{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:54:59Z","timestamp":1793066099254,"version":"4.5.0"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T00:00:00Z","timestamp":1609718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS073997"],"award-info":[{"award-number":["NS073997"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K24NS064050"],"award-info":[{"award-number":["K24NS064050"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>In some patients, migraine attacks are associated with symptoms of allodynia which can be localized (cephalic) or generalized (extracephalic). Using functional neuroimaging and cutaneous thermal stimulation, we aimed to investigate the differences in brain activation of patients with episodic migraine (n = 19) based on their allodynic status defined by changes between ictal and interictal pain tolerance threshold for each subject at the time of imaging. In this prospective imaging study, differences were found in brain activity between the ictal and interictal visits in the brainstem\/pons, thalamus, insula, cerebellum and cingulate cortex. Significant differences were also observed in the pattern of activation along the trigeminal pathway to noxious heat stimuli in no allodynia vs. generalized allodynia in the thalamus and the trigeminal nucleus but there were no activation differences in the trigeminal ganglion. The functional magnetic resonance imaging (fMRI) findings provide direct evidence for the view that in migraine patients who are allodynic during the ictal phase of their attacks, the spinal trigeminal nucleus and posterior thalamus become hyper-responsive (sensitized)\u2013to the extent that they mediate cephalic and extracephalic allodynia, respectively. In addition, descending analgesic systems seem as \u201cswitched off\u201d in generalized allodynia.<\/jats:p>","DOI":"10.1371\/journal.pone.0244320","type":"journal-article","created":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T18:33:14Z","timestamp":1609785194000},"page":"e0244320","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":42,"title":["Ictal and interictal brain activation in episodic migraine: Neural basis for extent of allodynia"],"prefix":"10.1371","volume":"16","author":[{"given":"Nasim","family":"Maleki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4087-5373","authenticated-orcid":true,"given":"Edina","family":"Szabo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lino","family":"Becerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Moulton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Scrivani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rami","family":"Burstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Borsook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,4]]},"reference":[{"key":"pone.0244320.ref001","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1002\/1531-8249(200005)47:5<614::AID-ANA9>3.0.CO;2-N","article-title":"An association between migraine and cutaneous allodynia","volume":"47","author":"R Burstein","year":"2000","journal-title":"Ann Neurol"},{"key":"pone.0244320.ref002","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1212\/01.wnl.0000310645.31020.b1","article-title":"Prevalence and characteristics of allodynia in headache sufferers","volume":"70","author":"ME Bigal","year":"2008","journal-title":"Neurology"},{"key":"pone.0244320.ref003","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/ana.21211","article-title":"Cutaneous allodynia in the migraine population","volume":"63","author":"RB Lipton","year":"2008","journal-title":"Ann Neurol"},{"issue":"Pt 8","key":"pone.0244320.ref004","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1093\/brain\/123.8.1703","article-title":"The development of cutaneous allodynia during a migraine attack: Clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine","volume":"123","author":"R Burstein","year":"2000","journal-title":"Brain J Neurol"},{"key":"pone.0244320.ref005","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/ana.10786","article-title":"Defeating migraine pain with triptans: A race against the development of cutaneous allodynia","volume":"55","author":"R Burstein","year":"2004","journal-title":"Ann Neurol"},{"key":"pone.0244320.ref006","first-page":"152","article-title":"Triggers in allodynic and non-allodynic migraineurs","volume":"53","author":"F Baldacci","year":"2013","journal-title":"A clinic setting study. Headache"},{"key":"pone.0244320.ref007","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1093\/brain\/awt251","article-title":"Cutaneous allodynia as a predictor of migraine chronification","volume":"136","author":"MA Louter","year":"2013","journal-title":"Brain J Neurol"},{"key":"pone.0244320.ref008","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1097\/WCO.0b013e3283532ca3","article-title":"Migraine changes the brain: Neuroimaging makes its mark","volume":"25","author":"T