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Article ; Online: Neuroimmune responses following joint mobilisation and manipulation in people with persistent neck pain: a protocol for a randomised placebo-controlled trial.

Lutke Schipholt, Ivo J / Scholten-Peeters, Gwendolyne / Bontkes, Hetty / Coppieters, Michel W

2022 Volume 12, Issue 3, Page(s) e055748

Abstract: Introduction: Joint 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 ... ...

Abstract	Introduction: Joint 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 analysis: This 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 dissemination: This trial is approved by the Medical Ethics Committee of Amsterdam University Medical Centre, location VUmc (Approval number: 2018.181). Trial registration number: NL6575 (trialregister.nl.
MeSH term(s)	Humans ; Leukocytes, Mononuclear ; Neck ; Neck Pain/therapy ; Physical Therapy Modalities ; Randomized Controlled Trials as Topic ; Treatment Outcome
Language	English
Publishing date	2022-03-08
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2021-055748
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Article ; Online: Immediate systemic neuroimmune responses following spinal mobilisation and manipulation in people with non-specific neck pain: a randomised placebo-controlled trial.

Lutke Schipholt, Ivo J / Coppieters, Michel W / Reijm, Martine / Bontkes, Hetty J / Scholten-Peeters, Gwendolyne G M

Scientific reports

2023 Volume 13, Issue 1, Page(s) 12804

Abstract: Spinal mobilisation/manipulation is a common intervention for spinal pain, yet the working mechanisms are largely unknown. A randomised placebo-controlled trial was conducted to (1) compare the immediate neuroimmune responses following spinal ... ...

Abstract	Spinal mobilisation/manipulation is a common intervention for spinal pain, yet the working mechanisms are largely unknown. A randomised placebo-controlled trial was conducted to (1) compare the immediate neuroimmune responses following spinal mobilisation/manipulation and placebo spinal mobilisation/manipulation; (2) compare the immediate neuroimmune responses of those with a good outcome with those of a poor outcome following spinal mobilisation/manipulation; and (3) explore the association between neuroimmune responses and pain reduction. One hundred patients were randomly allocated to spinal mobilisation/manipulation or a placebo mobilisation/manipulation. Primary outcomes were whole blood in-vitro evoked released concentrations of IL-1β and TNF-α measured 10 min and 2 h after the intervention. Immediate effects were studied because successful mobilisation/manipulation is often associated with immediate pain reduction, and immediate neuroimmune responses are less affected by potential confounders than long-term responses. Secondary outcomes included multiple systemic inflammatory marker concentrations, phenotypic analysis of white blood cells and clinical outcomes. Outcomes were compared between the experimental and placebo group, and between people with a good and poor outcome in the experimental group. Estimates of intervention effects were based on intention-to-treat analyses, by using linear mixed-effect models. Although there was a substantial difference in pain reduction between groups (mean (SD) difference visual analogue scale: 30 (21) mm at 10 min and 32 (21) mm at 2 h (p < 0.001) in favour of mobilisation/manipulation, there were no differences in primary outcomes between groups or between people with a good and poor outcome (p ≥ 0.10). In conclusion, possible neuroimmune responses following spinal mobilisations/manipulation cannot be identified at a systemic level. Future research may focus on longer treatment duration and more localised neuroimmune responses.
MeSH term(s)	Humans ; Neck Pain/therapy ; Neck ; Manipulation, Spinal ; Duration of Therapy
Language	English
Publishing date	2023-08-07
Publishing country	England
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-39839-3
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Article ; Online: Systemic Inflammation, Sleep, and Psychological Factors Determine Recovery Trajectories for People With Neck Pain: An Exploratory Study.

Lutke Schipholt, Ivo J / Coppieters, Michel W / Diepens, Maaike / Hoekstra, Trynke / Ostelo, Raymond W J G / Barbe, Mary F / Meijer, Onno G / Bontkes, Hetty J / Scholten-Peeters, Gwendolyne G M

The journal of pain

2024

Abstract: We conducted an explorative prospective cohort study with 6 months follow-up to 1) identify different pain and disability trajectories following an episode of acute neck pain, and 2) assess whether neuroimmune/endocrine, psychological, behavioral, ... ...

Abstract	We conducted an explorative prospective cohort study with 6 months follow-up to 1) identify different pain and disability trajectories following an episode of acute neck pain, and 2) assess whether neuroimmune/endocrine, psychological, behavioral, nociceptive processing, clinical outcome, demographic and management-related factors differ between these trajectories. Fifty people with acute neck pain (ie, within 2 weeks of onset) were included. At baseline, and at 2, 4, 6, 12, and 26 weeks follow-up, various neuroimmune/endocrine (eg, inflammatory cytokines and endocrine factors), psychological (eg, stress symptoms), behavioral (eg, sleep disturbances), nociceptive processing (eg, condition pain modulation), clinical outcome (eg, trauma), demographic factors (eg, age), and management-related factors (eg, treatment received) were assessed. Latent class models were performed to identify outcome trajectories for neck pain and disability. Linear mixed models or the Pearson chi-square test were used to evaluate differences in these factors between the trajectories at baseline and at each follow-up assessment and over the entire 6 months period. For pain, 3 trajectories were identified. The majority of patients were assigned to the "Moderate pain - Favourable recovery" trajectory (n = 25; 50%) with smaller proportions assigned to the "Severe pain - Favourable recovery" (n = 16; 32%) and the "Severe pain - Unfavourable recovery" (n = 9; 18%) trajectories. For disability, 2 trajectories were identified: "Mild disability - Favourable recovery" (n = 43; 82%) and "Severe disability - Unfavourable recovery" (n = 7; 18%). Ongoing systemic inflammation (increased high-sensitive C-reactive protein), sleep disturbances, and elevated psychological factors (such as depression, stress and anxiety symptoms) were mainly present in the unfavorable outcome trajectories compared to the favorable outcome trajectories. PERSPECTIVE: Using exploratory analyses, different recovery trajectories for acute neck pain were identified based on disability and pain intensity. These trajectories were influenced by systemic inflammation, sleep disturbances, and psychological factors.
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2018789-0
ISSN	1528-8447 ; 1526-5900
ISSN (online)	1528-8447
ISSN	1526-5900
DOI	10.1016/j.jpain.2024.02.010
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Article ; Online: Identifying the Most Important Confounders When Assessing the Association Between Low-Grade Systemic Inflammation and Musculoskeletal Pain: A Modified Delphi Study.

