Noninvasive brain stimulation beyond the motor cortex: a systematic review and meta-analysis exploring effects on quantitative sensory testing in clinical pain

Background: Noninvasive brain stimulation (NIBS) has been investigated increasingly as a means of treating pain. The effectiveness of NIBS in the treatment of pain has traditionally focused on protocols targeting the primary motor cortex (M1). However, over time, the effectiveness of M1 NIBS has been attributed to effects on interconnected cortical and subcortical sites rather than on M1 itself. Although previous reviews have demonstrated the effectiveness of non-M1 NIBS in improving subjective reports of pain intensity, the neurophysiological mechanisms underlying these effects remain incompletely understood. As chronic pain is associated with pain hypersensitivity and impaired endogenous descending pain modulation, it is plausible that non-M1 NIBS promotes analgesic effects by influencing these processes. Objective: The aim of this systematic review and meta-analysis was therefore to evaluate the effect of NIBS over non-M1 sites on quantitative sensory testing measures in clinical pain populations. Methods: A systematic search of electronic databases was conducted from inception to January 2024. Included articles (13 trials, n 1 / 4 565 participants) were appraised with the Physiotherapy Evidence Database (PEDro) scale and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE), and a random-effects model was used to meta-analyze outcomes where possible. Results: A small number of studies found that NIBS applied to the dorsolateral prefrontal cortex might improve pain modulation in patients with fibromyalgia and that stimulation of the posterior superior insula and prefrontal cortex could improve pain sensitivity in chronic neuropathic and osteoarthritic pain, respectively. However, findings varied among studies, and there remains a paucity of primary research. Conclusion: This review indicates that current literature does not provide clear evidence that NIBS over non-M1 sites influences pain processing.