Sprenger","year":"2012","journal-title":"Curr Opin Neurol"},{"key":"pone.0244320.ref009","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/ana.21994","article-title":"Thalamic sensitization transforms localized pain into widespread allodynia","volume":"68","author":"R Burstein","year":"2010","journal-title":"Ann Neurol"},{"key":"pone.0244320.ref010","doi-asserted-by":"crossref","first-page":"8183","DOI":"10.1523\/JNEUROSCI.22-18-08183.2002","article-title":"Somatotopic activation in the human trigeminal pain pathway","volume":"22","author":"AFM DaSilva","year":"2002","journal-title":"J Neurosci Off J Soc Neurosci"},{"key":"pone.0244320.ref011","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1523\/JNEUROSCI.4496-10.2011","article-title":"Trigeminal nociceptive transmission in migraineurs predicts migraine attacks","volume":"31","author":"A Stankewitz","year":"2011","journal-title":"J Neurosci Off J Soc Neurosci"},{"key":"pone.0244320.ref012","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11940-009-0001-0","article-title":"Allodynia as a complication of migraine: Background and management","volume":"11","author":"WB Young","year":"2009","journal-title":"Curr Treat Options Neurol"},{"key":"pone.0244320.ref013","first-page":"9","article-title":"The International Classification of Headache Disorders","volume":"24","author":"ICHD-II","year":"2004","journal-title":"Cephalalgia"},{"key":"pone.0244320.ref014","volume-title":"Beck Depression Inventory Manual","author":"AT Beck","year":"1996","edition":"2"},{"key":"pone.0244320.ref015","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0003799","article-title":"Interictal dysfunction of a brainstem descending modulatory center in migraine patients","volume":"3","author":"EA Moulton","year":"2008","journal-title":"PLoS ONE"},{"key":"pone.0244320.ref016","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1177\/0333102416644969","article-title":"Functional interictal changes of pain processing in migraine with ictal cutaneous allodynia","volume":"37","author":"A Russo","year":"2017","journal-title":"Cephalalgia"},{"key":"pone.0244320.ref017","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3389\/fneur.2017.00282","article-title":"Functional changes of the perigenual part of the anterior cingulate cortex after external trigeminal neurostimulation in migraine patients","volume":"8","author":"A Russo","year":"2017","journal-title":"Front Neurol"},{"issue":"Suppl 1","key":"pone.0244320.ref018","first-page":"S165","article-title":"Interictal cortical reorganization in episodic migraine without aura: an event-related fMRI study during parametric trigeminal nociceptive stimulation","volume":"32","author":"A Tessitore","year":"2011","journal-title":"Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol"},{"key":"pone.0244320.ref019","doi-asserted-by":"crossref","first-page":"S173","DOI":"10.1016\/j.neuroimage.2008.10.055","article-title":"Bayesian analysis of neuroimaging data in FSL","volume":"45","author":"MW Woolrich","year":"2009","journal-title":"NeuroImage"},{"key":"pone.0244320.ref020","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.neuroimage.2009.02.035","article-title":"Enhanced false discovery rate using Gaussian mixture models for thresholding fMRI statistical maps","volume":"47","author":"G Pendse","year":"2009","journal-title":"NeuroImage"},{"key":"pone.0244320.ref021","doi-asserted-by":"crossref","first-page":"10646","DOI":"10.1523\/JNEUROSCI.2305-06.2006","article-title":"Trigeminal neuropathic pain alters responses in CNS circuits to mechanical (brush) and thermal (cold and heat) stimuli","volume":"26","author":"L Becerra","year":"2006","journal-title":"J Neurosci Off J Soc Neurosci"},{"issue":"Suppl 1","key":"pone.0244320.ref022","doi-asserted-by":"crossref","first-page":"S44","DOI":"10.1016\/j.pain.2013.07.021","article-title":"Migraine pathophysiology: Anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain","volume":"154","author":"R Noseda","year":"2013","journal-title":"Pain"},{"key":"pone.0244320.ref023","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.neuroimage.2007.02.001","article-title":"Capsaicin-induced thermal hyperalgesia and sensitization in the human trigeminal nociceptive pathway: An fMRI study","volume":"35","author":"E Moulton","year":"2007","journal-title":"NeuroImage"},{"key":"pone.0244320.ref024","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1098\/rstb.2001.0915","article-title":"A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM)","volume":"356","author":"J Mazziotta","year":"2001","journal-title":"Philos Trans R Soc Lond Ser B"},{"key":"pone.0244320.ref025","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1038\/nn1075","article-title":"Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging","volume":"6","author":"TEJ Behrens","year":"2003","journal-title":"Nat