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An electric-field-responsive paramagnetic contrast agent enhances the visualization of epileptic foci in mouse models of drug-resistant epilepsy

Nature Biomedical Engineering volume 5, pages 278–289 (2021)Cite this article

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Abstract

For patients with drug-resistant focal epilepsy, excision of the epileptogenic zone is the most effective treatment approach. However, the surgery is less effective in the 15–30% of patients whose lesions are not distinct when visualized by magnetic resonance imaging (MRI). Here, we show that an intravenously administered MRI contrast agent consisting of a paramagnetic polymer coating encapsulating a superparamagnetic cluster of ultrasmall superparamagnetic iron oxide crosses the blood–brain barrier and improves lesion visualization with high sensitivity and target-to-background ratio. In kainic-acid-induced mouse models of drug-resistant focal epilepsy, electric-field changes in the brain associated with seizures trigger breakdown of the contrast agent, restoring the T1-weighted magnetic resonance signal, which otherwise remains quenched due to the distance-dependent magnetic resonance tuning effect between the cluster and the coating. The electric-field-responsive contrast agent may increase the probability of detecting seizure foci in patients and facilitate the study of brain diseases associated with epilepsy.

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Fig. 1: Non-invasive visualization of the epileptic focus with an electrically responsive T1W-MR contrast agent.
Fig. 2: Development of EMs.
Fig. 3: Characterization of the EMs.
Fig. 4: Electrically triggered T1W-MR signal enhancement of EMs in vitro.
Fig. 5: EM visualizing the epileptic focus in acute seizure mouse models.
Fig. 6: EMs visualizing the epileptic focus in mouse models with spontaneous seizures.
Fig. 7: A positive correlation exists between abnormal EEG power and EM-associated T1W-MR signal enhancement.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding authors on reasonable request. The availability of raw patient data is subject to approval from the Institutional Review Board of Huashan Hospital.

Code availability

The raw MATLAB codes are available in the Supplementary Information.

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Acknowledgements

We thank M. Kuang, R. Liang, L. Zhan and X. Liu for experimental help. We thank X. Zhu for help with statistical analysis. We also thank L. Zhou, M. Gao and S. Jiang for useful discussions. This work was supported by the National Natural Science Foundation of China (grant no. 81771895, 81971598, 81725009 and 81501120), the Shanghai Foundation for Development of Science and Technology (grant no. 19431900400), the Shanghai Municipal Science and Technology Major Project (grant no. 2018SHZDZX01), the Fudan-SIMM Joint Research Fund (grant no. 20173001), the Asia 3 Foresight Program (grant no. 81761148029), the Shanghai Shuguang Program (grant no. 19SG06) and the Shanghai Municipal Commission of Health and Family Planning (grant no. 2017BR003).

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Author notes

  1. These authors contributed equally: Cong Wang, Wanbing Sun, Jun Zhang.

Authors and Affiliations

  1. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China

    Cong Wang, Qinghua Guo, Xingyu Zhou, Dandan Fan, Haoran Liu & Cong Li

  2. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

    Wanbing Sun & Jianhong Wang

  3. Institute of Functional and Molecular Medical Imaging, Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China

    Jun Zhang & Cong Li

  4. Department of Nuclear Medicine, Shanghai Cancer Center, Fudan University, Shanghai, China

    Jianping Zhang & Ming Qi

  5. State Key Laboratory of Metal Matrix Composites, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Xihui Gao

  6. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Haiyan Xu & Zhaobing Gao

  7. Department of Nuclear Medicine, The Second Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Mei Tian & Hong Zhang

  8. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China

    Zixuan Wei & Ying Mao

  9. Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, UK

    Nicholas J. Long

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  1. Cong Wang
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Contributions

C.W., H.Z., M.T., Y.M. and C.L. conceived and designed the research. C.W., W.S., Jianping Zhang, Q.G., X.Z., H.L., M.Q., D.F., X.G., H.X. and J.W. performed the experiments. Z.W. and Y.M. provided clinical patient specimens. C.W., W.S., Jun Zhang, Z.G., J.W., Z.W. and C.L. analysed and interpreted the results. C.W., N.J.L. and C.L. wrote the manuscript. C.L. supervised the overall project.

Corresponding authors

Correspondence to Ying Mao or Cong Li.

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Supplementary information

Supplementary Information

Supplementary methods, figures, tables and references.

Reporting Summary

MATLAB code

Code for the processing of mouse magnetic-resonance images.

Supplementary Video 1

Monitoring of typical seizure behaviours in mice.

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Wang, C., Sun, W., Zhang, J. et al. An electric-field-responsive paramagnetic contrast agent enhances the visualization of epileptic foci in mouse models of drug-resistant epilepsy. Nat Biomed Eng 5, 278–289 (2021). https://doi.org/10.1038/s41551-020-00618-4

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