Identifying neural oscillation and phase synchronization abnormalities in migraine and their predictive values in transcranial magnetic stimulation

Background: Migraine is a prevalent neurological disorder that may substantially disrupt daily function. Repetitive transcranial magnetic stimulation (rTMS) has been shown to be a promising treatment for migraine, but its treatment efficacy still needs to be optimised. This study aimed to identify abnormal neural oscillations in patients with migraines and evaluate their predictive value for TMS treatments to obtain insights for the optimisation of rTMS paradigms. Methods: Patients with migraine received a course of rTMS delivered over the left dorsolateral prefrontal cortex (DLPFC). Resting-state electroencephalography (EEG) was assessed at baseline in both patients with migraine and age- and sex-matched healthy controls. Results: Compared with healthy controls, patients with migraine were characterised by a slower peak alpha frequency (PAF). In addition, patients with migraine demonstrated alpha-band hyperconnectivity between parieto-occipital regions and between fronto-occipital areas. More importantly, parieto-occipital connectivity showed predictive value for rTMS analgesic effects in this population. Conclusions: These findings support the potential utility of oscillatory biomarkers for optimising rTMS treatment in patients with migraine. Clinical Trial Registration: Chinese Clinical Trials Registry (ChiCTR2200060337).

Migraine; TMS; EEG; PAF; Alpha band

[1] Sprenger T, Goadsby PJ. Migraine pathogenesis and state of pharmacological treatment options. BMC Medicine. 2009; 7: 71.

[2] Johnston K, Powell LC, Popoff E, L’Italien GJ, Pawinski R, Ahern A, et al. Cost-effectiveness of rimegepant oral lyophilisate compared to best supportive care for the acute treatment of migraine in the UK. Journal of Medical Economics. 2024; 27: 627–643.

[3] Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018; 38: 1–211.

[4] Song P, Li S, Shao Y, Zhu S, Wang Y, Xu P, et al. HF-rTMS of the left DLPFC relieve headaches and enhance frontal-temporal connectivity in migraine. Clinical Neurophysiology. 2025; 173: 166–172.

[5] Clemente L, Paparella G, Scannicchio S, Abbatantuono C, Tancredi G, Ladisa E, et al. Dorso lateral prefrontal cortex stimulation with TMS in chronic migraine individuals refractory to anti-CGRP monoclonal antibodies: clinical, neuropsychological and neurophysiological 360 effects. Cephalalgia. 2025; 45: 3331024251364843.

[6] Cheng M, Che X, Ye Y, He C, Yu L, Lv Y, et al. Analgesic efficacy of theta-burst stimulation for postoperative pain. Clinical Neurophysiology. 2023; 149: 81–87.

[7] Liu Y, Sun J, Wu C, Ren J, He Y, Sun N, et al. Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: a randomized controlled trial. Pain. 2024; 165: 2035–2043.

[8] Ackermann L, Zeller D, Odorfer T, Homola GA, Kampf T, Pham M, et al. Effect of repetitive transcranial magnetic stimulation on the symptoms and brain imaging in patients with fibromyalgia syndrome: a randomized controlled pilot trial. Pain and Therapy. 2025; 14: 1547–1572.

[9] Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005; 45: 201–206.

[10] Sahu AK, Sinha VK, Goyal N. Effect of adjunctive intermittent theta-burst repetitive transcranial magnetic stimulation as a prophylactic treatment in migraine patients: a double-blind sham-controlled study. Indian Journal of Psychiatry. 2019; 61: 139–145.

[11] Tan BL, Chen JL, Liu Y, Lin Q, Wang Y, Shi S, et al. Differential analgesic effects of high-frequency or accelerated intermittent theta burst stimulation of M1 on experimental tonic pain: correlations with cortical activity changes assessed by TMS-EEG. Neurotherapeutics. 2024; 21: e00451.

[12] Zhou J, Wang Y, Luo X, Fitzgerald PB, Cash RFH, Fitzgibbon BM, et al. Revisiting the effects of rTMS over the dorsolateral prefrontal cortex on pain: an updated systematic review and meta-analysis. Brain Stimulation. 2024; 17: 928–937.

