Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Preliminary evidence for enhanced auditory cortex activation and mental development after gene therapy in children with autosomal recessive deafness 9

Nature Human Behaviour volume 9, pages 1457–1469 (2025)Cite this article

Subjects

Abstract

Individuals with congenital deafness that have received gene therapy represent a unique group who experience hearing recovery and speech development. However, it is unclear how hearing-related cortex changes because of gene therapy. Here we study neural processing in ten patients using functional near-infrared spectroscopy and electroencephalography during a six-month follow-up period. Patients showed an enhancement of activation in the auditory cortex, particularly in parts of the Sylvian parietotemporal area while listening to music. Activation in the right anterior temporal lobe and left Sylvian parietotemporal area was also enhanced when listening to speech. The electroencephalography data showed that the power of the resting-state electroencephalography beta band at time points T2 and T3 was statistically significantly increased after gene therapy, and mismatch negativity amplitudes at T2 and T3 were statistically significantly higher than those at T0. The mental developmental level of the patients also increased after gene therapy. These preliminary findings illuminate the neural and cognitive effects of gene therapy, supporting its potential effectiveness in auditory and mental development.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The arrangement of the light sources and detectors and the positions of the detection channels for fNIRS and paradigm design.
Fig. 2: The mean activation levels resulting from the music stimuli at different stages.
Fig. 3: The mean activation levels resulting from the speech stimuli at different stages.
Fig. 4: Resting-state EEG beta band power and its topographic maps at different stages.
Fig. 5: The results of the MMN responses at T0, T1, T2 and T3.
Fig. 6: Mental developmental assessment results for all patients at different time points.
Fig. 7: The correlation between H/Sp of the GMDS and EEG indices.

Similar content being viewed by others

Data availability

To respect the privacy of the participants, individual patient data are anonymized. The de-identified data (text, figures, tables and appendices) are available in the manuscript. The detailed data analysis is available in the Supplementary Information. Requests for more information on the trial should be directed to the corresponding author.

Code availability

Requests for the code used should be directed to the corresponding author.

References

  1. Lieu, J. E. C., Kenna, M., Anne, S. & Davidson, L. Hearing loss in children: a review. JAMA 324, 2195–2205 (2020).

    Article  PubMed  Google Scholar 

  2. Morton, C. C. & Nance, W. E. Newborn hearing screening—a silent revolution. N. Engl. J. Med. 354, 2151–2164 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Chen, L. C., Stropahl, M., Schonwiesner, M. & Debener, S. Enhanced visual adaptation in cochlear implant users revealed by concurrent EEG–fNIRS. NeuroImage 146, 600–608 (2017).

    Article  PubMed  Google Scholar 

  4. Anderson, C. A., Cushing, S. L., Papsin, B. C. & Gordon, K. A. Cortical imbalance following delayed restoration of bilateral hearing in deaf adolescents. Hum. Brain Mapp. 43, 3662–3679 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sevy, A. B. et al. Neuroimaging with near-infrared spectroscopy demonstrates speech-evoked activity in the auditory cortex of deaf children following cochlear implantation. Hear. Res. 270, 39–47 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Anderson, C. A., Wiggins, I. M., Kitterick, P. T. & Hartley, D. E. H. Adaptive benefit of cross-modal plasticity following cochlear implantation in deaf adults. Proc. Natl Acad. Sci. USA 114, 10256–10261 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee, H. J. et al. Preoperative differences of cerebral metabolism relate to the outcome of cochlear implants in congenitally deaf children. Hear. Res. 203, 2–9 (2005).

    Article  PubMed  Google Scholar 

  8. Zeng, F. G., Rebscher, S., Harrison, W., Sun, X. & Feng, H. Cochlear implants: system design, integration, and evaluation. IEEE Rev. Biomed. Eng. 1, 115–142 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lv, J. et al. AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial. Lancet 403, 2317–2325 (2024).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, H. et al. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nat. Med. 30, 1898–1904 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Qi, J. et al. AAV-mediated gene therapy restores hearing in patients with DFNB9 deafness. Adv. Sci. (Weinh.) 11, e2306788 (2024).

