221: Connectivity-Guided Repetitive Transcranial Magnetic Stimulation Targeting for Chronic Pain

Topic: Clinical Science
Subtopic: Non-specific to any diagnosis, Neuromodulation (e.g. TMS, TDCS, FUS, SCS, MCS, DBS, vagus nerve stimulation)

Background and Aims: Repetitive transcranial magnetic stimulation (rTMS) can induce analgesic effects when applied to several cortical targets, including the primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and posterosuperior insula (PSI) [1]. However, no established method exists to identify the optimal stimulation site at the individual level. This mechanistic, three-arm, randomized, double-blind clinical trial (NCT06395649) investigated whether a global phase-based connectivity index derived from transcranial magnetic stimulation and electroencephalography (TMS–EEG) could guide rTMS target selection in chronic pain. We hypothesized that stimulating cortical targets with lower pre-treatment global connectivity would result in a greater analgesic response [2].

Methods: Ninety patients with chronic pain were recruited. During pre-treatment assessment, TMS–EEG was applied to four cortical targets: M1, DLPFC, ACC, and PSI. Based on a phase-locking-based global connectivity index, participants were randomized to Low Connectivity, High Connectivity, or Classical M1 (connectivity-independent). The primary outcome was >30% pain reduction from baseline. Secondary outcomes included pain intensity (7 days, 24 hours), pain severity and interference, and quality of life. Exploratory analyses investigated the correlation between pain reduction and two pre-treatment connectivity indices: within-cluster connectivity of the stimulated region and cluster-to-all connectivity between the stimulated cluster and the rest of the cortex.

Results: Fourteen patients in the Low Connectivity group (48%), fifteen in the High Connectivity group (50%), and eleven in the Classic M1 group (37%) achieved a ≥30% reduction in pain. Responder rates did not differ significantly among groups (chi-squared test, p = 0.530). No significant differences were observed among the three groups for secondary outcomes. Pre-planned exploratory analyses showed that, in the Classic M1 arm only, greater reductions in pain intensity over the last 7 days and the last 24 hours were significantly correlated with lower pre-treatment within-cluster connectivity (both r ≥ 0.50, p ≤ 0.005).

Conclusions: Allocation based on a phase-locking-based global connectivity index did not improve clinical outcomes compared with classical M1 stimulation. However, preplanned exploratory analyses indicate that lower local connectivity within the stimulated M1 cluster is associated with greater pain relief, suggesting that local M1 connectivity may be a useful marker of rTMS response. Future studies should evaluate whether M1-local connectivity–based classification can improve patient stratification and treatment efficacy.

References: [1] Ciampi de Andrade D, García-Larrea L. Beyond trial-and-error: Individualizing therapeutic transcranial neuromodulation for chronic pain. European Journal of Pain 2023;27:1065–83. https://doi.org/10.1002/ejp.2164.
[2] Bach MM, De Martino E, Ciampi De Andrade D, Nascimento Couto AB, Graven-Nielsen T. Personalized pain treatment by transcranial magnetic stimulation in patients with chronic pain: a study on mechanisms. OSF 2025. https://doi.org/osf.io/b2e8h.

Presenting Author: Enrico De Martino
Submitting Author: Enrico De Martino

Senior Author: Daniel Ciampi de Andrade

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Enrico De Martino: PhD - Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
• Margit Midtgaard Bach: PhD - Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
• Anne Jakobsen: Master's degree - Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg
• Pedro Nascimento Martins: MD - Federal University of Juiz de Fora, Juiz de Fora, Brazil
• Bruno Nascimento Couto: Master's degree - Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine, Aalborg University
• Stian Ingemann-Molden: Master's degree - Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine, Aalborg University
• Adenauer Casali: PhD - Institute of Science and Technology, Federal University of São Paulo, São Paulo, Brazil
• Thomas Graven-Nielsen: PhD - Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
• Daniel Ciampi de Andrade: PhD - Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg