State- and frequency-specific high-definition transcranial alternating current stimulation of the dorsolateral prefrontal cortex for analgesia

The dorsolateral prefrontal cortex contributes to cognitive–affective pain regulation, but the optimal frequency and individualization strategy for high-definition transcranial alternating current stimulation remain unclear. Here we show, across three double-blind experiments in healthy human participants using a capsaicin-induced tonic pain model, that analgesia depends on stimulation frequency and the brain state used for frequency selection. Study 1 compares 10-Hz stimulation of the dorsolateral prefrontal cortex with 10-Hz stimulation of the primary sensorimotor cortex in 40 participants. Study 2 compares 7-Hz theta and 10-Hz alpha stimulation over the dorsolateral prefrontal cortex in 40 participants. Study 3 compares fixed 7-Hz stimulation with individualized theta frequencies derived from pain-free or pain-persistent oscillatory profiles in 28 participants. Participants receive 30 minutes of high-definition transcranial alternating current stimulation during tonic pain with continuous pain ratings. Alpha-band dorsolateral prefrontal cortex stimulation produces stronger acute and sustained analgesia than primary sensorimotor cortex stimulation. Theta-band stimulation produces greater and longer-lasting analgesia than alpha stimulation and is accompanied by increased prefrontal beta- and low-gamma activity. Individualized theta stimulation derived from pain- persistent states yields greater analgesia than fixed-frequency or pain-free-state-based stimulation. These findings identify frequency and brain state as key determinants of analgesic responses to dorsolateral prefrontal cortex stimulation. Three double-blind experiments test how frequency and brain state influence analgesia during tonic pain. Prefrontal theta stimulation tailored to brain activity during pain produces the strongest and most sustained pain relief.