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.

Advertisement

Scientific Reports
  • View all journals
  • Search
  • My Account Login
  • Content Explore content
  • About the journal
  • Publish with us
  • Sign up for alerts
  • RSS feed
  1. nature
  2. scientific reports
  3. articles
  4. article
Mismatch negativity-like responses in nitroglycerin-elicited migraine model
Download PDF
Download PDF
  • Article
  • Open access
  • Published: 25 March 2026

Mismatch negativity-like responses in nitroglycerin-elicited migraine model

  • Xingli Li1 na1,
  • Jilei Zhang1 na1,
  • Qi Liu1 na1,
  • Liyuan Zhang1,2,
  • Shiyang Zhao1,
  • Hao Zhao1,
  • Rui Zhao1,
  • Yuanyuan Jing1 &
  • …
  • Lisheng Yu1 

Scientific Reports , Article number:  (2026) Cite this article

  • 419 Accesses

  • 2 Altmetric

  • Metrics details

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Medical research
  • Neurology
  • Neuroscience
  • Physiology

Abstract

Mismatch negativity (MMN) is an endogenous event-related potential that reflects automatic information processing of the brain and exhibits alterations in latency and amplitude across various pathological conditions. The investigation of MMN-like responses in animal models has provided significant insights into the neural underpinnings of aberrant change-detection mechanisms. This study aims to investigate MMN-like responses in rat models of nitroglycerin (NTG)-induced migraine, to determine whether these responses resemble MMN alterations observed in migraine patients, and to explore novel tools for assessing cortical function in animal models of migraine. Male Wistar rats were assigned to two groups: an NTG-treated group, which received intermittent intraperitoneal injections of nitroglycerin to induce a migraine-like state, and a control group, which received equal volumes of saline. The classical oddball paradigm was employed as the stimulation protocol, and electroencephalography (EEG) signals were recorded concurrently. The latency and amplitude of MMN-like responses were compared between the NTG and control groups. During modeling, the mechanical threshold of rats in the NTG group gradually decreased over time, indicating the development of nociceptive hypersensitivity. Moreover, the mechanical threshold was significantly different from that of the control group on days 3, 5, 7, and 9 of drug administration. The latency in the NTG group exhibited an overall trend toward shortening compared with the control group, with significant differences observed between the second and third assays. The amplitude showed an overall upward trend compared with the control group, with significant differences detected in the third assay. Rats in the NTG group exhibited accelerated information processing and heightened cortical excitability during auditory stimulation, a finding consistent with observations in migraine patients.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Dodick, D. W. Migraine. Lancet 391 (10127), 1315–1330 (2018).

    Google Scholar 

  2. Burshtein, R. et al. Are episodic and chronic migraine one disease or two? Curr. Pain Headache Rep. 19 (12), 53 (2015).

    Google Scholar 

  3. Arakaki, X. et al. Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine. Brain Res. 1563, 110–121 (2014).

    Google Scholar 

  4. Bhola, R. et al. Single-pulse transcranial magnetic stimulation (sTMS) for the acute treatment of migraine: evaluation of outcome data for the UK post market pilot program. J. Headache Pain. 16, 535 (2015).

    Google Scholar 

  5. Kayan, A. & Hood, J. D. Neuro-otological manifestations of migraine. Brain 107 (Pt 4), 1123–1142 (1984).

    Google Scholar 

  6. Suhnan, A. P., Finch, P. M. & Drummond, P. D. Hyperacusis in chronic pain: Neural interactions between the auditory and nociceptive systems. Int. J. Audiol. 56 (11), 801–809 (2017).

    Google Scholar 

  7. Qi, R. et al. The auditory function in migraine model rats induced by postauricular nitroglycerin injection. Front. Neurol. 14, 1259982 (2023).

    Google Scholar 

  8. Näätänen, R. & Michie, P. T. Early selective-attention effects on the evoked potential: A critical review and reinterpretation. Biol. Psychol. 8 (2), 81–136 (1979).

    Google Scholar 

  9. Näätänen, R. et al. Mismatch negativity (MMN) as an index of cognitive dysfunction. Brain Topogr. 27 (4), 451–466 (2014).

    Google Scholar 

  10. Amenedo, E. & Escera, C. The accuracy of sound duration representation in the human brain determines the accuracy of behavioural perception. Eur. J. Neurosci. 12 (7), 2570–2574 (2000).

    Google Scholar 

  11. Qi, L. et al. Hyperacusis questionnaire and event-related potential correlation in migraine patients. Sci. Rep. 14 (1), 14117 (2024).

    Google Scholar 

  12. Mickleborough, M. J. et al. Cognitive processing of visual images in migraine populations in between headache attacks. Brain Res. 1582, 167–175 (2014).

    Google Scholar 

  13. Mickleborough, M. J. et al. Attentional network differences between migraineurs and non-migraine controls: fMRI evidence. Brain Topogr. 29 (3), 419–428 (2016).

