin-like growth factor-1 (IGF-1) (p p = 0.01) levels were higher; (2) At the dorsal root ganglia, brain-derived neurotrophic factor (BDNF)/BDNF mRNA levels (p = 0.004) and nerve growth factor (NGF)/NGF mRNA (p p = 0.006) were lower; at the dorsal horn, microglia (p p = 0.005) marker levels were lower; at the ventral horn, astrocyte marker levels (p p = 0.001); (5) in muscles, BDNF levels (p p Conclusion This review revealed widespread positive modulatory effects of aerobic exercise on neuroimmune responses following traumatic peripheral nerve injury. These changes are in line with a beneficial influence on pro-inflammatory processes and increased anti-inflammatory responses. Given the small sample sizes and the unclear risk of bias of the studies, results should be interpreted with caution.

Objective The association between low-grade systemic inflammation and musculoskeletal pain may be influenced by multiple factors. However, little is known about the relative importance of these factors, and few studies account for them. This Delphi study aimed to reach consensus on the most important confounders which influence the association between low-grade systemic inflammation and musculoskeletal pain. Methods The panel consisted of 48 experts. In Round 1, the experts proposed what they believed were important confounders. In Round 2, the experts indicated for each confounder whether they believed it was important (yes/no). At least 50% of experts had to indicate the confounder was important to be considered in the final round. In Round 3, the experts rated the importance of each confounder on a 7-point Likert scale. Consensus was reached if ≥75% of the experts considered the factor either extremely or moderately important. Results In Round 1, 120 confounders were proposed, which were synthesized into 38 distinct factors. In Round 2, 33 confounders met the criterion to be considered important. In Round 3, consensus was reached for 14 confounders: acute illness/trauma, immune disease, medication use, endocrine, nutritional, or metabolic disease, other musculoskeletal conditions, age, handling of blood samples, sex, cancer, body composition, pregnancy, cardiovascular disease, physical activity, and pain characteristics. Conclusions These findings provide insight in the complexity of the association between low-grade systemic inflammation and musculoskeletal pain. Some factors currently listed as confounders may be re-classified as moderators or mediators as insights progress.

IntroductionJoint mobilisation and manipulation often results in immediate pain relief in people with neck pain. However, the biological mechanisms behind pain relief are largely unknown. There is preliminary evidence that joint mobilisation and manipulation lessens the upregulated neuroimmune responses in people with persistent neck pain.Methods and analysisThis study protocol describes a randomised placebo-controlled trial to investigate whether joint mobilisation and manipulation influence neuroimmune responses in people with persistent neck pain. People with persistent neck pain (N=100) will be allocated, in a randomised and concealed manner, to the experimental or control group (ratio 3:1). Short-term (ie, baseline, immediately after and 2 hours after the intervention) neuroimmune responses will be assessed, such as inflammatory marker concentration following in vitro stimulation of whole blood cells, systemic inflammatory marker concentrations directly from blood samples, phenotypic analysis of peripheral blood mononuclear cells and serum cortisol. Participants assigned to the experimental group (N=75) will receive cervical mobilisations targeting the painful and/or restricted cervical segments and a distraction manipulation of the cervicothoracic junction. Participants assigned to the control group (N=25) will receive a placebo mobilisation and placebo manipulation. Using linear mixed models, the short-term neuroimmune responses will be compared (1) between people in the experimental and control group and (2) within the experimental group, between people who experience a good outcome and those with a poor outcome. Furthermore, the association between the short-term neuroimmune responses and pain relief following joint mobilisation and manipulation will be tested in the experimental group.Ethics and disseminationThis trial is approved by the Medical Ethics Committee of Amsterdam University Medical Centre, location VUmc (Approval number: 2018.181).Trial registration numberNL6575 (trialregister.nl

