{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:27:15Z","timestamp":1792718835503,"version":"4.5.0"},"reference-count":33,"publisher":"SAGE Publications","issue":"9","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Cephalalgia"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:p>Cortical spreading depolarization (depression) underlies migrainous aura and is posited to cause its headache. At times, aura may start before headache, auras may start at the same time as, or shortly after headache onset, or sometimes without any headache at all. We suggest that the extent of spread and not the spread limited to eloquent cortex, is the key variable in the genesis of headache. Consistent with this notion, a first human case studied electrophysiologically showed that cortical spreading depolarization spreads extensively and silently<\/jats:p>\n                  <jats:p>We propose a Buildup Hypothesis to explain headache generation in migraine with aura. Buildup occurs because cortical spreading depression releases noxious chemicals from cortical cells that accumulate in tissues and cerebrospinal fluid to reach levels sufficient to trigger pial afferents and cause pain. The extent of silent (or relatively silent) spread determines significant buildup. This Buildup Hypothesis helps to explain (1) typical and shorter latencies between end of aura and headache onset (approximately 0\u201320\u2005minutes) and (2) why headache may not develop after aura (insufficient buildup), and also addresses temporal discrepancies such as headaches starting before an aura (i.e. subclinical spread with buildup in advance of aura). Hence, aura and headache are distinct consequences of cortical spreading depolarization.<\/jats:p>","DOI":"10.1177\/03331024251370629","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T11:38:39Z","timestamp":1756813119000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":10,"title":["Rethinking migraine with aura: Why cortical spreading depolarization (depression), not aura, causes headaches"],"prefix":"10.1177","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9052-4937","authenticated-orcid":false,"given":"Michael A.","family":"Moskowitz","sequence":"first","affiliation":[{"name":"Harvard Medical School, Departments of Radiology and Neurology, Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","unstructured":"McLeod GA Josephson CB Engbers JDT et al. Mapping the migraine: intracranial recording of cortical spreading depression in migraine with aura. Headache 2025; 6: 658\u2013665.","DOI":"10.1111\/head.14907"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-030212-183717"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00027.2014"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.01.029"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3770"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.071582498"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410130609"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X241290606"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410430108"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199412223312505"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0202-136"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adl0544"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215435109"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.1990.14"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1231897"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.03.003"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-080422-105509"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae062"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(200101)49:1<4::AID-ANA3>3.0.CO;2-W"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/head.14932"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-019-1042-8"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00034.2015"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182824e66"},{"key":"e_1_3_2_25_2","first-page":"2251","article-title":"Trigeminal nerve microstructure is linked with neuroinflammation and brainstem activity in migraine","volume":"148","author":"Tohymam S","year":"2025","unstructured":"Tohymam S, Datko M, et al. Trigeminal nerve microstructure is linked with neuroinflammation and brainstem activity in migraine. Brain 2025; 148: 2251\u20132562.","journal-title":"Brain"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106072"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25731"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/head.14224"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.27197"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.07.021"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaf015"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-023-01656-4"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.13-03-01167.1993"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3003168"}],"container-title":["Cephalalgia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/03331024251370629","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/03331024251370629","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/03331024251370629","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T14:47:07Z","timestamp":1777387627000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/03331024251370629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":33,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1177\/03331024251370629"],"URL":"https:\/\/doi.org\/10.1177\/03331024251370629","relation":{},"ISSN":["0333-1024","1468-2982"],"issn-type":[{"value":"0333-1024","type":"print"},{"value":"1468-2982","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9]]},"article-number":"03331024251370629"}}