No Consistent Evidence For The Anti-Inflammatory Effect of Vagus Nerve Stimulation in Humans - A Systematic Review and Meta-Analysis

Brain, Behavior, and Immunity 116 (2024) 237–258
Contents lists available at ScienceDirect
Brain Behavior and Immunity

journal homepage: www.elsevier.com/locate/ybrbi
No consistent evidence for the anti-inflammatory effect of vagus nerve

stimulation in humans: A systematic review and meta-analysis
Carmen Schiweck a, 1, Sonja Sausmekat a, 1, Tong Zhao a, Leona Jacobsen a, Andreas Reif a,
Sharmili Edwin Thanarajah a, b, *
a
Department of Psychiatry, Psychotherapy and Psychosomatics, Goethe University Frankfurt, Germany
b
Max Planck Institute for Metabolism Research, Cologne, Germany
A R T I C L E I N F O A B S T R A C T
Keywords: Vagus nerve stimulation (VNS) has been identified as an innovative immunosuppressive treatment strategy in
Vagus Nerve Stimulation rodent studies. However, its’ clinical potential is still unclear. Therefore, we aimed to assess whether VNS can
Cholinergic Anti-inflammatory Pathway reduce inflammatory proteins and/or immune cells in humans, through a pre-registered systematic review and
Inflammation
meta-analysis according to PRISMA guidelines. The databases Cochrane, Pubmed and World of Knowledge were
Vagal
searched in duplicate up to the 3rd of March 2022 and publications from identified clinical trial registrations
Immune System
Cytokine were identified until 20th of August 2023. Studies were included if they provided peer-reviewed data for humans
Tumour necrosis factor who received VNS as short-term (<=1 day) or long-term (>=2 days-365 days) stimulation and reported at least
Interleukins one cytokine or immune cell after treatment. Screening of title, abstract, full text, and data extraction was
Inflammatory Reflex performed in duplicate by two independent reviewers. Data were pooled using a random-effects model and meta-
regression was performed for moderating factors. Reporting bias was assessed. The standardized mean difference
(Hedge’s g) was used to indicate overall differences of cytokine data (mean and standard deviation or median
and interquartile range at the study level) to test our a-priori hypothesis. The systematic review of 36 studies
with 1135 participants (355 receiving a control/sham condition and 780 receiving VNS) revealed anti-
inflammatory effects of VNS for cytokines in several reports, albeit often in subgroup analyses, but our meta-
analyses of 26 studies did not confirm these findings. Although most cytokines were numerically reduced, the
reduction did not reach statistical significance after VNS: not in the between-group comparisons (short-term:
TNF-α: g = − 0.21, p = 0.359; IL-6: g = − 0.94, p = 0.112; long-term: TNF-α: g = − 0.13, p = 0.196; IL-6: g =
− 0.67, p = 0.306); nor in the within-study designs (short-term: TNF-α: g = − 0.45, p = 0.630; IL-6: g = 0.28, p =
0.840; TNF-α: g = − 0.53, p = 0.297; IL-6:g = − 0.02, p = 0.954). Only the subgroup analysis of 4 long-term
studies with acute inflammation was significant: VNS decreased CRP significantly more than sham stimula
tion. Additional subgroup analyses including stimulation duration, stimulation method (invasive/non-invasive),
immune stimulation, and study quality did not alter results. However, heterogeneity was high, and most studies
had poor to fair quality. Given the low number of studies for each disease, a disease-specific analysis was not
possible. In conclusion, while numeric effects were reported in individual studies, the current evidence does not
substantiate the claim that VNS impacts inflammatory cytokines in humans. However, it may be beneficial
during acute inflammatory events. To assess its full potential, high-quality studies and technological advances
are required.
1. Introduction conditions. Therefore, maintaining a balance between pro- and anti-

