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. J.L. discloses support for the research of this work from the National Natural Science Foundation of China [grant number 82572197], the Shaanxi Province Key R&D Program [grant number 2024SF-ZDCYL-01-08], the Fundamental Research Funds for the Central Universities [grant number QTZX25103], and the Xidian University Specially Funded Project for Interdisciplinary Exploration [grant number TZJH2024016]. C.Z. discloses support for the research of this work from the Nanchong Municipal Science and Technology Bureau Young Scientific and Technological Talent Program [grant number 25KJCXRC0012], the Research and Development Plan Project of the Affiliated Hospital of North Sichuan Medical College [grant numbers 2023PTZK002, 2024GC012, and 2024MPZK008], and the Sichuan Provincial Health Commission Clinical Research Special Project [grant number 23LCYJ019].

Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi’an, China Jiahui Xia, Wen Li, Jinglei Chen, Fuqiang Qu, Chuan Zhang & Jixin Liu Engineering Research Center of Molecular and Neuroimaging, Ministry of Education, Xidian University, Xi’an, China Jiahui Xia, Wen Li, Jinglei Chen, Fuqiang Qu & Jixin Liu Department of Medical Imaging, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, North Sichuan Medical College, Nanchong, China Correspondence to Chuan Zhang or Jixin Liu. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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