Koop, Meghan A / Lutke Schipholt, Ivo J / Scholten-Peeters, Gwendolyne G M / Coppieters, Michel W

Pain medicine (Malden, Mass.)

2021 Volume 22, Issue 11, Page(s) 2661–2669

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Consensus ; Delphi Technique ; Humans ; Inflammation ; Musculoskeletal Pain/diagnosis ; Musculoskeletal Pain/epidemiology
Language	English
Publishing date	2021-08-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2015903-1
ISSN	1526-4637 ; 1526-2375
ISSN (online)	1526-4637
ISSN	1526-2375
DOI	10.1093/pm/pnab243
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Article: Systemic neuroimmune responses in people with non-specific neck pain and cervical radiculopathy, and associations with clinical, psychological, and lifestyle factors.

Lutke Schipholt, Ivo J / Scholten-Peeters, Gwendolyne G M / Koop, Meghan A / Bonnet, Petra / Bontkes, Hetty J / Coppieters, Michel W

Frontiers in molecular neuroscience

2022 Volume 15, Page(s) 1003821

Abstract: 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 ( ...

Abstract	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 (
Language	English
Publishing date	2022-10-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2022.1003821
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Article ; Online: The potential protective effects of pre-injury exercise on neuroimmune responses following experimentally-induced traumatic neuropathy: a systematic review with meta-analysis.

Koop, Meghan A / Sleijser-Koehorst, Marije L S / Hooijmans, Carlijn R / Tdlohreg, Paul Q / Lutke Schipholt, Ivo J / Scholten-Peeters, Gwendolyne G M / Coppieters, Michel W

Frontiers in immunology

2023 Volume 14, Page(s) 1215566

Abstract: 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 ... ...

Abstract	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-1β (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.
MeSH term(s)	Animals ; Hyperalgesia ; Exercise ; Neuralgia/etiology
Language	English
Publishing date	2023-09-11
Publishing country	Switzerland
Document type	Meta-Analysis ; Systematic Review ; Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1215566
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Article ; Online: The effects of aerobic exercise on neuroimmune responses in animals with traumatic peripheral nerve injury: a systematic review with meta-analyses.

Sleijser-Koehorst, Marije L S / Koop, Meghan A / Coppieters, Michel W / Lutke Schipholt, Ivo J / Radisic, Nemanja / Hooijmans, Carlijn R / Scholten-Peeters, Gwendolyne G M

Journal of neuroinflammation

2023 Volume 20, Issue 1, Page(s) 104

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Nerve Growth Factor/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Peripheral Nerve Injuries/metabolism ; Spinal Cord Dorsal Horn/metabolism ; Exercise ; RNA, Messenger/metabolism
Chemical Substances	Brain-Derived Neurotrophic Factor ; Nerve Growth Factor (9061-61-4) ; Tumor Necrosis Factor-alpha ; RNA, Messenger
Language	English
Publishing date	2023-05-03
Publishing country	England
Document type	Meta-Analysis ; Journal Article ; Review ; Systematic Review
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-023-02777-y
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Article ; Online: Effects of joint and nerve mobilisation on neuroimmune responses in animals and humans with neuromusculoskeletal conditions: a systematic review and meta-analysis.

Lutke Schipholt, Ivo J / Coppieters, Michel W / Meijer, Onno G / Tompra, Nefeli / de Vries, Rob B M / Scholten-Peeters, Gwendolyne G M

Pain reports

2021 Volume 6, Issue 2, Page(s) e927

Abstract: 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 ...

Abstract	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.
Language	English
Publishing date	2021-06-03
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2471-2531
ISSN (online)	2471-2531
DOI	10.1097/PR9.0000000000000927
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Article ; Online: Authors' Reply: Confounding and mediation to reveal the true association between systemic inflammation and musculoskeletal pain.

Lutke Schipholt, Ivo J / Scholten-Peeters, Gwendolyne G M / Bontkes, Hettie J / Coppieters, Michel W

The spine journal : official journal of the North American Spine Society

2019 Volume 19, Issue 11, Page(s) 1901

Language	English
Publishing date	2019-10-30
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	2037072-6
ISSN	1878-1632 ; 1529-9430
ISSN (online)	1878-1632
ISSN	1529-9430
DOI	10.1016/j.spinee.2019.06.013
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