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
Dodick, D. W. Migraine. Lancet 391 (10127), 1315–1330 (2018).
Burshtein, R. et al. Are episodic and chronic migraine one disease or two? Curr. Pain Headache Rep. 19 (12), 53 (2015).
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).
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).
Kayan, A. & Hood, J. D. Neuro-otological manifestations of migraine. Brain 107 (Pt 4), 1123–1142 (1984).
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).
Qi, R. et al. The auditory function in migraine model rats induced by postauricular nitroglycerin injection. Front. Neurol. 14, 1259982 (2023).
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).
Näätänen, R. et al. Mismatch negativity (MMN) as an index of cognitive dysfunction. Brain Topogr. 27 (4), 451–466 (2014).
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).
Qi, L. et al. Hyperacusis questionnaire and event-related potential correlation in migraine patients. Sci. Rep. 14 (1), 14117 (2024).
Mickleborough, M. J. et al. Cognitive processing of visual images in migraine populations in between headache attacks. Brain Res. 1582, 167–175 (2014).
Mickleborough, M. J. et al. Attentional network differences between migraineurs and non-migraine controls: fMRI evidence. Brain Topogr. 29 (3), 419–428 (2016).
Shiramatsu, T. I. & Takahashi, H. Mismatch-negativity (MMN) in animal models: Homology of human MMN?. Hear. Res. 399, 107936 (2021).
Jung, F. et al. Mismatch responses in the awake rat: Evidence from epidural recordings of auditory cortical fields. PLoS One. 8 (4), e63203 (2013).
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).
Pradhan, A. A. et al. Characterization of a novel model of chronic migraine. Pain 155 (2), 269–274 (2014).
Gonzalez-Cano, R. et al. Up–down reader: An open source program for efficiently processing 50% von Frey thresholds. Front. Pharmacol. 9, 433 (2018).
Gagnon, M. et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat. Med. 19 (11), 1524–1528 (2013).
Draper-Joyce, C. J. et al. Positive allosteric mechanisms of adenosine A(1) receptor-mediated analgesia. Nature 597 (7877), 571–576 (2021).
Chaplan, S. R. et al. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods. 53 (1), 55–63 (1994).
Shinba, T. Event-related potentials of the rat during active and passive auditory oddball paradigms. Electroencephalogr. Clin. Neurophysiol. 104 (5), 447–452 (1997).
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).
Näätänen, R. et al. The mismatch negativity (MMN) in basic research of central auditory processing: A review. Clin. Neurophysiol. 118 (12), 2544–2590 (2007).
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).
Eriksson, J. & Villa, A. E. P. Event-related potentials in an auditory oddball situation in the rat. Biosystems 79 (1), 207–212 (2005).
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).
Ahnaou, A. et al. Ketamine: Differential neurophysiological dynamics in functional networks in the rat brain. Transl. Psychiatry 7 (9), e1237 (2017).
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).
Bolay, H. et al. Subclinical dysfunction of cochlea and cochlear efferents in migraine: An otoacoustic emission study. Cephalalgia 28 (4), 309–317 (2008).
Yalin, O. et al. Phenotypic features of chronic migraine. J. Headache Pain. 17, 26 (2016).
Pulvermüller, F. & Shtyrov, Y. Automatic processing of grammar in the human brain as revealed by the mismatch negativity. Neuroimage 20 (1), 159–172 (2003).
Näätänen, R. & Tervaniemi, M. Primitive intelligence in the auditory cortex. Trends Neurosci. 24 (5), 283–288 (2001).
Grimm, S. & Escera, C. Auditory deviance detection revisited: Evidence for a hierarchical novelty system. Int. J. Psychophysiol. 85 (1), 88–92 (2012).
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).
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).
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).
Shiramatsu, T. I., Kanzaki, R. & Takahashi, H. Cortical mapping of mismatch negativity with deviance detection property in rat. PLoS One. 8 (12), e82663 (2013).
Latremoliere, A. & Woolf, C. J. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J. Pain. 10 (9), 895–926 (2009).
Acknowledgements
This work was supported by grants from National Key Research and Development Program of China (2023YFC2508403).
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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.
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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
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DOI: https://doi.org/10.1038/s41598-026-45645-4