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Peer-reviewedCC BY-NC-ND 4.0Proceedings of the National Academy of Sciences of the United States of America

FMRI-guided focal transcranial magnetic stimulation of anterior cingulate cortex reduces opioid seeking and restores connectivity

  • Zilu Ma1
  • Ying Duan1
  • Hieu Nguyen1,2,3
  • Sabrina Lin1
  • Md Mohaiminul Haque1,4
  • Danni Wang1
  • Samantha Hoffman1
  • Aidan Carney1
  • Taylor Scott1
  • Eleni Varlas1
  • Elliot Stein1
  • Zheng-Xiong Xi5
3 more authors
  • Yavin Shaham6
  • Hanbing Lu1
  • Yihong Yang1
6 affiliations
  1. 1Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224
  2. 2School of Electrical Engineering, International University, VNU-HCM, Ho Chi Minh City 71309, Vietnam
  3. 3Viet Nam National University Ho Chi Minh City, Ho Chi Minh City 71309, Vietnam
  4. 4Department of Electrical and Electronic Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588
  5. 5Molecular Targets and Medication Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224
  6. 6Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224
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Abstract

Relapse remains a major challenge in opioid addiction treatment. Transcranial magnetic stimulation (TMS) has emerged as a potential therapeutic strategy for addiction, yet results had been mixed due to empirically selected stimulation targets and limited knowledge of neural circuit engagement. Here, we used a focal rat TMS platform to test whether high-density theta-burst stimulation (hdTBS) of the anterior cingulate cortex (ACC), a corticostriatal node implicated in opioid relapse by prior causal and longitudinal functional MRI studies, decreases relapse-like oxycodone seeking and associated circuit dysfunction. Male rats self-administered oxycodone intravenously for 14 d and then underwent 13 d of electric barrier-induced abstinence, a procedure that suppresses drug taking while preserving drug availability and drug-associated context. During abstinence, the rats received seven daily sessions of sham stimulation or ACC-targeted hdTBS, with relapse tests and longitudinal functional MRI acquired during early and late abstinence to assess the behavioral and circuit-level effects of stimulation. Sham-treated rats showed a time-dependent increase (incubation) in oxycodone seeking and reduced ACC connectivity with dorsal and ventral striatum. In contrast, ACC-targeted hdTBS prevented incubation of oxycodone seeking and reversed abstinence-associated ACC-striatal connectivity reductions. Stimulation-sensitive functional circuits showed spatial correspondence with tracer-defined ACC projection patterns, suggesting that anatomical connectivity is critical to the circuit-level effects of focal stimulation. These findings support ACC-centered corticostriatal circuits as mechanistically informed targets for neuromodulation in opioid addiction and introduce a preclinical framework for linking stimulation, behavior, and longitudinal circuit remodeling.

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Cite

BibTeXRIS
BibTeX
@article{ma2026fmriguided,
  title = {{FMRI-guided focal transcranial magnetic stimulation of anterior cingulate cortex reduces opioid seeking and restores connectivity}},
  author = {Zilu Ma and Ying Duan and Hieu Nguyen and Sabrina Lin and Md Mohaiminul Haque and Danni Wang and Samantha Hoffman and Aidan Carney and Taylor Scott and Eleni Varlas and Elliot Stein and Zheng-Xiong Xi and Yavin Shaham and Hanbing Lu and Yihong Yang},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2619013123},
  url = {https://doi.org/10.1073/pnas.2619013123},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - FMRI-guided focal transcranial magnetic stimulation of anterior cingulate cortex reduces opioid seeking and restores connectivity
AU  - Zilu Ma
AU  - Ying Duan
AU  - Hieu Nguyen
AU  - Sabrina Lin
AU  - Md Mohaiminul Haque
AU  - Danni Wang
AU  - Samantha Hoffman
AU  - Aidan Carney
AU  - Taylor Scott
AU  - Eleni Varlas
AU  - Elliot Stein
AU  - Zheng-Xiong Xi
AU  - Yavin Shaham
AU  - Hanbing Lu
AU  - Yihong Yang
PY  - 2026
DA  - 2026/10/26
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2619013123
UR  - https://doi.org/10.1073/pnas.2619013123
AB  - Relapse remains a major challenge in opioid addiction treatment. Transcranial magnetic stimulation (TMS) has emerged as a potential therapeutic strategy for addiction, yet results had been mixed due to empirically selected stimulation targets and limited knowledge of neural circuit engagement. Here, we used a focal rat TMS platform to test whether high-density theta-burst stimulation (hdTBS) of the anterior cingulate cortex (ACC), a corticostriatal node implicated in opioid relapse by prior causal and longitudinal functional MRI studies, decreases relapse-like oxycodone seeking and associated circuit dysfunction. Male rats self-administered oxycodone intravenously for 14 d and then underwent 13 d of electric barrier-induced abstinence, a procedure that suppresses drug taking while preserving drug availability and drug-associated context. During abstinence, the rats received seven daily sessions of sham stimulation or ACC-targeted hdTBS, with relapse tests and longitudinal functional MRI acquired during early and late abstinence to assess the behavioral and circuit-level effects of stimulation. Sham-treated rats showed a time-dependent increase (incubation) in oxycodone seeking and reduced ACC connectivity with dorsal and ventral striatum. In contrast, ACC-targeted hdTBS prevented incubation of oxycodone seeking and reversed abstinence-associated ACC-striatal connectivity reductions. Stimulation-sensitive functional circuits showed spatial correspondence with tracer-defined ACC projection patterns, suggesting that anatomical connectivity is critical to the circuit-level effects of focal stimulation. These findings support ACC-centered corticostriatal circuits as mechanistically informed targets for neuromodulation in opioid addiction and introduce a preclinical framework for linking stimulation, behavior, and longitudinal circuit remodeling.
SN  - 0027-8424
SN  - 1091-6490
ER  -