    PubMed  Google Scholar 

  12. Zeng, F.-G. Gene therapy restored partial hearing in a dozen deaf children. Hear. J. 77, 1,2 (2024).

    Article  Google Scholar 

  13. Strenzke, N. A cure for deafness? Med 5, 285–287 (2024).

    Article  PubMed  Google Scholar 

  14. Dewey, R. S. & Hartley, D. E. Cortical cross-modal plasticity following deafness measured using functional near-infrared spectroscopy. Hear. Res. 325, 55–63 (2015).

    Article  PubMed  Google Scholar 

  15. Sandmann, P. et al. Rapid bilateral improvement in auditory cortex activity in postlingually deafened adults following cochlear implantation. Clin. Neurophysiol. 126, 594–607 (2015).

    Article  PubMed  Google Scholar 

  16. Sharma, A., Campbell, J. & Cardon, G. Developmental and cross-modal plasticity in deafness: evidence from the P1 and N1 event related potentials in cochlear implanted children. Int. J. Psychophysiol. 95, 135–144 (2015).

    Article  PubMed  Google Scholar 

  17. Quaresima, V., Bisconti, S. & Ferrari, M. A brief review on the use of functional near-infrared spectroscopy (fNIRS) for language imaging studies in human newborns and adults. Brain Lang. 121, 79–89 (2012).

    Article  PubMed  Google Scholar 

  18. Gagnon, L. et al. Quantification of the cortical contribution to the NIRS signal over the motor cortex using concurrent NIRS–fMRI measurements. NeuroImage 59, 3933–3940 (2012).

    Article  PubMed  Google Scholar 

  19. Pollonini, L. et al. Auditory cortex activation to natural speech and simulated cochlear implant speech measured with functional near-infrared spectroscopy. Hear. Res. 309, 84–93 (2014).

    Article  PubMed  Google Scholar 

  20. Anderson, C. A., Wiggins, I. M., Kitterick, P. T. & Hartley, D. E. H. Pre-operative brain imaging using functional near-infrared spectroscopy helps predict cochlear implant outcome in deaf adults. J. Assoc. Res. Otolaryngol. 20, 511–528 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wang, Y. et al. Differential auditory cortical development in left and right cochlear implanted children. Cereb. Cortex 32, 5438–5454 (2022).

    Article  PubMed  Google Scholar 

  22. Zhou, X. et al. Cortical speech processing in postlingually deaf adult cochlear implant users, as revealed by functional near-infrared spectroscopy. Trends Hear. 22, 2331216518786850 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhou, X. Q. et al. Cortical responses correlate with speech performance in pre-lingually deaf cochlear implant children. Front. Neurosci. 17, 1126813 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lawrence, R. J., Wiggins, I. M., Anderson, C. A., Davies-Thompson, J. & Hartley, D. E. H. Cortical correlates of speech intelligibility measured using functional near-infrared spectroscopy (fNIRS). Hear. Res. 370, 53–64 (2018).

    Article  PubMed  Google Scholar 

  25. Armony, J. L., Aubé, W., Angulo-Perkins, A., Peretz, I. & Concha, L. The specificity of neural responses to music and their relation to voice processing: an fMRI-adaptation study. Neurosci. Lett. 593, 35–39 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Whitehead, J. C. & Armony, J. L. Singing in the brain: neural representation of music and voice as revealed by fMRI. Hum. Brain Mapp. 39, 4913–4924 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Peretz, I., Vuvan, D., Lagrois, M. & Armony, J. L. Neural overlap in processing music and speech. Phil. Trans. R. Soc. B 370, 20140090 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hamilton, L. S., Oganian, Y., Hall, J. & Chang, E. F. Parallel and distributed encoding of speech across human auditory cortex. Cell 184, 4626–4639.e4613 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hickok, G. & Poeppel, D. The cortical organization of speech processing. Nat. Rev. Neurosci. 8, 393–402 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Ponton, C. W., Moore, J. K. & Eggermont, J. J. Prolonged deafness limits auditory system developmental plasticity: evidence from an evoked potentials study in children with cochlear implants. Scand. Audiol. Suppl. 51, 13–22 (1999).

