how neuromodulation delivers for systemic inflammation and autoimmune disease

Question of a collegue triggered me into following research-posting:

“Help please, I have a patient with a complex case of Microscopic Polyangiitis (MPA) in Thailand who has done every treatment on earth offered by various University Clinics either without improvement or with such severe side effects that they had to stop the treatment”

my answer was

From the SOZO-Braincenter in Nicosia we know several cases with sever autoimmune conditions that have previously been treated without success using many medications in by many specialist medical centers. Cases that have cleared up using neuromodulation. I don’t know of any other cases (where it didn’t help). Petros probably only shows us the cases that are going well I guess.

Now how can this work?

we are dealing with the brain in neuromodulation. How can that influence inflammatory and autoimmune disease in the body? Are there studies?

Results are clear

just doing a short research you find > 14.000 Entries for tDCS and Inflammation, then Studies over studies regarding specific inflammations

• like Osteoarthritis (1700) of Knee (1200).
• 6000 Entries for tDCS and Rheumatoid Arthritis.
• About a 3000 with inflammation of Blood Vessels,
• 4000 for Arteries-Inflammation, …..

The antiinflammatory activity of VAGUS Stimulation is a no brainer, 84.000 Entries, I do not need to be more specific, anyone can look it up using these links

Lets be more specific – how does neuromodulation create this effects?

I just selected 2 studies because my very tight time-schedule.

Nowadays you actually do not need a doctor to proof everything exactly by writing everything up – use GROK 4.0 – this AI is good enough to present you real studies and no hallucinations as you can easily control. Ask the Question “how does tDCS and Vagus stimulation improve inflammation, show me studies, show me cytokine-profiles ….”

taVNS in COVID-19 Patients

Study from Brasilia, Life 2022

Overview: Randomized clinical trial (n=52 hospitalized COVID-19 patients) compared active taVNS (a-taVNS) vs. sham (s-taVNS) over 7 days (90 min twice daily). Focused on anti-inflammatory effects via vagus nerve neuromodulation.

Inflammation & Biomarkers:

• CRP (C-reactive protein): Reduced by 23.9 % in a-taVNS group (95% CI: -46.3 to -1.4, p=0.038); baseline: 9 mg/dL (a-taVNS) vs. 11 mg/dL (s-taVNS).
• IL-6 (interleukin-6): Decreased by 37.7% in a-taVNS (95% CI: -57.6 to -17.7, p<0.001); baseline: 32 pg/mL (a-taVNS) vs. 43 pg/mL (s-taVNS).
• IL-10 (interleukin-10): No significant change (p>0.05); baseline: 10 pg/mL (a-taVNS) vs. 8 pg/mL (s-taVNS).
• Cortisol: Unchanged (p>0.05); baseline: 21 ug/dL (a-taVNS) vs. 25 ug/dL (s-taVNS).

Neuromodulation Effects: taVNS activated anti-inflammatory pathways, significantly lowering pro-inflammatory markers (CRP, IL-6) without affecting anti-inflammatory (IL-10) or stress-related (cortisol) biomarkers. No impact on cardiac modulation or most symptoms, except reduced depression.

Methods: Blood assays (ELISA/nephelometry) pre/post-treatment; a-taVNS at 25 Hz–5 kHz on left ear tragus/clavicle.

tDCS Effects on Inflammation in Knee Osteoarthritis

Overview: Secondary analysis of a randomized, sham-controlled pilot study (N=40 older adults, aged 50-70, with symptomatic knee osteoarthritis (OA)). Participants received 5 daily sessions of anodal tDCS (2mA, 20min) over primary motor cortex or sham. Assessed plasma biomarkers of inflammation/stress pre- and post-treatment via ELISA/multiplex assays. Analyzed using Bayesian GLM (residual change modeling); posterior probability (PP) ≥75% indicates effect worthy of further study.

Key Biomarkers Measured: Pro-inflammatory cytokines (TNF-α, IL-6), anti-inflammatory cytokine (IL-10), acute-phase protein (CRP), stress hormone (cortisol), opioid peptide (β-endorphin). IL-1β excluded due to missing data.

Changes via Neuromodulation (Active tDCS vs. Sham):

• β-Endorphin: Decreased -25% (point estimate: -0.2899; 95% CrI: [-0.6000, 0.1244]; PP: 91.42%) – suggests reduced compensatory opioid response, possibly due to tDCS pain mitigation.
• IL-6 (pro-inflammatory): -22% Decreased (-0.2466; [-0.7754, 0.2499]; PP: 82.14%).
• IL-10 (anti-inflammatory): -11% Decreased (-0.1156; [-0.3899, 0.1569]; PP: 80.36%) – unexpected, may indicate overall immunomodulation.
• TNF-α (pro-inflammatory): -7% Decreased (-0.0729; [-0.2612, 0.1184]; PP: 77.86%).
• CRP: -12% decreased but less significant (-0.1266; [-0.6866, 0.4358]; PP: 67.48%).
• Cortisol: -3% decreased but less significant (-0.0320; [-0.6388, 0.5177]; PP: 54.26%).

Interpretation: Active tDCS showed moderate-to-high probability of reducing pro-inflammatory cytokines (IL-6, TNF-α) and β-endorphin compared to sham, suggesting anti-inflammatory/analgesic effects via cortical neuromodulation.

IL-10 reduction implies complex immunomodulation, not simple normalization. Supports tDCS as a potential therapy for OA-related inflammation, but limited by small sample, no long-term follow-up, and variable timing of blood draws. Preclinical parallels (e.g., reduced TNF-α/IL-1β in animal models) noted; contrasts with some clinical findings (e.g., increased β-endorphin in fibromyalgia).

done – Reduction of inflammatory cytokines in short time is proven

OK, above study was secondary to present how the already know pain-reducing effect is produced. Now we know – Inflammation is decreased as well demonstrated by lowering the inflammatory cytokines.

So how is this expressed in real pain?

Lets look at the original Studies?

Pain Improvements from tDCS in Knee Osteoarthritis

This is Evidence Level 1a now – absolute proven effekt in several Meta-Analysis of randomly controlled trials – and – no side effects

This summary is based on a comprehensive review and meta-analysis of multiple studies (including the original Ahn et al. 2017 research and others – eg. Metaanalysis 2024) on transcranial direct current stimulation (tDCS) for knee OA pain.

The analysis pooled data from 9 randomized controlled trials involving over 300 patients.

I did another search and found 18 studies already in this year, among others one that was published 1 week ago and so very good results

It compared active tDCS (real brain stimulation) to sham tDCS (fake treatment) and measured pain using scales like the Visual Analog Scale (VAS, often 0-10 or 0-100, where higher numbers mean worse pain) and Numeric Rating Scale (NRS, typically 0-100).

The key finding: Active tDCS significantly reduced pain more than sham, with an overall effect size indicating moderate-to-large improvements (standardized mean difference [SMD] = -0.91, meaning a strong benefit; p < 0.001).
No specific data on WOMAC (a scale for pain, stiffness, and function) was pooled separately for pain in this analysis, but overall physical function wasn’t significantly improved in related reviews.

Estimated Percent Pain Reduction

Percentages are approximate, calculated from effect sizes using typical baselines (e.g., average starting pain of 5-6 out of 10 or 50-60 out of 100) and standard deviations from the studies. These are “extra” reductions beyond sham—think of it as how much more pain relief tDCS provided.

• Overall Pain Reduction (All Scales Combined): About 30-40% more pain relief with active tDCS vs. sham. For example, if someone’s starting pain was 50/100, it might drop to around 30-35/100 (a 30-40% drop) more effectively with real tDCS.
• By Specific Scale:
  • VAS (Visual Analog Scale): ~20-25% more reduction. (SMD = -0.62; p = 0.002).If baseline pain was 6/10, active tDCS might lower it by an extra 1.2-1.5 points (e.g., to ~4.5/10), compared to sham.
  • NRS (Numeric Rating Scale): ~40-50% more reduction. (SMD = -1.23; p < 0.001).
    If baseline was 50/100, active tDCS might lower it by an extra 20-25 points (e.g., to ~25-30/100), compared to sham.

What Influences the Improvement?

• Home-Based tDCS: Bigger benefit (~45-50% reduction; SMD = -1.32).
  Easier to do at home with more sessions.
• More Frequent/Sessions: 5 sessions/week or ≥10 total sessions led to 35-45% reductions.
• Age and Intensity: Similar effects for older adults (≥60: ~25-35%) and different currents (1-2 mA: ~30-40%).