inflammatory signalling is essential. In 2000, a key discovery revealed
Inflammation is vital in combating pathogens, eliminating damaged how the central nervous system regulates inflammatory responses via
tissue, and facilitating tissue repair. However, excess, or chronic the vagus nerve (VN) (Borovikova, 2000). Acetylcholine was shown to
inflammation contributes to the development of various pathological reduce cytokine production in human macrophages. In rodents,
* Corresponding author.
E-mail address: [email protected] (S. Edwin Thanarajah).
1
These authors contributed equally to this work. Shared first authorship.
https://doi.org/10.1016/j.bbi.2023.12.008
Received 11 September 2023; Received in revised form 17 November 2023; Accepted 4 December 2023
Available online 7 December 2023
0889-1591/© 2023 Elsevier Inc. All rights reserved.
C. Schiweck et al. Brain Behavior and Immunity 116 (2024) 237–258
inflammatory response to endotoxemia was amplified by vagotomy and for articles with no year restriction, or any filters set, until the 3rd of
attenuated by stimulation of distal vagal nerve endings, a mechanism March 2022. No restriction was set for journals. Clinical trial registra
since known as the cholinergic anti-inflammatory pathway (CAP) tions and references of eligible articles were also searched, and experts
(Tracey, 2002). were asked to identify literature. For clinical trial registrations, related
The CAP acts as a negative feedback loop. Detection of inflammatory publications were searched and included if all data was obtained before
proteins by afferent VN endings activates the nucleus of the solitary tract 20th of August 2023. Two articles published after the search was
(Andersson and Tracey, 2012). Consequently, acetylcholine release completed were included following recommendation during the peer
mediated by VN efferents suppresses cytokine release by immune cells review process.
(in particular, splenic macrophages). This anti-inflammatory effect re
quires sympathetic release of norepinephrine, which binds to ß2- 2.3. Search strategy
adrenergic receptors on choline acetyltransferase positive T cells (Rosas-
Ballina, 2011; Vida, 2011). The acetylcholine synthesized by these T Details on the search strategy, selection process, data collection
cells binds to alpha7 nicotinic receptor subunits on splenic macrophages process, extracted data items and risk of study bias assessment can be
and in turn, suppresses the release of cytokines such as tumor necrosis found in the supplementary information. In brief, all articles were
factor alpha (TNF-⍺) (see Alen, 2022; Kelly et al., 2022). screened for title and abstract. Subsequently the full text was assessed,
Translating these findings to humans has been hampered by the and data was extracted by at least two independent reviewers (all in
difficult accessibility of the nerve. Invasive vagus nerve stimulation duplicate) and reviewed by a senior author.
(iVNS), targeting the cervical VN via a surgically implanted electrode, is
FDA-approved for treatment-resistant depression and refractory epi 2.4. Selection process
lepsy, but its mechanism of action remains unclear. With emerging ev
idence linking inflammatory processes with these conditions, the anti- Articles were extracted in a merged literature library (Mendeley
inflammatory potential of iVNS has been investigated in implanted pa Reference Manager 2.77.0 © 2022 Mendeley Ltd) and reviewed in
tients, and clinical studies were performed in autoimmune diseases (e.g., duplicate and independently by two authors (SS and LJ/TZ) each for the
Crohn’s disease, rheumatoid arthritis (Bonaz, 2016; Sinniger, 2020; title screen, the abstract screen, and the full-text screen. Decisions on
Koopman, et al., 2016). Technical advances in non-invasive, trans full-text screenings were recorded independently and separately by each
cutaneous VNS (tVNS) targeting the vagal trunk in the neck or its sen author (merged table can be found in supplementary information 1).
sory branch in the cymba conchae of the ear have recently enabled The inclusion of articles was discussed by SS and TZ and all finally
investigations in a diverse range of inflammation-associated conditions included articles were discussed with CS and SET. In case of disagree
(Tornero, 2022; Badran, 2022). ment between SS and TZ in any of the steps, CS or SET were consulted for
Targeting the CAP via neuromodulation is an intriguing therapeutic a decision. If essential information to decide on inclusion or exclusion
option that is better tolerated, more specific, and has fewer side effects was missing, authors of articles were contacted by email, with one
than pharmacological manipulation with anticholinergics. However, to reminder.
date, the anti-inflammatory efficacy of VNS is still unclear. Although
several excellent narrative reviews and commentaries (Van Maanen 2.5. Data collection process
et al., 2009; Kelly et al., 2022), as well as a systematic review (Kwan,
2016) with a focus on rodent data concluded that VNS is a promising Data of full texts was extracted into tables, in duplicate and inde
anti-inflammatory approach, to the best of our knowledge, a systematic pendently by SS and TZ/LJ and additionally verified independently by
investigation of currently available human data is still lacking. To close either CS or SET. In case of disagreement, CS or SET were consulted. In
this gap, we performed a systematic review and meta-analysis and case of missing data, authors were contacted with the email address
investigated whether VNS can reduce inflammatory cytokines after both published for the corresponding author. In case of no reply and/or an
short and long stimulation, encompassing all available human data, invalid email address, authors were additionally contacted on research-
irrespective of study design and population. gate. If no response occurred, an additional reminder was sent.
2. Methods 2.6. Data items
This review was registered on PROSPERO [CRD42022308664]. Raw data was extracted when possible. For quantitative analyses (e.
g., meta-analyses) only data providing an estimate of the mean or me
2.1. Eligibility criteria dian and a measure of variance were included. Medians were converted
to means and standard deviations using the method proposed by Wan
Any study in languages spoken by the review team, which reported and colleagues (Wan et al., 2014). If subgroup data was reported, the
on circulating cytokines and/or immune cells in any disease/condition data was combined into one group. Data was not imputed. We opted for
after an intervention with VNS in humans was eligible. No participant two separate designs: one short-term analysis including studies with a
restrictions were set. Study designs could include clinical trials, case- short stimulation duration (i.e., <=1 day) and long-term designs with
control, cross-sectional and longitudinal studies in healthy subjects studies longer than one day. The following data was extracted: general
and subjects with any pathological condition across all age groups, study design (e.g., clinical trial, case-control design, or longitudinal
where ethical approval was obtained. No year restriction was set, and study); the study population, e.g., the diagnosis (if applicable), type of
studies had to be peer-reviewed articles with full texts published in condition (autoimmune/mental health/other). Disease duration (mean
English, German, French or Dutch. If studies did not report on cytokines/ in years) was rarely given and therefore not extracted. We also extracted
immune cells at the post-intervention time point or for within-group the type of intervention (invasive VNS (iVNS)/transcutaneous auricular
designs a pre- and post-value, or if they did not mention vagus nerve taVNS)/ transcutaneous cervical VNS (tcVNS)/other, specified), the
stimulation, they were not considered in the meta-analysis. Animal treatment duration: in days for long-term interventions, minutes for
studies were also excluded. short term interventions; the stimulation parameters: stimulation site
and side, current intensity (mA), pulse width (μs), frequency (Hz); the
2.2. Information sources type of placebo control (if applicable). Additionally, sample character
istics that were extracted included the number of participants, the mean
The databases Cochrane, Web of Science and Pubmed were searched age, sex, and the mean BMI. For the variables of interest (e.g., cytokines
238
immune cells) we included pre and post intervention concentrations 10 studies, given that these factors may yield different results due to
(mean or median and standard deviation/range). Moreover, we recor methodological differences. Additionally, we conducted a subgroup
ded if an immune cell stimulation with Lipopolysaccharide (LPS) was analysis only for studies with an acute inflammatory event.
performed.
2.10. Reporting bias and sensitivity analyses
2.7. Study risk of bias assessment
Publication bias was assessed with Egger’s test and Funnel plots,
The risk of bias was assessed by the quality assessment tools for influential case analysis using the leave-one-out method, and calculating
controlled intervention studies and pre-post studies with no control influence diagnostics following Viechtbauer & Cheung (Viechtbauer and
group provided by the NHLBI (https://www.nhlbi.nih.gov/health-topi Cheung, 2010) dmetar (v0.1.0) (Harrer et al., 2019).
cs/study-quality-assessment-tools). Study quality was scored for each
study independently by two authors (SS and TZ). Studies were graded as 3. Results
poor, fair or good based on each 12, respectively 14 quality criteria by SS
and TZ and confirmed by either CS or SET. Criteria considered for After duplicate removal 1076 studies were screened for eligibility
controlled trials included randomization, treatment allocation, blinding, (title/abstract). In the full text screen, 42 studies were excluded with
group similarities at baseline, low drop-out rates, high adherence, sim reason (Supplementary Table 1), yielding 36 eligible studies (Koop
ilarity or avoidance of background treatments, good outcome assess man, et al., 2016; D’Haens, 2023; Bonaz, 2016; Andreas, 2019; Tarn
ment, sufficient sample size, subgroup analysis, and if all randomized et al., 2019; Aranow, 2021; Corrêa, 2022; Seitz, 2022; Brock, 2021;
participants were analyzed in the group to which they were originally Chaudhry, 2019; Mion, 2020; De Herdt, 2009; Salama et al., 2020;
assigned. The quality criteria for studies without a control group covered Aalbers, 2012; Boström, 2019; Stavrakis, et al., 2017; Corcoran et al.,
a clearly formulated study question and eligibility criteria, if the study 2005; Bremner, 2020; Wu, 2023; Addorisio, et al., 2019; Brock et al.,
participants were representative of the group of interest, and if all 2017; Barone, et al., 2007; Veiz, 2022; Stavrakis, et al., 2015; Zhou,
eligible participants were enrolled. Moreover, it was verified if the 2022; Merchant et al., 2022; Drewes et al., 2021; Kox, 2015; Baro et al.,
treatment was clearly described and applied consistently across the 2022; Sinniger, 2020; Stavrakis, 2020; Majoie et al., 2010; de Moraes,
study. Additional criteria included outcome measures, blinding of 2023; Tornero, 2022; Lerman, 2016; Stakenborg, 2017) with 1135
evaluators, low loss to follow-up, and statistical methods. For the risk of participants (355 receiving a control condition and 780 receiving VNS)
bias ratings, studies were deemed as poor, fair or good based on two for the systematic review and 27 studies for the meta-analysis (See
independent reviewer’s ratings, who both followed the guidance for Fig. 1). Six studies were used in the between-group short-term analysis
quality ratings provided by the NHLBI. If inconsistent ratings were ob (Addorisio, et al., 2019; Kox, 2015; Stavrakis, et al., 2017; Veiz, 2022;
tained, a third reviewer (CS or SET) made the decision. The tools do not Zhou, 2022; Stavrakis, et al., 2015), 7 for the within-group short-term
provide a list with items which adds up to a score, but rather provide analysis (Addorisio, et al., 2019; Kox, 2015; Stavrakis, et al., 2017; Veiz,
guidance for reviewer’s to critically appraise and consider nuances of 2022; Zhou, 2022; Stavrakis, et al., 2015; Brock et al., 2017; Drewes
study designs. et al., 2021; Brock, 2021), 8 in the between-group long-term analyses
(Stavrakis, et al., 2017; Aalbers, 2012; Bremner, 2020; Chaudhry, 2019;
2.8. Statistical analysis Salama et al., 2020; Stavrakis, 2020; Corrêa, 2022) and 20 studies for
the within-group long-term analysis (Sinniger, 2020; D’Haens, 2023;
Where appropriate control groups were present, between-group an Addorisio, et al., 2019; Stavrakis, et al., 2017; Brock et al., 2017; Drewes
alyses were conducted for 1) short (<=1 day) and 2) long-term (>=2 et al., 2021; Bremner, 2020; Salama et al., 2020; Stavrakis, 2020;
day) stimulation designs; additionally, within-group analyses were Corrêa, 2022; Baro et al., 2022; Barone, et al., 2007; Boström, 2019;
conducted including studies without appropriate control group. Within- Chaudhry et al., 2015; Corcoran et al., 2005; De Herdt, 2009; Koopman,
group analyses included pre-post values of analyses 1) or 2). Meta- et al., 2016; Majoie et al., 2010; Merchant et al., 2022; Mion, 2020; Wu,
analyses were performed for cytokines reported in minimally 5 2023).
studies. Additionally, we conducted a subgroup analysis only for studies
with an acute inflammatory event. Here, the lower threshold of at least 5 3.1. Study characteristics
studies to perform a meta-analysis was disregarded due to the limited
availability of appropriate studies. Most studies were conducted in adults (>90 %), open-label (>60 %)
and around 50 % were performed without a control condition. Eleven
2.9. Effect measures and synthesis studies used iVNS (of which 3 as double-blind randomized controlled
trial (DB-RCT)), 25 used tVNS (10 as DB-RCT). Sample sizes were low
For between-group analyses, the standardized mean differences be ranging from 5 (Baro et al., 2022) to 62 (Wu, 2023) per condition. Study
tween groups (VNS vs. sham) post-treatment was computed (Hedge’s g). characteristics are summarized in Supplementary Table 2; cytokine
For within-group analyses, Hedge’s g was derived from the difference data in Table 1.
between pre (t1) and post-treatment (t2). Here, the standard deviation
at t1 was used for standardization, with an assumed pre-post correlation 3.2. Qualitative synthesis
coefficient of 0.7 (if no correlation was retrieved). Statistical analyses
were performed in R v4.3.1. (R Core Team. R: A, 2023), following the In short-term studies, there were various populations, amongst
guide for R (Harrer et al., 2021). The esc (v0.5.1) (Lüdecke et al., 2019) which healthy controls (Addorisio, et al., 2019; Kox, 2015; Veiz, 2022),
and meta (v6.5.0) (Balduzzi et al., 2019) packages were used for participants undergoing surgery (Zhou, 2022; Salama et al., 2020),
random-effects meta-analyses, metafor (v4.2–0) (Viechtbauer, 2010) for rheumatoid arthritis (Addorisio, et al., 2019) and patients with parox
additional visualizations and comparison. The inverse variance method ysmal atrial fibrillation (Stavrakis, et al., 2015). Brief (i.e., 2 min- 60 min
with restricted maximum likelihood estimator as a between-study (Addorisio, et al., 2019; Kox, 2015; Veiz, 2022; Stavrakis, et al., 2015)
(heterogeneity) variance estimator, and Hartung-Knapp adjustment and intermediate stimulation protocols (e.g., >60 min-24 h (Zhou, 2022;
was applied. The Q-Profile method for confidence interval estimation of Salama et al., 2020) were applied. While some studies reported strong
τ2 and τ was used. Subgroup analyses/meta-regression was performed suppression of IL-6 or TNF-α at various timepoints or in subgroups (e.g.,
for treatment modality (tVNS or iVNS), LPS stimulation (yes/no), in a healthy population (Addorisio, et al., 2019); 2 h after ex-vivo LPS
stimulation duration and study quality, for cytokines reported in at least stimulation (Kox, 2015), in the femoral vein (Stavrakis, et al., 2017), 1-
239
Fig. 1. PRISM FLOW Diagram. The diagram depicts the results of the systematic review. Reasons for exclusion were defined as follows: 1: findings from animal
data, 2: no original research data, 3: no ethical approval, 4: studies that doń t fit the following criteria: case-control, cross-sectional and longitudinal studies, 5:
unpublished, 6: Protocol (without study data), 7: studies that doń t investigate the effect of VNS on circulating inflammatory markers in a pre-post design, 8:
Retracted Article.
day post-surgery (Salama et al., 2020)), the same or other studies re Mion, 2020; Aranow, 2021; Tarn et al., 2019). The total stimulation
ported no change or even increased levels of cytokines (e.g., (Veiz, 2022) duration varied largely (3 days-1 year). Elevated inflammatory param
for other subgroups or timepoints. To illustrate, while Stavrakis et al eters were mostly not a requirement for inclusion and the change of
(Stavrakis, et al., 2017) did find significant reductions under tVNS in inflammation was usually not the primary outcome. Open-label designs
blood taken from the femoral vein, no change was observed in blood were common (15/26). Due to the small sample sizes, some studies re
from the coronary sinus. The authors interpreted their results as evi ported modulatory effects of VNS on the single subject level, or in
dence for activation of the CAIP rather than a local suppression, given clinically defined subgroups, and found significant differences for cy
that cytokines were suppressed in the femoral vein (i.e., systemically) tokines (Drewes et al, 2021; Brock, 2021; De Herdt, 2009; Koopman,
and not in the coronary sinus (i.e., locally). et al., 2016; Majoie et al., 2010; Merchant et al., 2022); these changes
The 26 long-term intervention studies with small sample sizes (5–50 were however not evident across the whole sample. With a few excep
per group) included patient samples with a long medical history and tions, the change of single cytokines was not associated with improve
often, treatment resistance (Bonaz, 2016; Aalbers, 2012; Chaudhry, ment in clinical symptoms. In 7 studies VNS was performed before or
2019; Baro et al., 2022; Barone, et al., 2007; Boström, 2019; Corcoran immediately after the onset of an event that induced an inflammatory
et al., 2005; De Herdt, 2009; Majoie et al., 2010; Merchant et al., 2022; response (surgery (Stavrakis, et al., 2017; Salama et al., 2020; Andreas,
240
C. Schiweck et al.
Table 1
Qualitative synthesis of inflammatory parameters in identified studies. p value codes: <0.05*; <0.01**; <0.001:***, Abbreviations: d:day; ns: no significant change in concentrations (p ≥ 0.05), nr: not reported, na: not
applicable, IL: Interleukin; CRP: C-reactive Protein; TNF: tumor necrosis factor; LOD: level of detection; LPS: lipopolysaccharide, PBMCs: peripheral blood mononuclear cells, RA = Rheumatoid Arthritis; PSA: Psoriasis
Arthritis; sd = standard deviation; sub p = substance p;DAS-28: Disease Acitivity Score for Rheumatoid Arthiritis (<3.2 low activity, 3.2–5.1 moderate activity, >5.1 high activity) ASDAS:Ankylosing Spondylitis Disease
Acitivity Score, Quality: As assessed with the Quality Rating Scheme for Studies and Other Evidence (modified from the Oxford Centre for Evidence-based Medicine for ratings of individual studies): 1:Properly powered
and conducted randomized clinical trial; systematic review with meta-analysis; 2: Well-designed controlled trial without randomization; prospective comparative cohort trial; 3:Case-control studies; retrospective cohort
study; 4: Case series with or without intervention; cross-sectional study;5:Opinion of respected authorities; case reports. All cytokine concentrations are given in pg/mL, CRP was measured in mg/L.
Short
Stimulation
Duration
First author, Intervention Diagnosis LPS TNF-α, mean IL6, mean ± Direction and Comment/Special Design Comment Quality*
year ± sd or sd or median significance /Inflammatory
median (range) in for VNS status, Disease
(range) in pg/mL condition Severity at baseline
pg/mL and after
intervention
sham VNS sham VNS between (VNS within (pre-post)