    CAS  PubMed  Google Scholar 

  31. Olds, C. et al. Cortical activation patterns correlate with speech understanding after cochlear implantation. Ear Hear. 37, e160–e172 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mushtaq, F., Wiggins, I. M., Kitterick, P. T., Anderson, C. A. & Hartley, D. E. H. Investigating cortical responses to noise-vocoded speech in children with normal hearing using functional near-infrared spectroscopy (fNIRS). J. Assoc. Res. Otolaryngol. 22, 703–717 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lawrence, R. J., Wiggins, I. M., Hodgson, J. C. & Hartley, D. E. H. Evaluating cortical responses to speech in children: a functional near-infrared spectroscopy (fNIRS) study. Hear. Res. 401, 108155 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wang, S. et al. Features of beta-gamma phase-amplitude coupling in cochlear implant users derived from EEG. Hear. Res. 428, 108668 (2023).

    Article  PubMed  Google Scholar 

  35. Gola, M., Magnuski, M., Szumska, I. & Wróbel, A. EEG beta band activity is related to attention and attentional deficits in the visual performance of elderly patients. Int. J. Psychophysiol. 89, 334–341 (2013).

    Article  PubMed  Google Scholar 

  36. Turgeon, C., Lazzouni, L., Lepore, F. & Ellemberg, D. An objective auditory measure to assess speech recognition in adult cochlear implant users. Clin. Neurophysiol. 125, 827–835 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Zhang, F. et al. Mismatch negativity and adaptation measures of the late auditory evoked potential in cochlear implant users. Hear. Res. 275, 17–29 (2011).

    Article  PubMed  Google Scholar 

  38. Jeong, S. W., Chung, S. H. & Kim, L. S. P1 cortical auditory evoked potential in children with unilateral or bilateral cochlear implants: implication for the timing of second cochlear implantation. Eur. Arch. Otorhinolaryngol. 275, 1759–1765 (2018).

    Article  PubMed  Google Scholar 

  39. Okada, K. et al. Hierarchical organization of human auditory cortex: evidence from acoustic invariance in the response to intelligible speech. Cereb. Cortex 20, 2486–2495 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Callan, A. & Callan, D. E. Understanding how the human brain tracks emitted speech sounds to execute fluent speech production. PLoS Biol. 20, e3001533 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Colletti, L., Mandalà, M., Zoccante, L., Shannon, R. V. & Colletti, V. Infants versus older children fitted with cochlear implants: performance over 10 years. Int. J. Pediatr. Otorhinolaryngol. 75, 504–509 (2011).

    Article  PubMed  Google Scholar 

  42. Yang, Y. et al. The longitude study on the mental development of congenital hearing-impaired infants and toddlers. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 50, 799–804 (2015).

    PubMed  Google Scholar 

  43. Dang, J. et al. The value of nonverbal intelligence in cochlear implant. Acta Otolaryngol. 143, 24–27 (2023).

    Article  PubMed  Google Scholar 

  44. Julien, C. The enigma of Mayer waves: facts and models. Cardiovasc. Res. 70, 12–21 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Costa, Á. et al. Decoding the attentional demands of gait through EEG gamma band features. PLoS ONE 11, e0154136 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Griffiths, R. & Huntley, M. Griffiths Mental Development Scales—Revised: Birth to 2 Years (American Psychological Association, 1996).

  47. Griffiths, R. The Abilities of Young Children: A Comprehensive System of Mental Measurement for the First Eight Years of Life (ARICD, 1984).

