Neuromodulation of the Cingulate Cortex for Pain.

The subgenual (sACC) and pregenual (pACC) anterior cingulate and anterior midcingulate (aMCC) cortices are structurally and functionally distinct subregions of the cingulate cortex with critical roles in pain processing. These regions may be promising therapeutic targets using non-invasive neuromodulation techniques, including transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), and low-intensity focused ultrasound (LIFU). In this review, we synthesize emerging evidence on the function and connectivity of these subregions in both acute and chronic pain, highlighting their differential roles in the sensory, affective, and autonomic contributions to pain processing. We compare the strengths and limitations of the different non-invasive neuromodulatory methods for accessing these deep midline structures and examine how technique-specific and target-specific effects influence analgesic outcomes. We also explore the influence of placebo mechanisms and stimulation context on therapeutic effects. Finally, we discuss emerging strategies such as personalized connectivity-based targeting to overcome anatomical and technical limitations to advance precision non-invasive neuromodulation for pain.