The research team, based at Ludwig-Maximilians-University Munich, took their laboratory into the field, following healthy volunteers on a five-day expedition through the Italian Alps in August 2022. Rather than simulating altitude in a hypoxic chamber, the investigators measured participants under genuine expedition conditions, ascending from the valley town of Varallo at 450 meters to the Capanna Regina Margherita at 4554 meters, one of the highest permanently staffed buildings in Europe. At each stage of the climb, participants completed structured headache questionnaires, rated their pain on a numerical scale from zero to ten, filled in the 2018 Lake Louise Acute Mountain Sickness Score, and provided samples of tear fluid for neuropeptide analysis. Certified mountain guides from the International Federation of Mountain Guides Association accompanied every group, and the protocol was approved by the university ethics committee.

The choice of tear fluid as the sampling medium is one of the study’s most intriguing technical features. Collecting blood at 4554 meters is cumbersome, and obtaining cerebrospinal fluid is out of the question in a field setting. Tear fluid, by contrast, can be aspirated from the lateral corner of each eye with a thin plastic capillary in under a minute, provided the investigator avoids irritating the ocular surface and triggering reflex tearing, which would dilute the sample. The researchers collected fluid from both eyes, pooled it after confirming no significant left-right differences at baseline, stabilized it in protein extraction reagent, kept it on dry ice, and later quantified CGRP concentrations with a commercial enzyme-linked immunosorbent assay read in duplicate on a spectrometer. The approach offers a noninvasive window into a neuropeptide that is otherwise difficult to track outside a hospital laboratory.

CGRP itself is a potent vasodilatory neuropeptide released from the endings of the trigeminovascular system, the network of sensory nerves that innervates the blood vessels of the brain’s protective membranes. Decades of work have established it as a central player in migraine: levels rise during spontaneous attacks, injecting CGRP can provoke migraine-like headaches in susceptible patients, and drugs that block the molecule or its receptor have transformed migraine prevention in recent years. Because high-altitude headache shares clinical features with migraine, including aggravation by physical activity, and because a history of migraine is a known risk factor for altitude headache, the Munich team hypothesized that hypobaric hypoxia might activate the same trigeminovascular pathway and drive CGRP release at altitude.

The expedition data gave that hypothesis substantial support. Of the 24 originally recruited participants, 13 completed the full protocol with usable tear samples, a reduction the authors attribute to early terminations and insufficient fluid volumes. Among these 13, headache burden climbed steadily with altitude. No one reported headache at baseline in the valley, but 46 percent did so after reaching 3498 meters on day two, 62 percent at 3647 meters on day three, and a striking 85 percent at 4554 meters on day four, when the mean pain score reached 3.2 on the ten-point scale. Eight participants, or 62 percent, fulfilled the formal ICHD-3 criteria for high-altitude headache at the highest hut, a figure consistent with the 36 to 73 percent incidence reported in earlier studies at comparable elevations.

The CGRP measurements revealed a pattern that was invisible in the group average. Across all participants, tear fluid CGRP levels at 4554 meters were not significantly different from baseline values, a result that on its own might have suggested the neuropeptide was irrelevant. But when the researchers split the cohort by symptom severity, a clear signal emerged. The six participants who developed moderate-to-severe headaches, with mean pain scores of 5.0, showed a substantial rise in tear fluid CGRP, averaging an increase of 1.86 nanograms per milliliter from baseline, while the seven participants with only mild headaches actually showed a slight decrease of 0.19 nanograms per milliliter. The difference between the groups was statistically significant, and baseline CGRP levels had been virtually identical, indicating that the elevation was triggered by the altitude exposure itself rather than reflecting a pre-existing trait.

The same dissociation appeared when participants were classified by diagnosis. Those meeting ICHD-3 criteria for high-altitude headache showed a mean CGRP increase of 1.49 nanograms per milliliter, compared with a decrease of 0.42 in those without the diagnosis. Even more striking, six participants, nearly half the cohort, developed a headache that met criteria for migraine without aura, complete with moderate-to-severe pulsating pain, nausea or vomiting in half of cases, and photophobia in some. These migraine-like sufferers reported higher pain intensity and a significantly larger CGRP rise of 1.75 nanograms per milliliter than their symptom-free counterparts. Notably, oxygen saturation, which hovered around 78 percent at the highest altitude for everyone, did not differ between headache and non-headache groups, suggesting that the degree of hypoxia alone did not determine who suffered.

The cerebral circulation told a quieter story. Using transcranial color-coded duplex sonography at baseline and at 4554 meters, the team measured blood flow velocity in the middle cerebral arteries on both sides, calculating mean flow velocities and the Lindegaard index to screen for vasospasm. Neither the presence of high-altitude headache nor of migraine-like symptoms was associated with differences in flow velocity or in the change from baseline, and there was no evidence of vasospasm in any group. This absence of a vascular signature is itself informative: it shifts attention away from simple blood-vessel constriction or dilation as the cause of altitude pain and toward neurogenic inflammation, the process by which activated trigeminal nerves release CGRP and other mediators directly around meningeal vessels.

Disentangling the two candidate triggers of that activation, hypoxia and reduced barometric pressure, remains difficult in a field design, and the authors are careful on this point. Animal experiments have shown that lowering atmospheric pressure by as little as 40 hectopascals increases firing in neurons of the spinal trigeminal nucleus, particularly those with corneal afferents, and human volunteers exposed to modest pressure drops in a climate chamber have reported head compression and mild-to-moderate headache. Meanwhile, chamber studies of pure normobaric hypoxia have induced headache in roughly 80 percent of healthy volunteers and elevated plasma CGRP in migraine patients. Because tear fluid CGRP did not rise uniformly across the expedition and did not track oxygen saturation, the new data hint that hypoxia by itself may be insufficient, and that the interplay of low pressure and low oxygen, possibly amplified in susceptible individuals, is what ignites the trigeminovascular system.

The study’s limitations are real and acknowledged by its authors. Thirteen completers is a small sample, nearly half the original cohort was excluded, tear fluid CGRP has not been formally validated against plasma or cerebrospinal fluid concentrations, and an observational design cannot establish whether the neuropeptide rise precedes the pain or merely accompanies it. Even so, the implications are tantalizing. If CGRP release genuinely drives altitude headache, then the CGRP-targeted monoclonal antibodies and small-molecule antagonists that have revolutionized migraine care might, in principle, be repurposed as prophylaxis for mountaineers, an idea the authors say deserves interventional study. And if tear fluid proves to be a reliable surrogate medium, field researchers could gain a practical, needle-free biomarker for headache severity in some of the most remote environments on Earth, from Himalayan base camps to aerospace settings, where the biology of low pressure and low oxygen has long outpaced our ability to measure it.

Subject of Research: The role of the neuropeptide CGRP in high-altitude headache and migraine-like headache during hypobaric hypoxia

Article Title: The Role of Calcitonin Gene‐Related Peptide in High‐Altitude Headache: A Prospective Field Study

Article References: Schniepp, R., Karrasch, L., Breitenstein, H., Straube, A., & Kamm, K. (2026). The Role of Calcitonin Gene‐Related Peptide in High‐Altitude Headache: A Prospective Field Study. Annals of Clinical and Translational Neurology, 13(10), 2046-2056. https://doi.org/10.1002/acn3.70374

Image Credits: AI Generated

DOI: 10.1002/acn3.70374

Keywords: high-altitude headache, CGRP, migraine, hypobaric hypoxia, trigeminovascular system, tear fluid biomarker, acute mountain sickness, transcranial duplex sonography, neuropeptides, Alps expedition, headache disorders, neurology