  48. Wechsler, D. Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) Vol. 1 (APA PsycTests, 2003).

Download references

Acknowledgements

We thank the patients and their families for their participation in and support of the study. This work was supported by the Eye & ENT Hospital of Fudan University. The study was supported by the National Natural Science Foundation of China (grant 82225014 (Y.S.), 82171148 (Y.S.), 62371217 (F.C.), 82192864 (H.L.), 82071048 (B.C.) and 82201306 (Y.S.)), the National Key R&D Program of China (grant 2020YFA0908201 (Y.S.), 2021YFA1101302 (Y.S.), 2023YFA0915000(04) (H.T. and B.Z.)) and 2023YFC2508402 (S.S.), the Science and Technology Commission of Shanghai Municipality (grant 23J31900100 (Y.S.)), Xuhui District Hospital and Site Cooperation Project (grant 23XHYD-05 (Y.S.)), the Shanghai Municipal Education Commission (grant 2023ZKZD12 (Y.S.)), the Construction Foundation of First Class Universities 219 (grant 01270021922201*035 (Z.G.)), the Basic Scientific Research Foundation (grant 02120022124005 (Z.G.)), the Research Projects of Shanghai Municipal Health Committee (2022XD059 (S.S.)) and the Key Patient Construction Project of Shanghai Municipal Health Commission (grant shslczdzk02903 (X.X.)). The study was also funded by Shanghai Refreshgene Therapeutics Co., Ltd. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Jiajia Zhang, Zengzhi Guo, Changjie Pan, Chunchun Hu, Xinyang Weng.

  2. These authors jointly supervised this work: Shan Sun, Xiu Xu, Huawei Li, Fei Chen, Yilai Shu.

Authors and Affiliations

  1. ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China

    Jiajia Zhang, Xinyang Weng, Yang-wenyi Liu, Xiaoting Cheng, Jun Lv, Qi Cao, Hui Wang, Yuxin Chen, Daqi Wang, Shaowei Hu, Mengzhao Xun, Longlong Zhang, Zijing Wang, Honghai Tang, Biyun Zhu, Luo Guo, Sha Yu, Bing Chen, Shan Sun, Huawei Li & Yilai Shu

  2. NHC Key Laboratory of Hearing Medicine Research and MOE Engineering Research Center of Gene Technology, Fudan University, Shanghai, China

    Jiajia Zhang, Xinyang Weng, Yang-wenyi Liu, Xiaoting Cheng, Jun Lv, Qi Cao, Hui Wang, Yuxin Chen, Daqi Wang, Shaowei Hu, Mengzhao Xun, Longlong Zhang, Zijing Wang, Honghai Tang, Biyun Zhu, Luo Guo, Sha Yu, Bing Chen, Shan Sun, Huawei Li & Yilai Shu

  3. Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Jiajia Zhang, Yang-wenyi Liu, Xiaoting Cheng, Jun Lv, Hui Wang, Yuxin Chen, Daqi Wang, Shaowei Hu, Mengzhao Xun, Longlong Zhang, Zijing Wang, Honghai Tang, Biyun Zhu, Luo Guo, Sha Yu, Bing Chen, Huawei Li & Yilai Shu

  4. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

    Jiajia Zhang, Yang-wenyi Liu, Xiaoting Cheng, Jun Lv, Hui Wang, Yuxin Chen, Daqi Wang, Shaowei Hu, Mengzhao Xun, Longlong Zhang, Zijing Wang, Honghai Tang, Biyun Zhu, Luo Guo, Sha Yu, Bing Chen, Huawei Li & Yilai Shu

  5. Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai, China

    Jiajia Zhang, Yang-wenyi Liu, Xiaoting Cheng, Jun Lv, Qi Cao, Hui Wang, Yuxin Chen, Daqi Wang, Shaowei Hu, Mengzhao Xun, Longlong Zhang, Zijing Wang, Honghai Tang, Biyun Zhu, Luo Guo, Sha Yu, Bing Chen, Huawei Li & Yilai Shu

