Personalizing neuromodulation for chronic pain: A connectivity-guided trial

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.