The potential protective effects of pre-injury exercise on neuroimmune responses following experimentally-induced traumatic neuropathy: a systematic review with meta-analysis.

Pre-clinical evidence shows that neuropathy is associated with complex neuroimmune responses, which in turn are associated with increased intensity and persistence of neuropathic pain. Routine exercise has the potential to mitigate complications of future nerve damage and persistence of pain through neuroimmune regulation. This systematic review aimed to explore the effect of pre-injury exercise on neuroimmune responses, and other physiological and behavioural reactions following peripheral neuropathy in animals. Three electronic databases were searched from inception to July 2022. All controlled animal studies assessing the influence of an active exercise program prior to experimentally-induced traumatic peripheral neuropathy compared to a non-exercise control group on neuroimmune, physiological and behavioural outcomes were selected. The search identified 17,431 records. After screening, 11 articles were included. Meta-analyses showed that pre-injury exercise significantly reduced levels of IL-1ß (SMD: -1.06, 95% CI: -1.99 to -0.13, n=40), but not iNOS (SMD: -0.71 95% CI: -1.66 to 0.25, n=82). From 72 comparisons of different neuroimmune outcomes at different anatomical locations, vote counting revealed reductions in 23 pro-inflammatory and increases in 6 anti-inflammatory neuroimmune outcomes. For physiological outcomes, meta-analyses revealed that pre-injury exercise improved one out of six nerve morphometric related outcomes (G-ratio; SMD: 1.95, 95%CI: 0.77 to 3.12, n=20) and one out of two muscle morphometric outcomes (muscle fibre cross-sectional area; SMD: 0.91, 95%CI: 0.27 to 1.54, n=48). For behavioural outcomes, mechanical allodynia was significantly less in the pre-injury exercise group (SMD -1.24, 95%CI: -1.87 to -0.61) whereas no overall effect was seen for sciatic function index. Post hoc subgroup analysis suggests that timing of outcome measurement may influence the effect of pre-injury exercise on mechanical allodynia. Risk of bias was unclear in most studies, as the design and conduct of the included experiments were poorly reported. Preventative exercise may have potential neuroprotective and immunoregulatory effects limiting the sequalae of nerve injury, but more research in this field is urgently needed.

Is there a geographic and gender divide in Europe regarding the biopsychosocial approach to pain research? An evaluation of the 12th EFIC congress.

OBJECTIVES: All pain research combined advances the different domains of the biopsychosocial model and its interactions. However, there may be discrepancies between individual countries in their biomedical, psychological or social focus to pain research. As a proxy for this possible discrepancy, we analysed the biopsychosocial orientation of presentations at a recent major international pain conference. METHODS: The primary aim was to investigate whether there are geographical differences across Europe regarding the biopsychosocial orientation of workshop presentations at the 12th EFIC congress. The secondary aim was to investigate whether there were differences between female and male presenters regarding the biopsychosocial focus of their presentations. All available workshop abstracts were blinded and categorised by two independent reviewers as biomedical, psychosocial, biopsychosocial, or not applicable. Psychosocial and biopsychosocial were merged to non-biomedical. RESULTS: Of the 140 available abstracts, 126 abstracts could be categorised (biomedical: 51 %; non-biomedical: 49 %). Three clusters of countries emerged: (1) countries with a clear majority (≥80 %) of non-biomedical presentations (The Netherlands and Belgium); (2) countries with a balance between biomedical and non-biomedical presentations (United Kingdom, Denmark, Norway, Sweden and Finland); and (3) countries with a clear majority (71-100 %) of biomedical presentations (Italy, Germany, Switzerland and France). Overall, women delivered more presentations than men (70 vs. 56 presentations), and delivered proportionally more non-biomedical presentations (57 %) whereas men delivered proportionally more biomedical presentations (61 %). CONCLUSIONS: Analysis of the 12th EFIC congress revealed geographical and gender differences in biopsychosocial orientation. Whether this reflects established differences in pain research requires further investigation.

The effects of aerobic exercise on neuroimmune responses in animals with traumatic peripheral nerve injury: a systematic review with meta-analyses.

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 < 0.001) and Growth Associated Protein 43 (GAP43) (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 < 0.05) levels were lower; (3) in the spinal cord, BDNF levels (p = 0.006) were lower; at the dorsal horn, microglia (p < 0.001) and astrocyte (p = 0.005) marker levels were lower; at the ventral horn, astrocyte marker levels (p < 0.001) were higher, and several outcomes related to synaptic stripping were favorably altered; (4) brainstem 5-HT2A receptor levels were higher (p = 0.001); (5) in muscles, BDNF levels (p < 0.001) were higher and TNF-α levels lower (p < 0.05); (6) no significant differences were found for systemic neuroimmune responses in blood or serum. 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.

Systemic neuroimmune responses in people with non-specific neck pain and cervical radiculopathy, and associations with clinical, psychological, and lifestyle factors.

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 (ß = 0.70, p = 0.004) and people with cervical radiculopathy (ß = 0.64, p = 0.04). There was no difference between non-specific neck pain and cervical radiculopathy (ß = 0.23, p = 0.36). Compared to non-specific neck pain, people with cervical radiculopathy showed lower numbers of monocytes (ß = -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 (ß = 0.25) and anxiety (ß = 0.23) in non-specific neck pain, visceral adipose tissue (ß = 0.43) and magnification (ß = 0.59) in cervical radiculopathy, and smoking (ß = 0.59) and visceral adipose tissue (ß = 0.52) in healthy participants. These associations were modified by sex, indicating different neuroimmune associations for females and males.

Identifying the Most Important Confounders When Assessing the Association Between Low-Grade Systemic Inflammation and Musculoskeletal Pain: A Modified Delphi Study.

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.