[13] McLain NJ, Yani MS, Kutch JJ. Analytic consistency and neural correlates of peak alpha frequency in the study of pain. Journal of Neuroscience Methods. 2022; 368: 109460.

[14] Chowdhury NS, Skippen P, Si E, Chiang AKI, Millard SK, Furman AJ, et al. The reliability of two prospective cortical biomarkers for pain: EEG peak alpha frequency and TMS corticomotor excitability. Journal of Neuroscience Methods. 2023; 385: 109766.

[15] Ellis S, Anzolin A, Doan DN, Grahl A, Gardiner L, Lee J, et al. Peak alpha frequency and alpha asymmetry as potential biomarkers of pain intensity and treatment outcomes in chronic pain patients. Journal of Pain. 2025; 29: 102–103.

[16] Ding K, Arginteanu T, Anderson White M, Lovell L, Thakor NV, Doshi T. Electroencephalographic power ratio and peak frequency difference associate with central sensitization in chronic pain. Journal of Neural Engineering. 2024; 21: 066035.

[17] Furman AJ, Thapa T, Summers SJ, Cavaleri R, Fogarty JS, Steiner GZ, et al. Cerebral peak alpha frequency reflects average pain severity in a human model of sustained, musculoskeletal pain. Journal of Neurophysiology. 2019; 122: 1784–1793.

[18] Ho RLM, Park J, Wang WE, Thomas JS, Cruz-Almeida Y, Coombes SA. Lower individual alpha frequency in individuals with chronic low back pain and fear of movement. Pain. 2024; 165: 1033–1043.

[19] Bjork MH, Stovner LJ, Nilsen BM, Stjern M, Hagen K, Sand T. The occipital alpha rhythm related to the “migraine cycle” and headache burden: a blinded, controlled longitudinal study. Clinical Neurophysiology. 2009; 120: 464–471.

[20] Chowdhury NS, Taseen KJ, Chiang AK, Chang WJ, Millard SK, Seminowicz DA, et al. A 5-day course of repetitive transcranial magnetic stimulation before pain onset ameliorates future pain and increases sensorimotor peak alpha frequency. Pain. 2025; 166: 1382–1394.

[21] Pan LLH, Chen WT, Wang YF, Chen SP, Lai KL, Liu HY, et al. Resting-state occipital alpha power is associated with treatment outcome in patients with chronic migraine. Pain. 2022; 163: 1324–1334.

[22] Zebhauser PT, Heitmann H, May ES, Ploner M. Resting-state electroencephalography and magnetoencephalography in migraine—a systematic review and meta-analysis. The Journal of Headache and Pain. 2024; 25: 147.

[23] Bie B, Ghosn S, Sheikh SR, Araujo MLD, Mehra R, Mays M, et al. Electroencephalographic signatures of migraine in small prospective and large retrospective cohorts. Scientific Reports. 2024; 14: 28673.

[24] Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiological Reviews. 2017; 97: 553–622.

[25] Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. A classification of chronic pain for ICD-11. Pain. 2015; 156: 1003–1007.

[26] Hershey AD. Current approaches to the diagnosis and management of paediatric migraine. The Lancet Neurology. 2010; 9: 190–204.

[27] Lipton RB, Nicholson RA, Reed ML, Araujo AB, Jaffe DH, Faries DE, et al. Diagnosis, consultation, treatment, and impact of migraine in the US: results of the OVERCOME (US) study. Headache. 2022; 62: 122–140.

[28] Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Screening questionnaire before TMS: an update. Clinical Neurophysiology. 2011; 122: 1686–1686.

[29] Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behavior Research Methods. 2009; 41: 1149–1160.

[30] Sarnthein J, Stern J, Aufenberg C, Rousson V, Jeanmonod D. Increased EEG power and slowed dominant frequency in patients with neurogenic pain. Brain. 2006; 129: 55–64.