    Google Scholar 

  14. Shiramatsu, T. I. & Takahashi, H. Mismatch-negativity (MMN) in animal models: Homology of human MMN?. Hear. Res. 399, 107936 (2021).

    Google Scholar 

  15. Jung, F. et al. Mismatch responses in the awake rat: Evidence from epidural recordings of auditory cortical fields. PLoS One. 8 (4), e63203 (2013).

    Google Scholar 

  16. Xu, Y. et al. Selective loss and transcriptional reprogramming of Nox4(+) GABAergic neurons in the trigeminal nucleus caudalis of NTG-induced chronic migraine model. J. Headache Pain. 26 (1), 263 (2025).

    Google Scholar 

  17. Pradhan, A. A. et al. Characterization of a novel model of chronic migraine. Pain 155 (2), 269–274 (2014).

    Google Scholar 

  18. Gonzalez-Cano, R. et al. Up–down reader: An open source program for efficiently processing 50% von Frey thresholds. Front. Pharmacol. 9, 433 (2018).

    Google Scholar 

  19. Gagnon, M. et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat. Med. 19 (11), 1524–1528 (2013).

    Google Scholar 

  20. Draper-Joyce, C. J. et al. Positive allosteric mechanisms of adenosine A(1) receptor-mediated analgesia. Nature 597 (7877), 571–576 (2021).

    Google Scholar 

  21. Chaplan, S. R. et al. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods. 53 (1), 55–63 (1994).

    Google Scholar 

  22. Shinba, T. Event-related potentials of the rat during active and passive auditory oddball paradigms. Electroencephalogr. Clin. Neurophysiol. 104 (5), 447–452 (1997).

    Google Scholar 

  23. Grupe, M. et al. Neuropharmacological modulation of the P3-like event-related potential in a rat two-tone auditory discrimination task with modafinil and NS9283, a positive allosteric modulator of α4β2 nAChRs. Neuropharmacology 79, 444–455 (2014).

    Google Scholar 

  24. Näätänen, R. et al. The mismatch negativity (MMN) in basic research of central auditory processing: A review. Clin. Neurophysiol. 118 (12), 2544–2590 (2007).

    Google Scholar 

  25. Adraoui, F. W. et al. Clozapine mitigates MK-801-induced mismatch negativity impairment in a rat electroencephalography study: Relevance for schizophrenia drug development. Prog Neuropsychopharmacol. Biol. Psychiatry. 143, 111555 (2025).

    Google Scholar 

  26. Eriksson, J. & Villa, A. E. P. Event-related potentials in an auditory oddball situation in the rat. Biosystems 79 (1), 207–212 (2005).

    Google Scholar 

  27. Ahnaou, A., Biermans, R. & Drinkenburg, W. H. Modulation of mGlu2 receptors, but not PDE10A inhibition normalizes pharmacologically-induced deviance in auditory evoked potentials and oscillations in conscious rats. PLoS One. 11 (1), e0147365 (2016).

    Google Scholar 

  28. Ahnaou, A. et al. Ketamine: Differential neurophysiological dynamics in functional networks in the rat brain. Transl. Psychiatry 7 (9), e1237 (2017).

    Google Scholar 

  29. Sand, T. & Vingen, J. V. Visual, long-latency auditory and brainstem auditory evoked potentials in migraine: relation to pattern size, stimulus intensity, sound and light discomfort thresholds and pre-attack state. Cephalalgia 20 (9), 804–820 (2000).

    Google Scholar 

  30. Bolay, H. et al. Subclinical dysfunction of cochlea and cochlear efferents in migraine: An otoacoustic emission study. Cephalalgia 28 (4), 309–317 (2008).

    Google Scholar 

  31. Yalin, O. et al. Phenotypic features of chronic migraine. J. Headache Pain. 17, 26 (2016).

    Google Scholar 

  32. Pulvermüller, F. & Shtyrov, Y. Automatic processing of grammar in the human brain as revealed by the mismatch negativity. Neuroimage 20 (1), 159–172 (2003).

    Google Scholar 

  33. Näätänen, R. & Tervaniemi, M. Primitive intelligence in the auditory cortex. Trends Neurosci. 24 (5), 283–288 (2001).

    Google Scholar 

  34. Grimm, S. & Escera, C. Auditory deviance detection revisited: Evidence for a hierarchical novelty system. Int. J. Psychophysiol. 85 (1), 88–92 (2012).

    Google Scholar 

  35. Menning, H., Roberts, L. E. & Pantev, C. Plastic changes in the auditory cortex induced by intensive frequency discrimination training. Neuroreport 11 (4), 817–822 (2000).

    Google Scholar 

  36. Chen, I. W., Helmchen, F. & Lütcke, H. Specific early and late oddball-evoked responses in excitatory and inhibitory neurons of mouse auditory cortex. J. Neurosci. 35 (36), 12560–12573 (2015).

