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Abnormal ventromedial-to-dorsolateral hierarchical topography of striatal circuits in cocaine use disorder and its modulations by brain stimulation

Neuropsychopharmacology volume 50, pages 1354–1363 (2025)Cite this article

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Abstract

Cocaine use disorder (CUD) has been linked to cortico-striatal dysfunctions, particularly within the prefrontal-striatal circuitry. However, previous studies have typically focused on discrete parcellations of the striatum, overlooking its continuous variations of neural organization. Moreover, while repetitive transcranial magnetic stimulation (rTMS) has shown benefits in CUD treatment, the neural effects of rTMS on striatal dysfunction in CUD remain poorly understood. Using connectome gradient-mapping techniques on three resting-state functional magnetic resonance imaging datasets, we derived the ventromedial-to-dorsolateral striatal functional topography. We identified specific alterations in this topography in the discovery cohort (41 CUD patients and 44 controls), validated findings in an independent cohort (53 CUD patients and 45 controls), and examined whether rTMS targeting the left dorsolateral prefrontal cortex (dlPFC) could normalize abnormalities in the rTMS-treatment cohort (44 patients). Across all datasets, we found a positive correlation between gradient variation and drug dependence severity in CUD. Compared to controls, CUD in both the discovery and replication cohorts exhibited elevated gradient values in the ventral striatum, while decreased values in the dorsal striatum were observed only in the discovery cohort. Furthermore, in the rTMS-treatment cohort, 5-Hz rTMS targeting the left dlPFC significantly normalized the aberrant gradient values in the ventral striatum, and these changes also related to cocaine craving changes. Overall, our study provides novel evidence of specific alterations in the ventromedial-to-dorsolateral functional topography of the striatum in CUD patients and highlights the impact of rTMS on striatal circuits through prefrontal modulation.

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Fig. 1: Gradient analysis, main questions and corresponding analytic workflow.
Fig. 2: Ventromedial-to-dorsolateral striatal functional gradient in patients with CUD and controls in the discovery cohort.
Fig. 3: Ventromedial-to-dorsolateral striatal gradient in patients with CUD and controls in the replication cohort.
Fig. 4: Gradient alterations in ventral striatum for the 2-week acute phase.

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Data availability

The datasets used in the discovery cohort and rTMS-treatment cohort are publicly available. The SUDMEX-CONN dataset is available from Zenodo (https://zenodo.org/record/5123331). The SUDMEX-TMS dataset is also available from Zenodo (https://zenodo.org/record/7126853). The data of replication cohort supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank E.A.G.-V. and colleagues for sharing data included in the discovery and rTMS-treatment cohorts. This work was partly supported by the National Natural Science Foundation of China (grant no. 31972906 to QH), and the Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning (grant no. CNLZD2102 to QH). XX and YY were supported by the Intramural Research Program of National Institute on Drug Abuse, National Institutes of Health, USA.

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Authors and Affiliations

  1. Faculty of Psychology and MOE Key Lab of Cognition and Personality, Southwest University, Chongqing, 400715, China

    Ran Zhang, Debo Dong, Ting Xu, Feng Zhou, Yawei Qi & Qinghua He

  2. State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, 100875, China

    Ran Zhang & Qinghua He

  3. Neuroimaging Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA

    Xiang Xiao, Tianye Zhai & Yihong Yang

  4. Department of Applied Psychology, Faculty of Arts and Sciences, Beijing Normal University at Zhuhai, Zhuhai, 519087, China

    Xiang Xiao

  5. Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou, 310058, China

    Yuzheng Hu

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Contributions

RZ, and QH conceptualized and designed the work. RZ, and TZ preprocessed the data. RZ, and XX performed data analysis. RZ, XX, YH, YY and QH were responsible for the interpretation of the data. DD, TX, FZ, and YQ provided important suggestions during the formal analysis. RZ drafted the manuscript. DD and FZ provided suggestions during manuscript writing. YH, YY, and QH revised the paper. QH supervised the project.

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Correspondence to Yihong Yang or Qinghua He.

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Zhang, R., Xiao, X., Dong, D. et al. Abnormal ventromedial-to-dorsolateral hierarchical topography of striatal circuits in cocaine use disorder and its modulations by brain stimulation. Neuropsychopharmacol. 50, 1354–1363 (2025). https://doi.org/10.1038/s41386-025-02098-z

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