vs sham)
Addorisio, tVNS Healthy yes pre: 4796 ± pre: 4541 ± pre: 6137 ± pre: 5979 ± nr TNF-α ↓ *; IL-6 Whole blood, LPS induced No elevation of 1
et al., (ex 607; 624; 369; 480; ↓**; IL-1β ↓*** stimulation ex vivo. inflammatory
2019 vivo) post:4477 ± post:3625 ± post:5577 ± post:4342 Significant reduction pre- parameters reported
653 645 401 ± 597 post tVNS (up to 80 %) but at baseline.
not in sham condition
Addorisio, tVNS Rheumatoid yes nr nr nr nr nr CRP ↓ * Whole blood, LPS induced Inclusion of patients 4
et al., Arthritis (ex stimulation ex vivo. In RA, with moderate to
2019 vivo) CRP levels significantly severe disease
241
reduced 2 ds post activity defined by

treatment; returned to DAS-28(>3.2).
baseline after 7 ds. Clinical Disease severity
improvement observed improved after 7
until d7. Clinical disease days of tVNS.
activity was reduced by
34–51 %
Brock et al., tVNS Healthy no na pre:1.95 ± nr nr na TNF-α ↓* (p = Reduction of TNF-α was No elevation of 4
2017 0.4; post:1.8 0.01); IL-10 = ns; significant at 24 h; no other inflammatory
± 0.6 IL-8 = ns; IL-4 = within-group differences parameters reported
ns; IFN-γ = ns for cytokines; increase in at baseline.
cardiac vagal tone and
slowing of heart rate
Brain Behavior and Immunity 116 (2024) 237–258

Brock, 2021 tVNS Psoriatic no na pre:1.5489 ± nr nr na PsA: TNF-α ↑ (d 5, In PsA and AS: decreased Disease severity was 4
arthritis (PsA) 0.7682; p = 0.005); heart rate with tVNS; not defined as
ankylosing post:1.5751 CRP↓** (p = In PsA: 20 % reduction in inclusion criteria.
spondylitis (AS) ± 0.7706 0.004); AS: IL10↓* CRP with tVNS; Mean DAS-28 PsA
(d 2,p = 0.02); IL- In AS: reduction in 2.54, Mean DAS-28
8 ↓* (d 2,p = interferon-γ, interleukin- AS 1.78
0.02); IFN-γ↓* (d (IL-) 8, and 10; but not
2,p = 0.02) CRP. Clinical composite Disease activity
score DAS28-CRP was (DAS-28) did not
unchanged in both. change with tVNS in
both groups. In PsA
ASDS decreased from
baseline to day 5.
(continued on next page)
C. Schiweck et al.
Table 1 (continued )
Short
Stimulation
Duration
pg/mL and after
intervention

vs sham)
Drewes tVNS Rheumatoid no na pre: 9.95 ± na pre:5.8 ± na TNF-α = ns; IL-6 In high disease activity Inclusion based on 4
et al., arthritis 19.3106; 14.4323; = ns; IL-8 = ns; IL- group, reductions in disease severity.
2021 post:10.3 ± post:3.05 ± 12 = ns; subgroup DAS28-CRP, CRP, and IFN-
19.7858 4.6890 1: CRP↓ (p = γ; low disease activity High-disease activity
0.02); IFN-γ↓* (p group: no difference for group (DAS-28 >
= 0.02); IL-10 = DAS28-CRP, decrease in 3.2): clinical
ns; subgroup2: IL- cardiac vagal tone and improvement
10↓ * (p = 0.02); reduction in IL-10; Overall on days 2 and 5 after
CRP = ns; IFN-γ = cardiac vagaltone was tVNS
ns negatively associated with Low-disease acitivity
DAS28-CRP. Participants group (DAS-28 <
with high disease activity 2.6): no clinical
had lower baseline cardiac improvement after
vagal tone than tVNS.
participants with low
242
disease activity.
Kox et al. transvenous Healthy yes pre: 6.43 ± pre:5.37 ± pre: 3.2 ± 0; pre: 7.91 ± TNF-α = ns; nr Intravenous (in vivo) LPS Inflammatory 1
2015 VNS (in 2.365608; 1.16; post: 3.2 ± 0 14.13; IL6 = ns; IL-10 administration and LPS cytokines within
vivo post: 8.61 ± post:7.06 ± post:7.62 ± = ns; IL-8 = ns induced stimulation ex normal range at
and 3.51 1.63 13,98 vivo; No difference baseline. Sharp
ex between symptoms of in increase after LPS
vivo) vivo LPS induced stimulation, no
endotoxemia, nor cytokine change by VNS
levels between-groups; Ex- compared to sham.
vivo LPS induced cytokine
production was not
different between-groups
Leukocyte increase after
LPS administration

followed by leukocytosis.
Normalization on day 2
Salama tVNS Resectable non- no nr nr pre: 63.4 ± pre:53.2 ± IL-6↓ (p = IL-6↑* (p = 0.03); Comparison to controls From baseline to 1st 1
et al. small cell lung 29.0; post: 20.0; 0.02); CRP↓ (p CRP = ns; IL- without sham condition. POD sharp increase
2020◦ cancer 258.6 ± 110 post:154.8 = 0.01); IL- 10↑** (p < 0.008) Differences of tVNS on the in IL-6 levels, 4th
± 93 10↑ (p = 0.03) acute inflammatory POD: return to BL
response after lung surgery values.
(baseline = pre-operative
value, post-intervention = VNS group showed
4th postoperative d). On shorter
the 1st postoperative d, IL- hospitalization time
6 levels were lower with and lower incidence
tVNS compared to sham
C. Schiweck et al.
Short
Stimulation
Duration
pg/mL and after
intervention

vs sham)
stimulation(p = 0.02). On of pneumonia.