  6. College of Medicine and Biologic Information Engineering, Northeastern University, Shenyang, China

    Zengzhi Guo

  7. Department of Electronic and Electrical Engineering, Southern University of Science and Technology, Shenzhen, China

    Changjie Pan & Fei Chen

  8. Department of Biomedical Engineering, Hong Kong Polytechnic University, Hong Kong, China

    Changjie Pan & Xiaoling Hu

  9. Department of Child Health Care, Children’s Hospital of Fudan University, Shanghai, China

    Chunchun Hu & Xiu Xu

  10. Auditory Research Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, China

    Lin Chen

  11. Department of Otolaryngology—Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA, USA

    Zheng-Yi Chen

  12. Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA, USA

    Zheng-Yi Chen

  13. Department of Otolaryngology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Zhejiang, China

    Yilai Shu

Authors
  1. Jiajia Zhang
    View author publications

    Search author on:PubMed Google Scholar

  2. Zengzhi Guo
    View author publications

    Search author on:PubMed Google Scholar

  3. Changjie Pan
    View author publications

    Search author on:PubMed Google Scholar

  4. Chunchun Hu
    View author publications

    Search author on:PubMed Google Scholar

  5. Xinyang Weng
    View author publications

    Search author on:PubMed Google Scholar

  6. Yang-wenyi Liu
    View author publications

    Search author on:PubMed Google Scholar

  7. Xiaoting Cheng
    View author publications

    Search author on:PubMed Google Scholar

  8. Jun Lv
    View author publications

    Search author on:PubMed Google Scholar

  9. Qi Cao
    View author publications

    Search author on:PubMed Google Scholar

  10. Hui Wang
    View author publications

    Search author on:PubMed Google Scholar

  11. Yuxin Chen
    View author publications

    Search author on:PubMed Google Scholar

  12. Daqi Wang
    View author publications

    Search author on:PubMed Google Scholar

  13. Shaowei Hu
    View author publications

    Search author on:PubMed Google Scholar

  14. Mengzhao Xun
    View author publications

    Search author on:PubMed Google Scholar

  15. Longlong Zhang
    View author publications

    Search author on:PubMed Google Scholar

  16. Zijing Wang
    View author publications

    Search author on:PubMed Google Scholar

  17. Honghai Tang
    View author publications

    Search author on:PubMed Google Scholar

  18. Biyun Zhu
    View author publications

    Search author on:PubMed Google Scholar

  19. Luo Guo
    View author publications

    Search author on:PubMed Google Scholar

  20. Sha Yu
    View author publications

    Search author on:PubMed Google Scholar

  21. Xiaoling Hu
    View author publications

    Search author on:PubMed Google Scholar

  22. Lin Chen
    View author publications

    Search author on:PubMed Google Scholar

  23. Bing Chen
    View author publications

    Search author on:PubMed Google Scholar

  24. Zheng-Yi Chen
    View author publications

    Search author on:PubMed Google Scholar

  25. Shan Sun
    View author publications

    Search author on:PubMed Google Scholar

  26. Xiu Xu
    View author publications

    Search author on:PubMed Google Scholar

  27. Huawei Li
    View author publications

    Search author on:PubMed Google Scholar

  28. Fei Chen
    View author publications

    Search author on:PubMed Google Scholar

  29. Yilai Shu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Y.S., H.L., X.X. and F.C. were the principal investigators of the study and conceived the trial. X.X., H.L., F.C. and Y.S. contributed to the study design. J.L., H.W. and Q.C. enrolled the patients. J.Z., C.H., Y.-w.L., X.C., M.X., L.Z., Z.W. and X.W. collected the data. J.Z., Z.G., C.H. and X.W. analysed the data and wrote the manuscript. J.Z., Z.G., C.H., C.P., X.W., S.S. and Y.S. accessed and verified the data. D.W., S.H., Y.C., H.T., B.Z., S.Y., X.H., L.C., B.C., Z.-Y.C., S.S., X.X., H.L., F.C. and Y.S. contributed to the revision of the manuscript. Y.C., H.T., B.C., Y.S., H.L. and X.X. obtained the funding. L.G., Y.S., D.W. and H.T. confirmed the genotypes of the patients. All authors vouch for the fidelity of the protocol and the accuracy and completeness of the reported data. All authors reviewed and approved the manuscript before submission. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Yilai Shu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Human Behaviour thanks Shuo Wang and Chen Chi Wu for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–13, Tables 1–3 and Methods.

Reporting Summary

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Guo, Z., Pan, C. et al. Preliminary evidence for enhanced auditory cortex activation and mental development after gene therapy in children with autosomal recessive deafness 9. Nat Hum Behav 9, 1457–1469 (2025). https://doi.org/10.1038/s41562-025-02184-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41562-025-02184-8

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing