Effect of Low-Intensity Transcranial Focused Ultrasound Stimulation on Neuropathic Pain: Protocol for a Randomized, Single-Blind, Placebo-Controlled, 3-Arm, Parallel-Group Trial

Abstract

Abstract Background Neuropathic pain (NP) remains difficult to manage because conventional pharmacological therapies often have limited efficacy and intolerable side effects. Noninvasive neuromodulation techniques have emerged as potential alternatives with fewer adverse effects. Meta-analyses of randomized controlled trials suggest that high-frequency repetitive transcranial magnetic stimulation over the primary motor cortex has analgesic effects; however, its efficacy is modest and restricted by the inability to stimulate deeper brain regions. Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel approach that enables precise targeting of deep brain structures and modulation of neural activity. Although promising in preclinical and preliminary human studies, its long-term therapeutic efficacy for NP remains unknown. Objective This trial aims to explore the therapeutic effects and safety of repeated TUS sessions in patients with NP. Methods This randomized, participant-blinded, placebo-controlled, 3-arm, parallel-group clinical trial will enroll 39 participants with NP (pain duration ≥3 months; pain intensity ≥4 on the numerical rating scale). Participants will be randomly allocated to one of three groups: (1) TUS targeting the primary motor cortex, (2) TUS targeting the posterior superior insula, or (3) sham stimulation. Each participant will undergo weekly sessions for 8 weeks. The primary outcome is change in weekly average pain intensity scores recorded in a pain diary. Secondary outcomes include additional pain scales, quality of life measures, psychological assessments, quantitative sensory testing, motor cortical excitability, and adverse events. Results The first participant was enrolled on April 30, 2025, and 20 participants had been enrolled as of February 28, 2026, with enrollment ongoing. The final analysis will be conducted after completion of follow-up and data verification. Conclusions To our knowledge, this will be the first randomized controlled trial to examine the long-term therapeutic effects of repeated low-intensity TUS for NP. It will provide exploratory proof-of-concept data regarding its clinical efficacy and safety.