the 4th d IL-6 levels were
comparable in both groups
(sham and tVNS).
Stavrakis tVNS Paroxysmal no pre:7.8 ± pre:9.1 ± 5.5; pre: 5.7 ± pre:5.5 ± TNF-α = ns; nr No significant between- No elevation of 1
et al. atrial 3.3; post: 6.3 post: 7.4 ± 5 2.9; post:5.9 2.7; post: IL-6 = ns; IL- group difference between inflammatory
2015 fibrillation, AF ± 2.8 ± 2.7 6.3 ± 3.3 10 = ns; CRP sham and tVNS in coronary parameters reported
(coronary catheter = ns sinus. tVNS decreased AF at baseline.
sinus) ablation duration
No elevation
reported by AF-
induction.
Stavrakis tVNS Paroxysmal no pre: 7.6 ± pre: 9.2 ± pre:3.9 ± pre:3.2 ± TNF-α↓** (p = nr A significantly greater No elevation of 1
et al. atrial 3.0; post: 6.8 4.8; post: 6.9 2.9; post: 5.7 2.0; post:4.3 0.006); IL-6 = reduction was achieved in inflammatory
243
2015 fibrillationAF, ± 3.0 ± 4.4 ± 3.0 ± 2.1 ns; IL-10 = ns; the intervention group parameters reported
(femoral catheter CRP↓*** (comparison of change at baseline.
vein) ablation scores); BL levels were non-
significantly higher in the No elevation
intervention group. reported by AF-
tVNS decreased AF induction.
duration
Stavrakis tVNS Patients no pre:46.2 ± pre: 46.7 ± pre:700.3 ± pre: 696.3 TNF-α: nr; TNF-α ↓ (p < Significant changes for all Inflammatory 1
et al. undergoing 1.5; 1.4; post:39.7 94.5; ± 181.3; IL-6:nr; IL10: 0.001)***; cytokines with time in both parameters were
2017 cardiac surgery post:39.9 ± ± 1.5 post:555.4 ± post:349.0 nr; CRP:nr IL-6:nr; IL-10: nr; groups, suggesting a increased at baseline
1.4 97.4 ± 54.4 CRP: nr significant decrease in immediately after
cytokine levels over time, surgery and
as part of the post- decreased over time.
operative natural course;
clinically significant Atrial fibrillation

reduction of post-operative free survival was
atrial fibrillation better in the tNVS
group. Length of
hospitalization was
not different
between groups.
Veiz et al. tVNS Healthy, no pre:16.01 ± pre: 18.17 ± pre:13.74 ± pre: 9.91 ± TNF-α = ns; IL- TNF-α = ns; IL-6↑ IL-6 and IL-1β sig. No elevation of 1
2022 younger cohort 21.94; post: 17.06; post: 9.47; post: 8.21; post: 6↑**(p = * (p = 0.016); IL- Increased in VNS group but inflammatory
13.38 ± 18.41 ± 16.9. 12.39 ± 9.48 13.07 ± 0.01); IL-1β↑* 1β↑ ** (p = decreased in sham group, parameters reported
15.00 9.22 (p = 0.01); IL- 0.002); IL-8 = ns no change in TNF-α at baseline.
8 = ns
Veiz et al. tVNS Healthy, older no pre: 3.48 ± pre:3.63 ± pre: 11.02 ± pre: 8.71 ± TNF-α = ns; IL- TNF-α = ns; IL-6 IL-1β and IL-8 significantly No elevation of 1
2022 cohort 2.64; 2.5; post: 8.15; 5.43; 6 = ns; IL-1β↑ = ns; IL-1β↑* (p = increased after VNS, no inflammatory
4.24 ± 2.47 ** (p = 0.001); change in TNF-α parameters reported
C. Schiweck et al.
Short
Stimulation
Duration
pg/mL and after
intervention

vs sham)
post:3.5 ± post:10.79 ± post:10.59 IL-8↑** (p = 0.010); IL-8↑* (p at baseline.

2.47 9.18 ± 6.18 0.007) = 0.019)
Zhou et al. tVNS Elderly patients no pre: 6.7 ± pre: 6.56 ± pre: 6.07 ± pre: 6.3 ± TNF-α = ns; IL- TNF-α↑*; IL-6↑* Post-operative: All All inflammatory 1
2022 undergoing 1.59; 1.58; post: 3.3; 4.03; 6↓*; inflammatory factors in the parameters within
total joint post:10.74 10.32 ± 3.07 post:39.56 ± post:31.08 two groups were normal range at
arthroplasty ± 2.89 20.34 ± 15.21 significantly higher after baseline, increased
surgery than those before after surgery in both
surgery (P < 0.05); 1β groups.
below LOD in several
samples, not assessed) tVNS decreased the
postoperative
incidence of delayed
neurocognitive
recovery.
Long
244
stimulation
duration
TNF-α, IL6, mean ± Direction and Comment/Special Quality*
mean ± sd sd or median significance Design
or median (range)
(range)
First Intervention Diagnosis LPS sham VNS sham VNS between within
author,
year
Aalbers iVNS Refractory epilepsy no nr nr pre: 1.16 pre: 1.16 IL-6 = ns; IL-10 IL-6 = ns; IL- Lower baseline IL-6 No elevation of 1
et al. (children) (0.23–9.57); (0.23–9.57); post: = ns; IL-1β = ns 10 = ns; IL- levels indicated inflammatory
2012 post 1.09 1.27 (0.30–10.13) 1β = ns more significant parameters reported
(0.25–17.39) seizure frequency at baseline.
reduction during
add-on phase [R2 =

0.105 (1.35), p =
0.050], but cytokine
levels were not
modulated by VNS.
Baro et al. iVNS Refractoryepilepsy yes na pre:67.90 ± na nr na TNF-α = ns; Comparison of pre- No elevation of 4
2022 (children) (ex 64.18; CRP = ns; IL- implantation values inflammatory
vivo) post:42.84 ± 1β = ns with values acquired parameters reported
31.36 42 ds post-surgery. at baseline.
Cytokines were
assessed after LPS-
stimulation ex-vivo.
Stimulation was not
turned on
immediately after
C. Schiweck et al.
implantation;
stimulation duration
was different
between
participants.
No change in CRP,
ESR, white blood
cells, lymphocytes,
CD3+, CD4 + CD8+,
CD19+, CD56 + or
ratio of CD4+/CD8
+ cells; nor for IgG,
IgA,IgM or IgE..
Barone iVNS Refractory epilepsy no na pre:0.09 ± na pre:0.06 ± 0.05; na TNF-α = ns; Comparison of pre- No elevation of 4
et al. 0.01; post:0.06 ± 0.07 IL-6 = ns; implantation values inflammatory
2007 post:0.10 ± CRP = ns with values acquired parameters reported
0.03 3 months post- at baseline.
surgery. HF-HRV
and rmssd obtained
of a 24-h ECG non-
significantly
decreased after 3
months of VNS.
Boström tVNS healthy/migraine no na nr na nr na IL-1β↑ * Cytokine levels at No elevation of 2
et al. (refractory baseline and 3 inflammatory
2019 headache disorder) months post- parameters reported
245
intervention were at baseline.

acquired in an inter-
ictal period. No tVNS reduced
association was headache severity
found between and frequency
increase in IL-1β compared to baseline
level and reduction (no control
in headache intervention).
frequency.
No association was
found between
increase in IL-1β level
and reduction in
headache frequency.
Bremner tVNS Non-PTSD: history no pre: 2.37 ± pre:2.81 ± pre: 0.7343 pre:0.82 ± 0.57; TNF-α = ns; IL- nr No elevation of 1

et al. of psychological 0.8708; 1.29; ± 0.4263; post:0.99 ± 1.32 1β = ns; IL-2 = inflammatory
2020 trauma without post: 2.199 post:2.35 ± post:0.63 ± ns; IL-5:nr; IL- parameters reported
PTSD ± 0.94 0.38 0.30 13: nr; PTSD at baseline.
PTSD: history of subgroup: IL-
psychological 6↓* (p = Exposure to a
trauma with PTSD 0.046); IFN-γ ↓ traumatic script
*(p = 0.032) increased IL-6 in
PTSD patients, this
was blunted by tVNS
compared to sham
stimulation.
Brock, tVNS Psoriatic arthritis no na pre:1.55 ± na nr na PsA: TNF- Subgroup PsA, d 5: t- Disease severity was 4
2021 (PsA)ankylosing 0.76; α↑** (d 5, p VNS induced an not defined as
spondylitis (AS) = 0.005); increase in TNF-α inclusion criteria.
C. Schiweck et al.
post:1.67 ± CRP↓** (p = (1.65 vs. 1.81, p = Disease activity (DAS-
0.78 0.004); AS: 0.005). Subgroup 28) did not change
IL10↓* (d2, AS, d 2: t-VNS with tVNS in both
p = 0.02); IL- induced a decrease groups. In PsA ASDS
8 ↓* (d 2,p = in IL-10 (0.46 vs. decreased from
0.02); IFN- 0.42, p = 0.008). a baseline to day 5.
γ↓* (d 2,p = 20 % reduction in
0.02) CRP (p = 0.004) in
the subgroup of
patients with
Psoriatic Arthritis.
Subgroup
Ankylosing
Spondylitis, d 2: t-
VNS induced a
decrease in IL-8
(3.83 vs, 3.03, p =
0.02).
Chaudhry nVNS refractory episodic no pre:0.82 ± pre:0.92 ± pre:0.95 ± pre:2.5 ± 1.1; TNF-α = ns; IL- TNF-α = ns; Interical IL-1β was No elevation of 1
et al. migraine, chronic 0.08; 0.06; 0.19; post: post:2.44 ± 1.18 6 = ns; IL-10: IL-6 = ns; IL- acquired at baseline inflammatory
2019 migraine post:0.73 post:0.86 ± 0.95 ± 0.14 ns; IL-1β↓* 10 = ns; IL- and after 2 months of parameters reported
± 0.07 0.04 1β = ns VNS. at baseline.
VNS compared to
sham stimulation was
associated with a
reduction in severe
migraine attacks. No
246
association with IL-1β

change.
Corcoran iVNS treatment resistant no na pre:1.20 ± na pre:1.80 ± 0.696; na TNF-α ↑ ** Samples were taken No elevation of 4
et al. major depression 0.82; post:5.11 ± 5.28 (p = 0.008); 2 weeks prior and 12 inflammatory
2005 post:2.73 ± IL-6 ↑* (p = weeks after VNS parameters reported
1.64 0.019); IL- surgery. After an at baseline.
10 = ns; adjustment period of
CRP = ns; IL- 2 weeks, the Change in symptoms
1β = ns; stimulation was not reported.
TGF-β↑*** unchanged for 10
(p < 0.001) weeks.
Corrêa tVNS COVID-19 no nr nr pre: 42.76 ± pre:32.12 ± 27.99 IL-6 ↓***; IL- IL-6 ↓*, IL- Participants within No elevation of 1
et al. 37.89; post:6.32 ± 4.39 10 = ns; CRP ↓ 10 = ns, CRP 10 ds after the inflammatory
2022 post:23.11 ± (p = 0.038) ↓* beginning of the parameters reported
25.86 COVID-19 at baseline.

symptoms.
No difference of
No change in heart clinical symptoms
rate variablity, and except for lower
cortisol levels. depressive symptoms
HF-HRV did not were detected in the
change significantly tVNS group compared
(but was numerically to sham after 7 ds of
lower post stimulation.
treatment).
De Herdt iVNS Refractory epilepsy yes na pre:1007 na pre:69445 na TNF-α = ns; PBMCs, LPS induced No elevation of 4
et al (ex (71–7658); (38251–184922); IL-6 = ns; IL- stimulation ex vivo. inflammatory
vivo) 10 = ns; In the 2 patients with parameters reported
C. Schiweck et al.
post:927 post: 49,869 CRP = ns,IL- generalized epilepsy, at baseline.
(22–3571) (32098–147871) 8 ↓* there was a marked
increase in IL-10 Seizure reduction
induction after 6 (>30 %) was reported
months of VNS, in 3/10 treated
compared to the patients.
patients with
localized epilepsy.
Drewes tVNS Rheumatoid no na pre:9.79 ± na pre:5.92 ± 15.14; na TNF-α = ns; See above Inclusion based on 4
et al., Arthritis 19.22; post: 4.10 ± 5.52 IL-6 = ns; IL- disease severity:
2021 post:9.92 ± 10: ↓* (low -high-disease activity
20.15 RA disease group (DAS-28 > 3.2)
activity)(p showed clinical
= 0.02),ns improvement
(high RA on days 2 and 5.
disease -low disease acitivity
activity); group (<2.6) showed
no clinical
improvement.
Koopman iVNS Rheumatoid no na pre:2900.00 na nr na TNF-α↓**, The reduction of Only participants 4
et al. Arthritis ± 566.00; CRP↓*** cytokine levels was with active disease
2016 post:1776.00 found in the state were included
± 342.00 combined cohort. (mean DAS-28 across
After turning off VNS both cohorts: 5.99).
on d 42, TNF-α
increased till d 56. Disease severity in the
And, when combined cohorts
stimulation was was substantially
247
turned on again, lower at day 42

TNF-α decreased by compared to baseline
d 84. On d 42, IL-6 after iVNS.
levels were
negatively
associated with
improvement in
clinical scores in the
responders. LPS
induced stimulation
ex vivo
Majoie iVNS Refractory epilepsy no na pre:1.03 na pre:0.50 na TNF-α = ns; In clinical Inclusion was not 2
et al., (0.5–2.39); (0.2–1.45); IL-6 = ns; IL- responders (seizure based on elevated
2010 post:0.5 post:0.61 10 = ns frequency reduction inflammatory
(0.5–2.56) (0.2–1.42) > 50 %) IL-6 was parameters.

higher at baseline
and decreased after Elevated baseline
VNS, IL-10 was low inflammatory
and increased after parameters were
VNS. In the non- reported in clinical
responders VNS responder with a 50
resulted in an % reduction of
increase of IL-6 and a seizure frequency.
decrease of IL-10.
None of the changes
was statistically
significant.
C. Schiweck et al.
Merchant tVNS pediatric nephrotic no na pre:7.33 ± na pre:4.39 ± 6.19; na TNF-α ↓* (p TNF-alpha decreased Baseline 4
et al. syndrome (I + II) 3.56; post:4.27 ± 7.67 = 0.03); IL-6 in all but one patient. inflammatory
2022 post:6.176 ± = ns; IL-10 parameters were not
3.11 = ns; IL-2 = considered as
ns; IFN-γ = inclusion criteria.
ns; IL-1β =
ns; IL-8 = ns; All of the patients
IL-17 = ns; suffering from
IL-5:nr; IL-12 frequent relapsing
(p70):nr; IL- nephrotic syndrome
13:nr; IL-23: reported a relapse-
nr free period during
VNS. Three out of
four patients with
steroid resistant
nephrotic syndrome
showed reduced
urinary protein
concentration.
Mion tVNS irritable bowel no na pre:1.05 ± na pre:1.24 ± 0.27; na TNF-α = ns; CRP decreased non- No elevation of 4
et al., syndrome 0.39; post:1.10 ± 0.27 IL-6 = ns; IL- significantly, TNF- inflammatory
2020 post:1.11 ± 10 = ns; alpha numerically parameters were
0.40 CRP = ns; IL- increased. reported at baseline.
8 = ns; IL-17
= ns The symptom severity
decreased after VNS.
Faecal calprotectin as
a marker for
248
intestinal
inflammation did not
change after VNS.
Salama tVNS Patients undergoing No nr nr pre: 63.4 ± pre:53.20 ± 20.00; IL-6 = ns; CRP IL-6 ↓ * (p < Comparison to From baseline to 1st 1
et al. surgery for lung 29.0; post:93.70 ± 32.90 = ns; IL-10 = ns 0.05); CRP controls without POD sharp increase in
2020 cancer post:98.30 ± = ns; IL-10 sham condition. IL-6 levels, 4th POD:
39.70 ns Differences of tVNS return to BL values.
on the acute
inflammatory VNS group showed
response after lung shorter
surgery (baseline = hospitalization time
pre-operative value, and lower incidence
post-intervention = of pneumonia.
4th postoperative
day(POD)).

1st POD: IL 6 levels
tVNS < IL 6 levels
sham
4th POD: IL 6 levels
tVNS = IL 6 levels
sham
1st POD – BL: tVNS:

IL 10 significantly
increased, controls:
IL 10 unchanged.

C. Schiweck et al.
Sinniger iVNS Crohń s disease no na pre:8.36 ± na pre:6.34 ± 5.32; na TNF-α:nr; IL- CRP levels were Inclusion of patients 4
et al., 6.55; post:3.47 ± 1.95 6:nr; IL-10: elevated in 7/8 with at least
2020 post:5.89 ± nr; IL-1β:nr; patients at BL and moderate disease
2.91 IL-2:nr; IL- decreased in 4/8. activity with elevated
17:nr; IFN-γ: CRP and or elevated
nr; IL-12 On patient level, HF- fecal calprotectin and
(p70):nr; IL- HRV (normalized disease severity
23:nr; MIP- units) changed from confirmed by
1α:nr; TGF-β: pre to post endoscopic biopsy.
nr; IL-21:nr; treatment.
MCP1:nr; After 12 months VNS
GM-CSF:nr; Cytokines from gut 5/8 patients were in
CRP:nr biopsies collected clinical remission, 2
from inflamed reported
tissues reduced in improvements.
most patients.
Stavrakis transvenous patients undergoing no pre:46.2 ± pre:46.70 ± pre:700.3 ± pre:696.30 ± TNF-α ↓* (p = TNF-α ↓ * * Stimulation was Inflammatory 1
et al. VNS cardiac surgery 1.5; 1.40; 94.5; 181.30; 0.01); IL-6 ↓* *; IL-6 ↓ * * initiated after parameters were
2017 post:38.30 post:33.00 ± post:275.30 post:147.10 ± (p = 0.03); IL- *; IL-10 ↓ * * cardiac surgery upon increased at baseline
± 1.40 1.40 ± 66.20 22.20 10 = ns; CRP = *; CRP ↓ * * * arrival the intensive immediately after
ns care unit. surgery and
decreased over time.
Blood samples were
drawn after arrival Atrial fibrillation free
the ICU as well as 24 survival was better in
h and 72 h later. the tNVS group.
Length of
249
TNF-α level was hospitalization was

lower after tVNS not different between
compared to control groups.
after 72 h. IL-6 was
lower compared to
control after 24 and
72 h.
See above
Stavrakis tVNS paroxysmal AF no pre:5.4 pre:6.9 pre: 2.0 pre:1.6 (0.5–3.7); TNF-α ↓** (p = nr The average burden No elevation of 1
et al., (4.3–9.1); (4.6–9.3); (0.9–3.7); post:1.5 (0.7–3.2) 0.009); IL-6 = of Atrial fibrillation inflammatory
2020 post:5.4 post:5.5 post:2.3 ns; IL-10 = ns, after 3 and 6 months parameters reported
(4.4–8.3) (3.9–8.3) (1.0–4.4) IL-1β = ns; IL- VNS was lower at baseline.
17 = ns compared to

baseline. No elevation reported
by AF-induction.
See above
Wu et al., tVNS sepsis no pre: 87.0 ± pre:114.02 ± pre: 61.5 ± pre: 83.0 ± 75.1; TNF-α ↓** (p = TNF-α ↓* (p TVNS was applied on Inclusion of sepsis 1
2023 14.5; post: 84.71; 6.8; post: post: 69.71 ± 0.002); = 0.024); IL- five consecutive ds. patients treated on a
81.94 ± post:88.3 ± 56.58 ± 7.76 61.74 IL-1β ↓** (p = 1β↓*(p = Blood samples were Intensive care unit
18.40 55.61 0.002); IL-6 ↓** 0.04); IL-6 = taken on d 1,3,5 and after 1 week of sepsis
(p = 0.002); IL- ns, CRP = ns; 7. onset.
10:nr d 7: IL-10
↑** (p = In the tVNS group,
0.009); IL- TNF-α levels were Disease severity was
4↑** (p = lower on d 3,5, and 7 lower on day 5 and
0.002) compared to d 1. On day 7 compared to
d 7 TNF-α, IL-6 and day 1 in the tVNS
C. Schiweck et al.
IL-1β were lower in group but not in the
the tVNS group control group.
compared to the
control group. The
increase of IL-4 and
IL-10 from d 1 to d 7
were stronger in the
tVNS group
compared to the
control group.
Studies in systematic
Review only (not
included in meta-
analysis)
First Intervention Diagnosis LPS Assessed cytokines Direction and Findings Quality*
author, significance
year
between within between within
Andreas tVNS Patients after no CRP, IL-6 IL-6 = ns; CRP = ns nr -tVNS significantly reduced nr CRP increased 2 day 1
et al. cardiac surgery incidence of POAF (p = after end of surgery and
(2019) 0.022) returned to normal
-duration and time of onset ranger onday 7. IL-6
of arrhythmia remained was increased at the
uninfluenced-no difference end of surgery and
with tVNS for CRP or IL-6 returned to normal
levels range on day 7.
250
No effect of tVNS on
inflammation.
tVNS reduced the

number of patients with
post-operative atrial
fibrillation compared to
control condition.
Aranow tVNS Systemic lupus yes CRP, substance P, nr sub p↓** (p = 0.008); -tVNS: substance P ↓ (p = nr Patients with active 1
et al. erythematosus neuropeptide Y, CRP = ns; IL1b = ns; IL- 0.008) disease were recruited.
(2021) calcitonin gene- 10 = ns; TNF = ns; IL-6 –no other significant
related peptide, = ns; IL-1RA = ns; changes in any levels of Except for substance p
IL1RA, IL-18, IL-1β, Neuropeptide Y = ns; circulating biomarkers none of the circulating
IFNα, IL-1, IL-6, IL-8, IFNα = ns; IL-18 = ns; -subjects receiving tVNS biomarkers were

IL-10, TNF CGRP = ns; IL-8 = ns had a significant decrease reduced by tVNS.
in pain (p = 0.049) and
fatigue symptoms
compared with sham-
median reduction of tender
and swollen joints for tVNS
was 100 % compared to 5.3
%/9.1 % for sham (p =
0.019)
Bonaz et al. iVNS Crohn’s disease no CRP na CRP:nr na − 2 of the 7 patients were Patients with mild to 4
(2016) removed from the study at moderate CD were
3 months for clinical included with either
worsening elevated CRP or fecal
-the remaining 5 patients calprotectin and
C. Schiweck et al.
improved their Crohń s positive endoscopic
disease activity index biopsy.
(CDAI) over the 6 months
study period, 4 were even Disease activity
in clinical remission improved in all patients
-among the 3 patients with that were followed up.
an elevated CRP on
inclusion (>5μg/L), 2 2/3 of patient with
improved their CRP toward elevated CRP-levels
a normal value showed a decrease after
-all patients reported iVNS.
decreased digestive pain
-the change of vagal tone
depended on its level before
VNS onset (inverse effect)-
VNS has restored an
equilibrated autonomic
balance I5 (LF/HF ratio)
D’Haens iVNS Treatment- No CRP, TNF-α, IFN-γ, Na TNF-α↓; IFN-γ↓; CRP = Na 46 % and 52 % decrease Clinical response X
et al. refractory IL-17 ns; IL-17 = ns from baseline in mean correlated with changes
(2023) Crohn’s disease levels of TNF and IFN-γ in TNF, IL-17, and IFN-γ
levels.
de Moraes tVNS Metabolic no CRP, monocytes na CRP:nr; CD14 + na − 8 weeks of tVNS caused a Elevation of 2
et al. syndrome monocytes↑; CD16 + significant decrease in inflammatory
(2023) monocytes↓ systolic and diastolic blood parameters was not
pressure and heart rate, considered as an
non-significant increase of inclusion criteria.
HF-HRV (absolute)
251
–no change in metabolic The effect of tVNS on

parameters-significant circulating cytokines
increase (three times) in the was not investigated.
percentage of classical
monocytes (CD14 + ) and a
significant decrease (50 %)
of non-classical monocytes
(CD16 + )
Lerman tVNS healthy yes MCP-1, MIP-1α, 90 min: IL-8↓*; 24 24 h: TNF↓*; IL1b↓*; -at 90 min: tVNS -> greater -at 24 h: tVNS -> significant No elevation of 1
et al. MIP-1ß, TNF, IL-1β, h: TNF↓*; IL1b↓*; MIP-1α↓*; MCP-1↓*; IL- IL-8 level decrease (p < decrease in IL-1β, TNF, inflammatory
(2016) IL-6, IL-8, IL-10 MCP-1↓*; IL-8↓*; 8↓* 0.05) than sham-at 24 h: MIP-1a,MCP-1 and IL-8 parameters at baseline
IL-10↑* (LPS tVNS -> greater decrease levels (p < 0.05) reported.
stimulated) (p < 0.05) in TNF, IL-1β,
MCP-1 and IL-8 than sham After 24 h significant
decrease of several

cytokines compared to
sham stimulation.
Seitz et al. tVNS COVID-19 no IL-6, TNF-α, IFN-γ, TNF-α = ns; IL-6 ↓* TNF-α = ns; IL-6 = ns; comparison with standard nr Patients with acute 1
(2022) IL-18, IL-10, CRP (T4 vs T0, p = CRP = ns; IL-10 = ns; IL- of care group (no sham) Covid-19 infection
0.046); CRP ↓* 18 = ns –no IFN-γ elevation at any requiring ventilation on
(T72 vs T0, p = timepoint a ICU were included.
0.018); IL-10↑* -decrease of IL-6 (p =
(T72 vs T0, p = 0.048) and TNF- α (p = IL-6 and CRP decreased
0.048); IL-18 = ns 0.048) from T0 to T4: at different timepoints
statistically significantly after tVNS compared to
stronger in tVNS than in control condition.
SOC group
-decrease of CRP from T0 to After 72 h and 168 h the
T72 (p = 0.003): increase of IL-10 was
C. Schiweck et al.
statistically significantly stronger after tVNS
stronger in tVNS group compared to controls.
-decrease of CRP (p =
0.018) from T0 to T168:
statistically significantly
stronger in tVNS group-
increase of IL-10 from T0 to
T72 and T168: significantly
higher in the VNS group (p
= 0.041 and p = 0.048)
Stakenborg iVNS (hemi)colorectal yes TNF-α, IL-6; IL-8, TNF-α = ns; IL-6 ↓*; nr -high (20 Hz) but not low nr Blood samples were 1
et al. surgery for MCP-1 IL-8↓*; MCP-1 = ns (5 Hz) frequency taken before surgery
(2017) colorectal abdominal VNS: significant and 24 h and 48 h after
malignancy reduction of LPS induced surgery.
IL-6 and IL-8 on POD1
compared to sham (p < LPS induced cytokine
0.05) release ex-vivo was
–no difference for MCP-1 investigated.
and TNF-α-abdominal VNS
did not affect heart rate After 24 h LPS induced
release of IL-6 and IL-8
was reduced after tVNS
compared to sham.
Tarn et al. tVNS primary yes IFN-γ, IL12-p70, na IL-6↓; IL-1β↓; IP-10↓; na -Physical fatigue (measured Disease severity and 4
252
(2019) Sjörgeń s TNF-α, MIP-1α, MIP-1α↓; TNF-α↓; using PRO-F) and dtime elevated inflammatory
Syndrome IFNα, IL-10, IL-1β, (undetectable: IFN-γ, sleepiness (measured by parameters at baseline
IL-6, IP-10 IL12-p70, IFNα, IL-10) ESS) were significantly were not considered as
reduced across three TPs (p inlusion criteria.
< 0.0003 and 0.02)-tVNS
-> levels of MIP1α, IL-1β, LPS-induced release of
TNF-α, IL-6, and IP-10 were all inflammatory
significantly reduced across parameters decreased
the 5 TPs regardless of after 28 days.
responder grouping
Day time sleepiness and
fatigue were improved
after 7 days.
Tornero tVNS COVID-19 No CRP, PCT, IL-1β, IL- CRP↓; PCT↓;, IL-1β NA CRP and PCT levels nr No significant X
et al. 6, TNF-α, D-Dimer = ns; IL-6 = ns; decreased to a significantly differences for clinical

(2022) TNF-α = ns; D- greater degree in the tVNS respiratory outcomes
Dimer = ns group than in the SoC group
2019), acute COVID-19 infection (Corrêa, 2022; Tornero, 2022; Seitz, 3.3. Quantitative synthesis
2022), sepsis (Wu, 2023), psychological stress (Bremner, 2020)) and
except for one study (Andreas, 2019) all showed that VNS alleviated the Meta-analysis was possible for 27 studies, with pooled sample sizes
heightened inflammatory response. These findings indicate that the ranging from 85/88 (VNS/sham) in the short-term between analyses up
onset of stimulation in relation to the acute inflammatory event as well to 273 (VNS) in the short-term within analysis.
as the temporal dynamics of the cytokine levels during the inflammatory
response may be relevant for the efficacy of VNS. 3.3.1. Short-term between and within- group analysis
The predetermined minimum number of articles (n = 5) to conduct a
meta-analysis, was only reached for IL-6 and TNF-α. A random effects
model revealed no difference between sham and VNS groups for either
Fig. 2. Forest-Plots of Meta-analysis for short-term between and within-group comparison. Analysis was performed between verum and control intervention
for A. IL-6 and B. TNF-α. Within-group comparison of pre- vs. post- values were performed in the verum group for C. IL-6 and D. TNF-α. Concentrations for cytokines
were given in pg/mL, for CRP in mg/L.
253
Fig. 2. (continued).
cytokine (TNF-α: g = − 0.21, 95 % CI: − 0.74–0.32, P = 0.359; I2 = 61.5 3.4. Sub-group analysis/ Meta-regression: Stimulation duration, LPS,
%, 95 % CI: [43.9 %; 89.0 %]) or IL-6 (g = − 0.94, 95 % CI: [− 2.18; stimulation length and study quality
0.31], p = 0.112, I2 = 91.0 %, 95 % CI: [83.1 %; 95.2 %]) (See Fig. 2A-
B.) No within-group changes for VNS were found for TNF-α (g = − 0.45, For all cytokines where at least 10 studies were identified we per
95 % CI: [− 2.59; 1.70], p = 0.630, I2 = 97 %, 95 % CI: [95.4 %; 98.0 %]) formed a within-group analysis for stimulation method (iVNS vs non-
or IL-6 (g = 0.28, 95 % CI: [− 3.11; 3.67], p = 0.840, I2 = 97.6 %, 95 % invasive VNS), stimulation duration, LPS stimulation and study qual
CI: [96.3 %; 98.4 %]). Prediction intervals of all analyses indicated that ity. No difference between subgroups was found for any of the moder
future studies may find both positive and negative effects. Fig. 2C-D for ating variables: stimulation method all P > 0.05 and stimulation
forest plots. Data from (Stavrakis, et al., 2017) are for the femoral vein duration (all r2 = 0 % and P > 0.05), except for LPS, where IL-1β was
sampling, data from (Kox, 2015) were used for the 240-minute time lower in studies which had used an LPS stimulation versus those who did
point. not. While iVNS generally had stronger reductive effects than tVNS, the
difference between both treatments was not significant, and confidence
3.3.2. Long-term between-group analysis intervals for the separate effects per treatment always included 0. See
In the long-term analyses, no difference of VNS compared to sham Supplementary Table 3 for detailed results of the stimulation method,
stimulation was found for any cytokine (TNF-α: g = − 0.13, 95 % CI: Supplementary Fig. 3 and Supplementary Table 4 shows results for
[− 0.35–0.10], p = 0.196; IL-6: g = − 0.67, 95 % CI: [− 2.10; 0.76], p = the stimulation duration, and Supplementary Table 5 results for LPS.
0.306; IL-1β: g = − 0.02, 95 % CI: [− 0.06; 0.02], p = 0.270; IL-10 g = Next, we tested whether study quality had an influence on the results
− 0.08, 95 % CI:[− 0.30; 0.14], p = 0.387). Heterogeneity was large for using the quality scores derived with the instruments (NLHBI). For TNF-
IL-6 (I2 = 91.1 % CI: [84.8 %; 94.7 %]). Point estimates were low, but α, (4 poor, 11 fair, 2 good quality), IL-6, (3 poor, 9 fair, 3 good quality),
uncertainty intervals were large for TNF-α (I2 = 0.0 %, CI: [0.0 %-79.2 IL-10 (2 poor, 9 fair 3 good quality) and CRP (3 poor, 6 fair 2 good
%]), IL-10 (I2 = 0.0 % [0.0 %; 74.6 %]) and IL-1β (I2 = 0.0 %, CI: [0.0 quality), study quality did not influence results (TNF-α: Q = 1.79, P =
%-79.2 %]). Prediction intervals included both positive and negative 0.408; IL-6: Q = 0.31, P = 0.855; IL-10: Q = 1.63, P = 0.442, CRP =
effect sizes. The forest plots are depicted in Fig. 3. 0.19, P = 0.911). For IL-1β, only 1 study had poor and good quality
respectively, and analyses was not possible.
3.3.3. Long-term within-group analysis
Eight cytokines were reported in at least 5 studies and TNF-α in 17
studies for the long-term within-group analysis. We did not find a sig 3.5. Publication bias and sensitivity analysis
nificant difference after VNS for any cytokine. (Table 2), forest plots can
be found in Supplementary Fig. 1. Heterogeneity was high in all Inspection of funnel plots revealed some asymmetry for IL-1β, CRP
studies, with only two analyses below an I2 of 75 % (Table 2). and IL-10. No statistically significant results were observed for TNF-α (P
= 0.112), IL-6 (P = 0.944), IL-10 (P = 0.160), CRP (P = 0.095) using
3.3.4. Additional analyses within inflammatory subgroup Egger’s test. However, a significant Egger’s test was detected for IL-1β
All above analyses were repeated including only studies where acute (bias estimate: p = 0.017), with more studies showing a reductive
inflammation, as evidenced by increased inflammation scores at base change being published. Funnel plots are displayed in Supplementary
line or the induction of an inflammatory event (i.e., via LPS adminis Figure 4. Influential case analysis did not alter results regarding sig
tration, surgical intervention) took place. A significantly stronger nificance, but narrowed down prediction intervals for effect sizes and
decrease in the VNS than sham condition was found for CRP for the long- did change the direction of some effects (See Supplementary Table 7).
term between group results (g = − 0.58, 95 %CI: [− 1.09; − 0.061], p = A particularly prevalent outlier was the study by Stavrakis et al. (2017)
0.038), see Supplementary Fig. 2. Although all other results showed a (7/13 outliers in total). No more than 1 outlier per analysis was found.
decreasing effect of VNS on inflammatory parameters, they remained
non-significant. See Supplementary Fig. 2 for details. 4. Discussion
In this first systematic review with meta-analysis on the effect of VNS

on inflammatory cytokines, we identified 36 studies including healthy
participants and patients with a variety of medical conditions. While the
254
Fig. 3. Forest-Plots of Meta-analysis for long-term between-group analysis. Comparison of verum vs. control condition was performed after long-term treatment
for A. TNF-α, B. IL-6, C. IL-1β and D. IL-10. Concentrations for cytokines were given in pg/mL, for CRP in mg/L.
255
Table 2
Summary of meta-analytic test results with random effects model for long-term within-group comparison. Cytokines were measured in pg/mL, CRP in mg/L. Ab
breviations: k = Number of studies; g = Hedge’s g, 95 %CI: 95 % confidence Interval; t = t value, p = p value, PI = 95 % Prediction Interval, I2: Heterogeneity estimate,
I2 95 %CI: Confidence interval for heterogeneity.
Cytokine k g 95 %CI t P 95 %PI I2 I2 95 %CI
TNF-α 17 − 0.53 [− 1.57;0.51] − 1.08 0.297 [− 4.12;3.07] 86.80 % [80.4 %;91.1 %]