[31] Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. The Journal of Pain. 2008; 9: 105–121.

[32] Conforto AB, Amaro E III, Goncalves AL, Mercante JP, Guendler VZ, Ferreira JR, et al. Randomized, proof-of-principle clinical trial of active transcranial magnetic stimulation in chronic migraine. Cephalalgia. 2014; 34: 464–472.

[33] Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987; 30: 191–197.

[34] Grafton KV, Foster NE, Wright CC. Test-retest reliability of the Short-Form McGill Pain Questionnaire: assessment of intraclass correlation coefficients and limits of agreement in patients with osteoarthritis. The Clinical Journal of Pain. 2005; 21: 73–82.

[35] Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Archives of Internal Medicine. 2006; 166: 1092–1097.

[36] Löwe B, Decker O, Müller S, Brähler E, Schellberg D, Herzog W, et al. Validation and standardization of the generalized anxiety disorder screener (GAD-7) in the general population. Medical Care. 2008; 46: 266–274.

[37] Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. Journal of General Internal Medicine. 2001; 16: 606–613.

[38] Manea L, Gilbody S, McMillan D. A diagnostic meta-analysis of the Patient Health Questionnaire-9 (PHQ-9) algorithm scoring method as a screen for depression. General Hospital Psychiatry. 2015; 37: 67–75.

[39] Backhaus J, Junghanns K, Broocks A, Riemann D, Hohagen F. Test-retest reliability and validity of the Pittsburgh Sleep Quality Index in primary insomnia. Journal of Psychosomatic Research. 2002; 53: 737–740.

[40] Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Research. 1989; 28: 193–213.

[41] Furman AJ, Meeker TJ, Rietschel JC, Yoo S, Muthulingam J, Prokhorenko M, et al. Cerebral peak alpha frequency predicts individual differences in pain sensitivity. Neuroimage. 2018; 167: 203–210.

[42] Lefaucheur JP, Nguyen JP. A practical algorithm for using rTMS to treat patients with chronic pain. Clinical Neurophysiology. 2019; 49: 301–307.

[43] Beam W, Borckardt JJ, Reeves ST, George MS. An efficient and accurate new method for locating the F3 position for prefrontal TMS applications. Brain Stimulation. 2009; 2: 50–54.

[44] Che XW, Cash R, Chung SW, Bailey N, Fitzgerald PB, Fitzgibbon BM. The dorsomedial prefrontal cortex as a flexible hub mediating behavioral as well as local and distributed neural effects of social support context on pain: a Theta Burst Stimulation and TMS-EEG study. Neuroimage. 2019; 201: 116053.

[45] Rogasch NC, Thomson RH, Daskalakis ZJ, Fitzgerald PB. Short-latency artifacts associated with concurrent TMS-EEG. Brain Stimulation. 2013; 6: 868–876.

[46] Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. Journal of Neuroscience Methods. 2004; 134: 9–21.

[47] Selesnick IW, Burrus CS. Generalized digital Butterworth filter design. IEEE Transactions on Signal Processing. 1998; 46: 1688–1694.

[48] Korhonen RJ, Hernandez-Pavon JC, Metsomaa J, Mäki H, Ilmoniemi RJ, Sarvas J. Removal of large muscle artifacts from transcranial magnetic stimulation-evoked EEG by independent component analysis. Medical & Biological Engineering & Computing. 2011; 49: 397–407.

[49] Oostenveld R, Fries P, Maris E, Schoffelen JM. FieldTrip: open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data. Computational Intelligence and Neuroscience. 2011; 2011: 156869.

[50] May ES, Tiemann L, Gil Avila C, Bott FS, Hohn VD, Gross J, et al. Assessing the predictive value of peak alpha frequency for the sensitivity to pain. Pain. 2025; 166: 2076–2090.

[51] O'Hare L, Menchinelli F, Durrant SJ. Resting-state alpha-band oscillations in migraine. Perception. 2018; 47: 379–396.