Neuroimmune responses remain understudied in people with neck pain. This study aimed to (1) compare a broad range of systemic neuroimmune responses in people with non-specific neck pain (N = 112), cervical radiculopathy (N = 25), and healthy participants (N = 23); and (2) explore their associations with clinical, psychological and lifestyle factors. Quantification of systemic neuroimmune responses involved ex vivo serum and in vitro evoked-release levels of inflammatory markers, and characterization of white blood cell phenotypes. Inflammatory indices were calculated to obtain a measure of total immune status and were considered the main outcomes. Differences between groups were tested using analyses of covariance (ANCOVA) and multivariable regression models. Compared to healthy participants, the ex vivo pro-inflammatory index was increased in people with non-specific neck pain (β = 0.70, p = 0.004) and people with cervical radiculopathy (β = 0.64, p = 0.04). There was no difference between non-specific neck pain and cervical radiculopathy (β = 0.23, p = 0.36). Compared to non-specific neck pain, people with cervical radiculopathy showed lower numbers of monocytes (β = −59, p = 0.01). There were no differences between groups following in vitro whole blood stimulation (p ≥ 0.23) or other differences in the number and phenotype of white blood cells (p ≥ 0.07). The elevated ex vivo neuroimmune responses in people with non-specific neck pain and radiculopathy support the contention that these conditions encompass inflammatory components that can be measured systemically. There were multiple significant associations with clinical, psychological and lifestyle factors, such as pain intensity (β = 0.25) and anxiety (β = 0.23) in non-specific neck pain, visceral adipose tissue (β = 0.43) and magnification (β = 0.59) in cervical radiculopathy, and smoking (β = 0.59) and visceral adipose tissue (β = 0.52) in healthy participants. These associations were modified by sex, indicating different neuroimmune associations for females and males.

Supplemental Digital Content is Available in the Text. There is evidence that joint and nerve mobilisations compared with sham or no intervention positively influence various neuroimmune responses in animal and human neuromusculoskeletal conditions., Several animal and human studies revealed that joint and nerve mobilisations positively influence neuroimmune responses in neuromusculoskeletal conditions. However, no systematic review and meta-analysis has been performed. Therefore, this study aimed to synthesize the effects of joint and nerve mobilisation compared with sham or no intervention on neuroimmune responses in animals and humans with neuromusculoskeletal conditions. Four electronic databases were searched for controlled trials. Two reviewers independently selected studies, extracted data, assessed the risk of bias, and graded the certainty of the evidence. Where possible, meta-analyses using random effects models were used to pool the results. Preliminary evidence from 13 animal studies report neuroimmune responses after joint and nerve mobilisations. In neuropathic pain models, meta-analysis revealed decreased spinal cord levels of glial fibrillary acidic protein, dorsal root ganglion levels of interleukin-1β, number of dorsal root ganglion nonneuronal cells, and increased spinal cord interleukin-10 levels. The 5 included human studies showed mixed effects of spinal manipulation on salivary/serum cortisol levels in people with spinal pain, and no significant effects on serum β-endorphin or interleukin-1β levels in people with spinal pain. There is evidence that joint and nerve mobilisations positively influence various neuroimmune responses. However, as most findings are based on single studies, the certainty of the evidence is low to very low. Further studies are needed.

We wholeheartedly agree with Klyne and Hodges [1] who emphasized in response to our Perspective [2] that the association between systemic inflammation and musculoskeletal pain is complex. In our Perspective, we called for a prudent interpretation of the literature because multiple confounders influence the association between low-grade systemic inflammation and musculoskeletal pain. A recent systematic review reiterated our viewpoint (“The potential role of confounding factors on the association between (pro)inflammatory biomarkers and nonspecific low back pain needs to be better controlled for and/or evaluated in future research”) [3]. Furthermore, we proposed to create a core set of potentially important confounders to assist researchers with their selection of factors. This was also echoed by the authors of another recent systematic review who “did not find relevant information in the literature to decide a-priori which confounders would be the most relevant in this field” [4]. Although we focussed on confounders in our Perspective, Klyne and Hodges [1] appropriately expanded on the topic and highlighted the distinction between confounders and mediators in their Letter-to-the-Editor.