Neurosci"},{"key":"pone.0244320.ref026","first-page":"31","article-title":"Functional-anatomical validation and individual variation of diffusion tractography-based segmentation of the human thalamus","volume":"15","author":"H Johansen-Berg","year":"2005","journal-title":"Cereb Cortex N Y N 1991"},{"key":"pone.0244320.ref027","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1097\/j.pain.0000000000001231","article-title":"Quantitative sensory testing in patients with migraine: A systematic review and meta-analysis","volume":"159","author":"H Nahman-Averbuch","year":"2018","journal-title":"Pain"},{"key":"pone.0244320.ref028","doi-asserted-by":"crossref","first-page":"e83277","DOI":"10.1371\/journal.pone.0083277","article-title":"Pain and disgust: The facial signaling of two aversive bodily experiences","volume":"8","author":"M Kunz","year":"2013","journal-title":"PLOS ONE"},{"key":"pone.0244320.ref029","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1093\/brain\/awy228","article-title":"Induction of migraine-like headache, but not aura, by cilostazol in patients with migraine with aura","volume":"141","author":"JH Butt","year":"2018","journal-title":"Brain J Neurol"},{"key":"pone.0244320.ref030","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s10194-018-0927-2","article-title":"Migraine induction with calcitonin gene-related peptide in patients from erenumab trials","volume":"19","author":"CE Christensen","year":"2018","journal-title":"J Headache Pain"},{"key":"pone.0244320.ref031","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1177\/0333102419864507","article-title":"PACAP27 induces migraine-like attacks in migraine patients","volume":"40","author":"H Ghanizada","year":"2020","journal-title":"Cephalalgia"},{"key":"pone.0244320.ref032","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1093\/brain\/awt320","article-title":"Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks","volume":"137","author":"FH Maniyar","year":"2014","journal-title":"Brain J Neurol"},{"key":"pone.0244320.ref033","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1093\/brain\/aws175","article-title":"Her versus his migraine: Multiple sex differences in brain function and structure","volume":"135","author":"N Maleki","year":"2012","journal-title":"Brain"},{"key":"pone.0244320.ref034","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1177\/0333102412445622","article-title":"Concurrent functional and structural cortical alterations in migraine","volume":"32","author":"N Maleki","year":"2012","journal-title":"Cephalalgia"},{"key":"pone.0244320.ref035","article-title":"Cortico-cortical connections of primary sensory areas and associated symptoms in migraine","volume":"3","author":"DJ Hodkinson","year":"2017","journal-title":"eNeuro"},{"key":"pone.0244320.ref036","first-page":"435","article-title":"Painful heat reveals hyperexcitability of the temporal pole in interictal and ictal migraine states","volume":"21","author":"EA Moulton","year":"2011","journal-title":"Cereb Cortex N Y N 1991"},{"key":"pone.0244320.ref037","doi-asserted-by":"crossref","first-page":"366","DOI":"10.3389\/fnhum.2016.00366","article-title":"Increased functional activation of limbic brain regions during negative emotional processing in migraine","volume":"10","author":"SL Wilcox","year":"2016","journal-title":"Front Hum Neurosci"},{"key":"pone.0244320.ref038","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S1474-4422(14)70193-0","article-title":"Functional MRI of migraine","volume":"14","author":"TJ Schwedt","year":"2015","journal-title":"Lancet Neurol"},{"key":"pone.0244320.ref039","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1586\/ern.13.20","article-title":"Relevance of functional neuroimaging studies for understanding migraine mechanisms","volume":"13","author":"G Tedeschi","year":"2013","journal-title":"Expert Rev Neurother"},{"key":"pone.0244320.ref040","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1177\/0271678X17722109","article-title":"Functional and structural alterations in the migraine cerebellum","volume":"39","author":"J Mehnert","year":"2019","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0244320.ref041","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1212\/01.wnl.0000171862.17301.84","article-title":"Individual differences in endogenous pain modulation as a risk factor for chronic pain","volume":"65","author":"RR Edwards","year":"2005","journal-title":"Neurology"},{"key":"pone.0244320.ref042","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.jpain.2012.04.006","article-title":"Mechanical and heat hyperalgesia highly predict clinical pain intensity in patients with chronic musculoskeletal pain syndromes","volume":"13","author":"R Staud","year":"2012","journal-title":"J Pain Off J Am Pain Soc"},{"key":"pone.0244320.ref043","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.rdc.2009.05.006","article-title":"Abnormal pain modulation in patients with spatially distributed