Multi-focal ultrasound neuromodulation to the dorsal anterior cingulate cortex disrupts behavioural and neural pain processing

Transcranial ultrasound stimulation (TUS) is a promising non-invasive technique for modulating deep brain regions involved in pain. TUS applied to the dorsal anterior cingulate cortex (dACC), a region implicated in chronic pain and established target for deep brain stimulation, has shown potential for reducing pain. This study aimed to investigate the neural mechanisms underlying TUS effects on pain in healthy participants using neuroimaging. Thirty-two participants underwent two double-blind, randomised TUS-fMRI sessions (active or sham). A tonic cold stimulus was applied during multifocal dACC-TUS and during fMRI and magnetic resonance spectroscopy (MRS) blocks. While no significant main effect of TUS on pain intensity was observed, active TUS showed a significantly greater reduction in pain ratings between 28- and 55-minutes post-stimulation, suggesting a delayed analgesic effect. Active TUS also disrupted the typical relationship between stimulus temperature and reported pain intensity, indicating altered sensory encoding. There was increased functional connectivity between the dACC and the supplementary motor area, pre-motor cortex, mid-ACC and the supramarginal gyrus, along with decreased coupling with the periaqueductal grey (PAG), and altered salience network connectivity. Overall, these findings suggest TUS to the dACC has multidimensional effects across behavioural and neural aspects of pain processing, supporting its potential therapeutic value.