Personalizing neuromodulation for chronic pain: A connectivity-guided trial
- Journal
- Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (Q1)
- Published
- 15 July 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Enrico De Martino, Margit Midtgaard Bach, Bruno Nascimento Couto, Anne Jakobsen, Pedro Nascimento Martins, Stian Ingemann-Molden, et al.
- PMID
- 42456233
- DOI
- 10.1016/j.neurot.2026.e00960
Why clinicians should know about it
- Picked for Anesthesiology and Pain Medicine (paper of the day, 16 July 2026).
Abstract
In this randomized, double-blind, controlled trial, we evaluated 8 weeks of repetitive transcranial magnetic stimulation (rTMS) for chronic pain, comparing classic primary motor cortex (M1) stimulation with a novel target-selection strategy based on pre-therapy cortical connectivity. Guided by homeostatic plasticity, we hypothesized that stimulating the cortical site with the lowest pre-therapy global connectivity would produce more pain relief than stimulating the site with the highest connectivity or stimulating M1 independent of connectivity. Before treatment, TMS-evoked EEG potentials were recorded from four cortical targets: M1, dorsolateral prefrontal cortex, anterior cingulate cortex, and posterosuperior insular cortex. For each target, connectivity was quantified using a distance-weighted, phase-based measure (debiased weighted phase lag index, wPLI) that reflects the magnitude and spatial extent of TMS-induced oscillatory phase locking across cortical regions. Ninety patients with chronic pain were randomized to Low-Connectivity, High-Connectivity, or Classic-M1 groups and received 12 rTMS sessions over 8 weeks. The primary outcome was the proportion of patients achieving at least 30% reduction in pain intensity. Secondary outcomes included pain intensity, pain interference, sleep, fatigue, mood, quality of life, and patient global impression of change. No significant between-group differences were observed for primary or secondary outcomes (all p > 0.05). In prespecified mechanistic exploratory analyses, 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. These findings suggest that global connectivity-based target selection did not enhance analgesic efficacy and that the local M1 associations are hypothesis-generating and require prospective validation.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.