[52] Vinck M, Oostenveld R, van Wingerden M, Battaglia F, Pennartz CM. An improved index of phase-synchronization for electrophysiological data in the presence of volume-conduction, noise and sample-size bias. Neuroimage. 2011; 55: 1548–1565.

[53] Hardmeier M, Hatz F, Bousleiman H, Schindler C, Stam CJ, Fuhr P. Reproducibility of functional connectivity and graph measures based on the phase lag index (PLI) and weighted phase lag index (wPLI) derived from high resolution EEG. PLOS ONE. 2014; 9: e108648.

[54] Nichols TE, Holmes AP. Nonparametric permutation tests for functional neuroimaging: a primer with examples. Human Brain Mapping. 2002; 15: 1–25.

[55] Mazaheri A, Seminowicz DA, Furman AJ. Peak alpha frequency as a candidate biomarker of pain sensitivity: the importance of distinguishing slow from slowing. Neuroimage. 2022; 262: 119560.

[56] Boord P, Siddall PJ, Tran Y, Herbert D, Middleton J, Craig A. Electroencephalographic slowing and reduced reactivity in neuropathic pain following spinal cord injury. Spinal Cord. 2008; 46: 118–123.

[57] McLain N, Cavaleri R, Kutch J. Peak alpha frequency differs between chronic back pain and chronic widespread pain. European Journal of Pain. 2025; 29: e4737.

[58] Goto F, Oishi N, Tsutsumi T, Ito T, Arai M, Ogawa K. Characteristic electroencephalographic findings by photic driving in patients with migraine-associated vertigo. Acta Oto-Laryngologica. 2013; 133: 253–256.

[59] Zou X, He J, Zhou M, Zhao F, Tian X, Xu X, et al. Photophobia and visual triggers in vestibular migraine. Neurology and Therapy. 2024; 13: 1191–1201.

[60] Bjork M, Hagen K, Stovner L, Sand T. Photic EEG-driving responses related to ictal phases and trigger sensitivity in migraine: a longitudinal, controlled study. Cephalalgia. 2011; 31: 444–455.

[61] Coppola G, Di Renzo A, Tinelli E, Di Lorenzo C, Di Lorenzo G, Parisi V, et al. Thalamo-cortical network activity during spontaneous migraine attacks. Neurology. 2016; 87: 2154–2160.

[62] Wu D, Zhou Z, Wang Y, Liu H, Yu Y, Chen Q, et al. Altered neuromagnetic activity under visual stimuli in migraine: a multi-frequency magnetoencephalography study. Frontiers in Neurology. 2025; 16: 1567150.

[63] Matt E, Aslan T, Amini A, Sariçiçek K, Seidel S, Martin P, et al. Avoid or seek light—a randomized crossover fMRI study investigating opposing treatment strategies for photophobia in migraine. The Journal of Headache and Pain. 2022; 23: 99.

[64] Schwedt TJ, Nikolova S, Dumkrieger G, Li J, Wu T, Chong CD. Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab. The Journal of Headache and Pain. 2022; 23: 159.

[65] Hsiao FJ, Chen WT, Wu YT, Pan LH, Wang YF, Chen SP, et al. Characteristic oscillatory brain networks for predicting patients with chronic migraine. The Journal of Headache and Pain. 2023; 24: 139.

[66] Mei Y, Qiu D, Xiong Z, Li X, Zhang P, Zhang M, et al. Disrupted topologic efficiency of white matter structural connectome in migraine: a graph-based connectomics study. The Journal of Headache and Pain. 2024; 25: 204.

[67] Coppola G, Di Lorenzo C, Schoenen J, Pierelli F. Habituation and sensitization in primary headaches. The Journal of Headache and Pain. 2013; 14: 65.

[68] Vecchia D, Pietrobon D. Migraine: a disorder of brain excitatory-inhibitory balance? Trends in Neurosciences. 2012; 35: 507–520.

[69] Suzuki K, Suzuki S, Shiina T, Kobayashi S, Hirata K. Central sensitization in migraine: a narrative review. Journal of Pain Research. 2022; 15: 2673–2682.

