{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:41:02Z","timestamp":1787506862783,"version":"build-2736575974"},"reference-count":109,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    High\u2010altitude headache (HAH) is the most common neurological manifestation triggered by hypoxia during rapid ascent above 2500\u00a0m, often presenting as an isolated symptom or as part of acute mountain sickness (AMS). HAH shares clinical features with migraine, cluster headache and other primary headache, complicating differential diagnosis. Prevalence varies widely depending on ascent speed and altitude, with higher rates observed in populations ascending rapidly by passive transport and lower rates in those ascending gradually on foot. Controlled normobaric hypoxic chamber studies confirm hypoxia as a potent trigger, with most participants developing HAH within hours. Environmental factors, including fluctuations in barometric pressure, further contribute to headache onset. We propose that the pathophysiology involves activation and sensitization of the trigeminovascular system, with key molecular mediators such as nitric oxide, adenosine, calcitonin gene\u2010related peptide (CGRP) and pituitary adenylate cyclase\u2010activating polypeptide (PACAP) playing central roles. Hypoxia stabilizes hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1), driving transcriptional changes that can prime vascular and neuronal pathways for head pain. Although HAH typically responds to simple analgesics and oxygen, its similarity with migraine suggests that targeted therapies against CGRP and PACAP may offer additional benefits. Future research should clarify the mechanistic continuum between HAH and AMS and evaluate multitarget therapeutic approaches.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70617-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1113\/jp289704","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T08:11:34Z","timestamp":1780474294000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["High\u2010altitude headache: Insights into pathophysiology and potential treatment implications"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7477-3020","authenticated-orcid":false,"given":"Marika","family":"Falla","sequence":"first","affiliation":[{"name":"Institute of Mountain Emergency Medicine Eurac Research  Bolzano Italy"},{"name":"Center for Mind\/Brain Sciences \u2013 CIMeC University of Trento  Rovereto Italy"},{"name":"Mountain Clinic Eurac Research  Bolzano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7236-5557","authenticated-orcid":false,"given":"Florian","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Neurology Medical University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4402-8633","authenticated-orcid":false,"given":"Giacomo","family":"Strapazzon","sequence":"additional","affiliation":[{"name":"Institute of Mountain Emergency Medicine Eurac Research  Bolzano Italy"},{"name":"Mountain Clinic Eurac Research  Bolzano Italy"},{"name":"Department of Medicine \u2013 DIMED University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2166-7966","authenticated-orcid":false,"given":"Justin","family":"Lawley","sequence":"additional","affiliation":[{"name":"Institute of Mountain Emergency Medicine Eurac Research  Bolzano Italy"},{"name":"Institute of Sport Science, Performance Physiology and Prevention University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"issue":"8","key":"e_1_2_2_2_1","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1111\/j.1526-4610.2009.01501.x","article-title":"Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents","volume":"49","author":"Akerman S.","year":"2009","journal-title":"Headache"},{"issue":"10","key":"e_1_2_2_3_1","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/nrn3057","article-title":"Diencephalic and brainstem mechanisms in migraine","volume":"12","author":"Akerman S.","year":"2011","journal-title":"Nature Reviews Neuroscience"},{"issue":"1","key":"e_1_2_2_4_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s10194-025-02022-2","article-title":"PACAP38\u2010induced migraine attacks are independent of CGRP signaling: A randomized controlled trial","volume":"26","author":"Al\u2010Karagholi M. 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