chronic pain: fibromyalgia","volume":"35","author":"R Staud","year":"2009","journal-title":"Rheum Dis Clin North Am"},{"key":"pone.0244320.ref044","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.pain.2006.06.001","article-title":"Mechanisms underlying development of spatially distributed chronic pain (fibromyalgia)","volume":"124","author":"CJ Vierck","year":"2006","journal-title":"Pain"},{"key":"pone.0244320.ref045","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/nrn1704","article-title":"Pain and emotion interactions in subregions of the cingulate gyrus","volume":"6","author":"BA Vogt","year":"2005","journal-title":"Nat Rev Neurosci"},{"key":"pone.0244320.ref046","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.neuroimage.2014.03.050","article-title":"Distinct regions of anterior cingulate cortex signal prediction and outcome evaluation","volume":"95","author":"A Jahn","year":"2014","journal-title":"NeuroImage"},{"key":"pone.0244320.ref047","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jchemneu.2016.01.010","article-title":"Midcingulate cortex: Structure, connections, homologies, functions and diseases","volume":"74","author":"BA Vogt","year":"2016","journal-title":"J Chem Neuroanat"},{"key":"pone.0244320.ref048","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/brain\/awt162","article-title":"The role of the posterior cingulate cortex in cognition and disease","volume":"137","author":"R Leech","year":"2014","journal-title":"Brain J Neurol"},{"key":"pone.0244320.ref049","doi-asserted-by":"crossref","first-page":"R1083","DOI":"10.1016\/j.cub.2018.07.018","article-title":"Orbitofrontal cortex","volume":"28","author":"PH Rudebeck","year":"2018","journal-title":"Curr Biol CB"},{"key":"pone.0244320.ref050","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1002\/ar.a.20126","article-title":"Convergence of sensory systems in the orbitofrontal cortex in primates and brain design for emotion","volume":"281A","author":"ET Rolls","year":"2004","journal-title":"Anat Rec A Discov Mol Cell Evol Biol"},{"key":"pone.0244320.ref051","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1046\/j.1468-2982.2002.00351.x","article-title":"Spatial contrast sensitivity of migraine patients without aura","volume":"22","author":"K Benedek","year":"2002","journal-title":"Cephalalgia"},{"key":"pone.0244320.ref052","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1177\/0333102418795163","article-title":"Cortical abnormalities in episodic migraine: A multi-center 3T MRI study","volume":"39","author":"S Magon","year":"2019","journal-title":"Cephalalgia"},{"key":"pone.0244320.ref053","first-page":"632","article-title":"The Insula: A \u201cHub of Activity\u201d in Migraine","volume":"22","author":"D Borsook","year":"2016","journal-title":"Neurosci Rev J Bringing Neurobiol Neurol Psychiatry"},{"key":"pone.0244320.ref054","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s12264-016-0016-y","article-title":"Insular cortex is critical for the perception, modulation, and chronification of pain","volume":"32","author":"C Lu","year":"2016","journal-title":"Neurosci Bull"},{"key":"pone.0244320.ref055","doi-asserted-by":"crossref","DOI":"10.1016\/j.nicl.2019.101790","article-title":"Association between migraine frequency and neural response to emotional faces: An fMRI study","volume":"22","author":"E Szab\u00f3","year":"2019","journal-title":"NeuroImage Clin"},{"key":"pone.0244320.ref056","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/1744-8069-7-71","article-title":"Migraine attacks the Basal Ganglia","volume":"7","author":"N Maleki","year":"2011","journal-title":"Mol Pain"},{"key":"pone.0244320.ref057","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/1744-8069-6-27","article-title":"A key role of the basal ganglia in pain and analgesia\u2014insights gained through human functional imaging","volume":"6","author":"D Borsook","year":"2010","journal-title":"Mol Pain"},{"key":"pone.0244320.ref058","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.nicl.2016.10.023","article-title":"Structural alterations of the brainstem in migraine","volume":"13","author":"CD Chong","year":"2016","journal-title":"NeuroImage Clin"},{"key":"pone.0244320.ref059","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.tics.2012.12.004","article-title":"Revisiting human hemispheric specialization with neuroimaging","volume":"17","author":"P-Y Herv\u00e9","year":"2013","journal-title":"Trends Cogn Sci"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0244320","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T18:33:29Z","timestamp":1609785209000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0244320"}},"subtitle":[],"editor":[{"given":"Andrea","family":"Antal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,1,4]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0244320","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,4]]}}}