[70] Vaninetti M, Lim M, Khalaf A, Metzger-Smith V, Flowers M, Kunnel A, et al. fMRI findings in MTBI patients with headaches following rTMS. Scientific Reports. 2021; 11: 9573.

[71] Cole E, Phillips A, Bentzley B, Stimpson K, Nejad R, Schatzberg A, et al. A double-blind, randomized, sham-controlled trial of accelerated intermittent theta-burst (aiTBS) for treatment-resistant depression. Biological Psychiatry. 2021; 89: S90.

[72] Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, et al. Stanford neuromodulation therapy (SNT): a double-blind randomized controlled trial. American Journal of Psychiatry. 2022; 179: 132–141.

[73] Zhao H, Jiang C, Zhao M, Ye Y, Yu L, Li Y, et al. Comparisons of accelerated continuous and intermittent theta burst stimulation for treatment-resistant depression and suicidal ideation. Biological Psychiatry. 2024; 96: 26–33.

[74] Chen Y, Zhou J, Hu Z, Jin Y, Tan B, Wang Y, et al. Cerebello-cortical inhibition underlies the effects of cerebellar magnetic stimulation on spinocerebellar ataxia type 3: a randomized controlled trial. Brain Stimulation. 2025; 18: 1821–1833.

[75] Cash RFH, Cocchi L, Lv J, Fitzgerald PB, Zalesky A. Functional magnetic resonance imaging-guided personalization of transcranial magnetic stimulation treatment for depression. JAMA Psychiatry. 2021; 78: 337–339.

[76] Cash RFH, Zalesky A. Personalized and circuit-based transcranial magnetic stimulation: evidence, controversies, and opportunities. Biological Psychiatry. 2024; 95: 510–522.

[77] Morriss R, Briley PM, Webster L, Abdelghani M, Barber S, Bates P, et al. Connectivity-guided intermittent theta burst versus repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled trial. Nature Medicine. 2024; 30: 403–413.

[78] Bai Y, Pacheco-Barrios K, Pacheco-Barrios N, Liang G, Fregni F. Neurocircuitry basis of motor cortex-related analgesia as an emerging approach for chronic pain management. Nature Mental Health. 2024; 2: 496–513.

[79] Motzkin JC, Kanungo I, D’Esposito M, Shirvalkar P. Network targets for therapeutic brain stimulation: towards personalized therapy for pain. Frontiers in Pain Research. 2023; 4: 1156108.

[80] Cui H, Ding H, Hu L, Zhao Y, Shu Y, Voon V. A novel dual-site OFC-dlPFC accelerated repetitive transcranial magnetic stimulation for depression: a pilot randomized controlled study. Psychological Medicine. 2024; 54: 1–14.

[81] Liu J, Shu Y, Wu G, Hu L, Cui H. A neuroimaging study of brain activity alterations in treatment-resistant depression after a dual target accelerated transcranial magnetic stimulation. Frontiers in Psychiatry. 2023; 14: 1321660.

[82] Xu B, Lin C, Wang Y, Wang H, Liu Y, Wang X. Using dual-target rTMS, single-target rTMS, or Sham rTMS on post-stroke cognitive impairment. Journal of Integrative Neuroscience. 2024; 23: 161.

[83] Lei XY, Wei M, Wang L, Liu C, Liu Q, Wu X, et al. Resting-state electroencephalography microstate dynamics altered in patients with migraine with and without aura—a pilot study. Headache. 2023; 63: 1087–1096.

[84] Yang C, Bi Y, Hu L, Gong L, Li Z, Zhang N, et al. Effects of different transcranial magnetic stimulations on neuropathic pain after spinal cord injury. Frontiers in Neurology. 2023; 14: 1141973.

[85] Vuckovic A, Hasan MA, Fraser M, Conway BA, Nasseroleslami B, Allan DB. Dynamic oscillatory signatures of central neuropathic pain in spinal cord injury. The Journal of Pain. 2014; 15: 645–655.