    Google Scholar 

  37. Duque, D., Ayala, Y. A. & Malmierca, M. S. Deviance detection in auditory subcortical structures: What can we learn from neurochemistry and neural connectivity?. Cell Tissue Res. 361 (1), 215–232 (2015).

    Google Scholar 

  38. Shiramatsu, T. I., Kanzaki, R. & Takahashi, H. Cortical mapping of mismatch negativity with deviance detection property in rat. PLoS One. 8 (12), e82663 (2013).

    Google Scholar 

  39. Latremoliere, A. & Woolf, C. J. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J. Pain. 10 (9), 895–926 (2009).

    Google Scholar 

Download references

Acknowledgements

This work was supported by grants from National Key Research and Development Program of China (2023YFC2508403).

Author information

Author notes
  1. Xingli Li, Jilei Zhang and Qi Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Otorhinolaryngology-Head and Neck Surgery, Peking University People’s Hospital, Beijing, 100044, China

    Xingli Li, Jilei Zhang, Qi Liu, Liyuan Zhang, Shiyang Zhao, Hao Zhao, Rui Zhao, Yuanyuan Jing & Lisheng Yu

  2. Department of Otorhinolaryngology, Hearing International Jiangsu Ear and Hearing Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China

    Liyuan Zhang

Authors
  1. Xingli Li
    View author publications

    Search author on:PubMed Google Scholar

  2. Jilei Zhang
    View author publications

    Search author on:PubMed Google Scholar

  3. Qi Liu
    View author publications

    Search author on:PubMed Google Scholar

  4. Liyuan Zhang
    View author publications

    Search author on:PubMed Google Scholar

  5. Shiyang Zhao
    View author publications

    Search author on:PubMed Google Scholar

  6. Hao Zhao
    View author publications

    Search author on:PubMed Google Scholar

  7. Rui Zhao
    View author publications

    Search author on:PubMed Google Scholar

  8. Yuanyuan Jing
    View author publications

    Search author on:PubMed Google Scholar

  9. Lisheng Yu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

X. L. L., J. L. Z. and Q. L. wrote the main manuscript text, L. Y. Z., S. Y. Z., H. Z. and R. Z. collected and organized the data, Y. Y. J. and L. S. Y. modified the text. All authors reviewed the manuscript.X. L. L., J. L. Z. and Q. L. contributed equally to this work.

Corresponding authors

Correspondence to Yuanyuan Jing or Lisheng Yu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1 (download DOCX )

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, X., Zhang, J., Liu, Q. et al. Mismatch negativity-like responses in nitroglycerin-elicited migraine model. Sci Rep (2026). https://doi.org/10.1038/s41598-026-45645-4

Download citation

  • Received: 14 October 2025

  • Accepted: 20 March 2026

  • Published: 25 March 2026

  • DOI: https://doi.org/10.1038/s41598-026-45645-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Keywords

  • Mismatch negativity
  • Migraine
  • Rat model
  • Cortical excitability
Download PDF

Advertisement

Explore content

  • Research articles
  • News & Comment
  • Collections
  • Subjects
  • Follow us on Facebook
  • Follow us on X
  • Sign up for alerts
  • RSS feed

About the journal

  • About Scientific Reports
  • Contact
  • Journal policies
  • Guide to referees
  • Calls for Papers
  • Editor's Choice
  • Journal highlights
  • Open Access Fees and Funding

Publish with us

  • For authors
  • Language editing services
  • Open access funding
  • Submit manuscript

Search

Advanced search

Quick links

  • Explore articles by subject
  • Find a job
  • Guide to authors
  • Editorial policies

Scientific Reports (Sci Rep)

ISSN 2045-2322 (online)

nature.com footer links

About Nature Portfolio

  • About us
  • Press releases
  • Press office
  • Contact us

Discover content

  • Journals A-Z
  • Articles by subject
  • protocols.io
  • Nature Index

Publishing policies

  • Nature portfolio policies
  • Open access

Author & Researcher services

  • Reprints & permissions
  • Research data
  • Language editing
  • Scientific editing
  • Nature Masterclasses
  • Research Solutions

Libraries & institutions

  • Librarian service & tools
  • Librarian portal
  • Open research
  • Recommend to library

Advertising & partnerships

  • Advertising
  • Partnerships & Services
  • Media kits
  • Branded content

Professional development

  • Nature Awards
  • Nature Careers
  • Nature Conferences

Regional websites

  • Nature Africa
  • Nature China
  • Nature India
  • Nature Japan
  • Nature Middle East
  • Privacy Policy
  • Use of cookies
  • Legal notice
  • Accessibility statement
  • Terms & Conditions
  • Your US state privacy rights
Springer Nature

© 2026 Springer Nature Limited

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