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Global connectivity-based target selection for rTMS did not enhance analgesic efficacy in chronic pain patients compared to classic M1 stimulation

In a randomized, double-blind trial, 90 chronic pain patients received 12 sessions of rTMS over 8 weeks, comparing stimulation of the cortical site with lowest pre-therapy global connectivity, highest connectivity, or classic M1 stimulation. No significant between-group differences were found for the primary outcome (≥30% pain reduction) or secondary outcomes (all p > 0.05). Exploratory analyses showed that lower local M1 connectivity was associated with greater pain reduction only in the Classic-M1 group (r = 0.50, p = 0.005).

Last updated: Jul 19, 2026•1 RCTs•📖 Read as article →

Evidence Score

Evidence Score48/100
Human RCT★★☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism★★★★★
Safety★★★★☆
Confidencelow

Study Evidence

Study 1. Personalizing neuromodulation for chronic pain: A connectivity-guided trial.

observational

De Martino E, Midtgaard Bach M, Nascimento Couto B, Jakobsen A, Nascimento Martins P, Ingemann-Molden S, Casali AG, Graven-Nielsen T, Ciampi de Andrade D · Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (2026)

Participants: N/A
Duration: 8 weeks
Intervention: rTMS targeting the cortical site with lowest pre-therapy global connectivity vs. highest connectivity vs. classic M1 stimulation
Outcome: Proportion of patients achieving ≥30% reduction in pain intensity; secondary outcomes included pain intensity, pain interference, sleep, fatigue, mood, quality of life, and patient global impression of change
Effect Size: N/A (no significant between-group differences for primary outcome)
Population: 90 patients with chronic pain

Result:

PubMed: 42456233DOI: 10.1016/j.neurot.2026.e00960

Mechanism Graph

Pre-therapy TMS-evoked EEG potentials recorded from four cortical targets
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Connectivity quantified using distance-weighted, phase-based measure (debiased wPLI)
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Stimulation applied to site with lowest global connectivity (Low-Connectivity group), highest connectivity (High-Connectivity group), or classic M1 (Classic-M1 group)
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No significant difference in pain reduction between groups; local M1 connectivity correlated with outcome only in Classic-M1 group

Limitations

  • ⚠Exploratory mechanistic analyses were prespecified but not primary, limiting causal inference
  • ⚠Findings from local M1 connectivity association are hypothesis-generating and require prospective validation

Frequently Asked Questions

Did the novel connectivity-guided rTMS approach improve pain relief compared to standard M1 stimulation?▼

No, the study found no significant differences between the connectivity-guided groups and the classic M1 stimulation group for any primary or secondary outcomes.

What was the primary outcome measure in this trial?▼

The primary outcome was the proportion of patients achieving at least 30% reduction in pain intensity after 8 weeks of rTMS.

How was cortical connectivity measured in this study?▼

Connectivity was quantified using a distance-weighted, phase-based measure called the debiased weighted phase lag index (wPLI), derived from TMS-evoked EEG potentials recorded from four cortical targets.

What did the exploratory analysis reveal about local M1 connectivity?▼

Lower pre-therapy local M1 connectivity was associated with greater pain reduction in the Classic-M1 group (r = 0.50, p = 0.005), but not in the Low- or High-Connectivity groups.

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References

  1. 1.De Martino E, Midtgaard Bach M, Nascimento Couto B, Jakobsen A, Nascimento Martins P, Ingemann-Molden S, Casali AG, Graven-Nielsen T, Ciampi de Andrade D. "Personalizing neuromodulation for chronic pain: A connectivity-guided trial.." Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2026. PMID: 42456233 DOI: 10.1016/j.neurot.2026.e00960
Disclaimer: This content is for educational purposes only and is not medical advice. Evidence scores reflect the quality and quantity of available research, not clinical recommendations. Always consult a healthcare professional before starting any supplement or intervention.