IL-6 15 − 0.02 [− 0.81;0.76] − 0.06 0.954 [− 2.76;2.71] 92.00 % [88.4 %;94.4 %]
IL-1β 11 0.47 [− 0.30;1.24] 1.36 0.205 [− 2.01;2.95] 86.60 % [77.8 %;91.9 %]
CRP 11 − 0.66 [− 1.74;0.42] − 1.36 0.204 [− 4.03;2.70] 87.70 % [89 %;92.5 %]
IL-8 7 − 0.12 [− 0.47; 0.24] − 0.83 0.442 [− 0.95; 0.72] 66.90 % [21.0 %; 86.1 %]
IL-10 14 − 0.33 [− 0.84;0.18] − 1.41 0.183 [− 2.09;1.43] 82.30 % [71.4 %;89.0 %]
IFN-y 5 − 0.11 [− 0.42;0.21] − 0.94 0.401 [− 0.83;0.62] 51.50 % [0.0 %-82.2 %]
IL-17 5 0.03 [− 0.63;0.68] 0.11 0.916 [− 1.62;1.67] 75.80 % [40.7 %;90.1 %]
majority of studies in our systematic review reported a significant line, the subgroup analysis of four long term studies with an acute in
change of at least one inflammatory protein in at least one subgroup flammatory event showed lower CRP values after VNS compared to
analysis when exposed to VNS, we found no statistically convincing sham stimulation. However, due to the heterogeneity in experimental
effect of VNS on any inflammatory cytokine in our meta-analysis, neither designs, the results of these studies were not uniform (i.e., we did not
for long-term (between-group: IL-6, TNF-⍺, IL-1β, IL-10; within-group: find these effects for the other cytokines and the other subgroups), yet
TNF-⍺, IL-1β, IL-6, IL-8, IL-10, and CRP) nor short-term stimulation they clearly underscore the potential of VNS to mitigate acute inflam
(between- and within-group: TNF-⍺, IL-6). Only the subgroup analysis of matory responses rather than suppressing chronically elevated cyto
4 long-term studies with acute inflammatory events was significant: CRP kines. Moreover, the timing of VNS to interfere/ reduce distinct
values were lower after VNS compared to sham stimulation. Yet, no inflammatory processes seems to be pivotal for VNS efficacy. Although it
differences were evident for the other cytokines in any setting. In gen was not statistically possible to assess this effect in our analysis, this
eral, heterogeneity (I2) and/or confidence intervals for I2 were high. The should be considered in future studies. It is also plausible that VNS’s
inclusion of modifying factors such as stimulation duration, LPS stimu anti-inflammatory effect has a cumulative dynamic by inducing neuro
lation of cytokines, stimulation procedure (invasive vs non-invasive), or plasticity, comparable to its impact on clinical outcomes in epilepsy or
study quality as well as the exclusion of influential cases did not change depression treatment, as well as on brain signalling (Kibleur, 2018).
the results. When interpreting the present findings, it is crucial to note the variations
This result holds considerable significance given the attention elec across studies in key aspects, including patient samples (11 different
trical VNS has gained across medical disciplines following Borovikova disorders), proteins tested (>10), and the condition under which these
et al.’s landmark discovery of VNS’s capacity to decrease TNF-⍺ levels proteins were assessed (e.g., baseline with and without elevated in
and prevent septic shock in rodents during endotoxemia (Borovikova, flammatory levels, after systemic or ex-vivo LPS-stimulation, or intra
2000). Over the past two decades, an increasing number of studies have operatively). In addition, the quality of most studies ranged from poor to
explored the VNS’s anti-inflammatory potential, with renewed attention fair: The sample sizes were small (iVNS: 5–14, tVNS: 5–62) and only a
during the COVID-19 pandemic. The fact that the meta-analysis hardly limited number of studies employed appropriate control conditions. This
provided any significant findings, despite the promising results in rodent is due to 1) the invasive nature of iVNS, and 2) the lack of standardized
studies (Kwan, 2016) and a substantial number of positive findings in sham conditions. Particularly for iVNS sham conditions are difficult to
our own systematic review, calls for an exploration of the underlying realize: Current procedures such as leaving the device turned off (easily
reasons and a refocusing in the research field to advance this innovative detectable by the patients due to missing side effects such as a hoarse
technology. voice) or using low-frequency stimulation (1 Hz-stimulation impacts
In line with Borovikova et al. (Borovikova, 2000), rodent studies brain signaling and clinical symptoms) (Cao et al., 2021; Straube et al.,
mostly administered VNS prior to an inflammatory event (e.g., LPS- 2015) have been proven inadequate. Since the introduction of
infusion) (30 out of 32 studies (Kwan, 2016)). In contrast, most non-invasive VNS, more RCTs have been conducted. However, these
human studies have focused on VNS in chronic and often treatment- studies show a large variability in stimulation methodology (differences
resistant conditions. In these cases, chronic inflammation and prior in stimulation site, side, duration of stimulation, parameter settings and
(anti-inflammatory) therapies may have caused compensatory mecha control condition). The primary obstacle to a comprehensive investi
nisms (e.g. immune cell activation, altered cytokine production, gation of optimal stimulation settings is the lack of easily accessible
changes/dysfunctionality of T-and B-cell subpopulations, neuronal biomarkers: On the one hand, biological measures are required for pa
reconfiguration) which may confound the anti-inflammatory effects of tient stratification. For instance, identifying patients with elevated in
VNS (Cain et al., 2009; Li, 2022). Moreover, only a minority of studies on flammatory parameters and/or reduced “vagal tone” by assessing heart
chronic diseases (Koopman, et al., 2016; Bonaz, 2016; Addorisio, et al., rate variability has been discussed as useful options (Pellissier, 2014).
2019; Drewes et al., 2021; Sinniger, 2020) defined disease activity and/ Second, we need efficacy measures for VNS. In this context, traditional
or elevated inflammatory parameters as inclusion criteria and demon measures such as heart rate variability and pupillary reactivity have
strated a beneficial effect of VNS. In most of the studies, however, failed to provide reliable information about VN activation thus far
stratification was not performed, resulting in samples which may or may (Vespa, 2022; Wolf et al., 2021; Keute et al., 2019) most probably due to
not have had elevated baseline levels of inflammatory proteins. methodological limitations. Current advances in the field are showing
In contrast, clinical studies that performed VNS during or immedi first promising results and provide new insights into the mechanisms of
ately after inflammatory events - such as surgeries (Stavrakis, et al., vagal signalling. For instance, phasic burst stimulation in contrast to
2017; Salama et al., 2020; Stakenborg, 2017), acute COVID-19 infection tonic VNS is able to modulate pupillary reactivity during the pupillary
(Corrêa, 2022; Tornero, 2022; Seitz, 2022), sepsis (Wu, 2023) and light reflex (Wienke et al., 2023; D’Agostini, 2023). Moreover, explo
emotional stress (Bremner, 2020)– did confirm the anti-inflammatory ration of more direct measures such as somatosensory evoked potentials
potential of VNS, with only a minority of small-scale studies showing (Fallgatter, 2003; de Gurtubay et al., 2021) or microneurography of the
contrary outcomes (Kox, 2015; Corrêa, 2022; Andreas, 2019). Particu VN (Ottaviani et al., 2020) could provide a crucial step in closing this
larly striking were the findings of peri- or postoperative VNS, which gap.
significantly reduced cytokine levels amid surgical inflammation. In It is still unknown how electrical VNS interferes with afferent and
256
efferent signals transmitted via the VN to induce its anti-inflammatory curation, Writing – original draft. Leona Jacobsen: Investigation, Data
effect. Except for tVNS at the cymba conchae (Burger et al., 2020; curation, Writing – original draft. Andreas Reif: Writing – original draft,
Warren, 2019) that exclusively stimulates the afferent sensory fibers of Writing – review & editing. Sharmili Edwin Thanarajah: Conceptu
the auricular branch of the VN (Kaniusas, 2019), current devices non- alization, Methodology, Validation, Investigation, Data curation,
selectivity engage afferents and efferents as well as fibres of different Writing – original draft, Writing – review & editing, Visualization, Su
diameter and myelination status. Efferent fiber stimulation is believed to pervision, Project administration.
activate the canonical CAP (anterograde) and the efferent brainstem
nuclei (retrograde). Afferent fiber stimulation, conversely, activates the Declaration of competing interest
NTS (anterograde), leading to a.) CAP activation through efferent nuclei,
b.) initiation of the vagus-sympathetic reflex via C1 neurons in the The authors declare that they have no known competing financial
medulla oblongata, and c.) engagement of the Hypothalamic-Pituitary- interests or personal relationships that could have appeared to influence
Adrenal (HPA) axis through hypothalamic nuclei (Tanaka, 2021). the work reported in this paper.
Additionally, retrograde afferent stimulation can prompt the release of
anti-inflammatory neuropeptides at nerve endings (Chavan et al., 2017), Data availability
that can have a direct impact on intra-tissue cytokines, that are not
considered in the meta-analysis due to the lack of data (evidence on Data will be made available on request.
intratissue cytokines was only provided by one study (Sinniger, 2020)..
In conclusion, non-selective stimulation of afferent and efferent circuits Acknowledgments
may have a potentiating effect. Moreover, the spatial arrangement of
different morphological types of fibre within the nerve is organ- and CS and SET received intramural funding (Fokus Grant) to investigate
function-specific changing along the nerve (Jayaprakash, 2023) and Vagus nerve stimulation. SET was funded by the Else-Kröner Frisenius
different between the right and left nerves (Han, 2018; Jayaprakash, Stiftung and by the Leistungszentrum Innovative Therapeutics (Ther
2023). In line with this, selective stimulation of distinct fascicles has aNova) funded by the Fraunhofer Society and the Hessian Ministry of
been shown to achieve organ-specific stimulation in pigs (Jayaprakash, Science and Art.
2023). Hence, we urgently need selective stimulation techniques to
achieve a breakthrough with this technology. Appendix A. Supplementary data
5. Conclusion Supplementary data to this article can be found online at https://doi.

org/10.1016/j.bbi.2023.12.008.
In conclusion, our meta-analysis found no consistent evidence sup
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No Consistent Evidence For The Anti-Inflammatory Effect of Vagus Nerve Stimulation in Humans - A Systematic Review and Meta-Analysis

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Brain, Behavior, and Immunity 116 (2024) 237–258

Contents lists available at ScienceDirect

Brain Behavior and Immunity

No consistent evidence for the anti-inflammatory effect of vagus nerve

1. Introduction conditions. Therefore, maintaining a balance between pro- and anti-

2. Methods 2.6. Data items

sham VNS sham VNS between (VNS within (pre-post)

reduced 2 ds post activity defined by

Brain Behavior and Immunity 116 (2024) 237–258

sham VNS sham VNS between (VNS within (pre-post)

Brain Behavior and Immunity 116 (2024) 237–258

sham VNS sham VNS between (VNS within (pre-post)

stimulation(p = 0.02). On of pneumonia.

Brain Behavior and Immunity 116 (2024) 237–258

sham VNS sham VNS between (VNS within (pre-post)

post:3.5 ± post:10.79 ± post:10.59 IL-8↑** (p = 0.010); IL-8↑* (p at baseline.

Brain Behavior and Immunity 116 (2024) 237–258

intervention were at baseline.

Brain Behavior and Immunity 116 (2024) 237–258

association with IL-1β

Brain Behavior and Immunity 116 (2024) 237–258

turned on again, lower at day 42

Brain Behavior and Immunity 116 (2024) 237–258

Brain Behavior and Immunity 116 (2024) 237–258

1st POD – BL: tVNS:

(continued on next page)

TNF-α level was hospitalization was

Brain Behavior and Immunity 116 (2024) 237–258

tVNS reduced the

Brain Behavior and Immunity 116 (2024) 237–258

–no change in metabolic The effect of tVNS on

Brain Behavior and Immunity 116 (2024) 237–258

Brain Behavior and Immunity 116 (2024) 237–258

In this first systematic review with meta-analysis on the effect of VNS

TNF-α 17 − 0.53 [− 1.57;0.51] − 1.08 0.297 [− 4.12;3.07] 86.80 % [80.4 %;91.1 %]

5. Conclusion Supplementary data to this article can be found online at https://doi.

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