Exploring the Biomarker Modalities of Migraines

Doctor and patient using digital tablet in hospital
The authors of this review provided a summary of research advances in migraine within genetics, provocation modeling, biochemistry, and neuroimaging.

In diagnosing migraine based on clinical criteria, neurologists may overlook genetic and neurobiological factors. Study researchers presented the latest findings on biomarker modalities for migraines and their respective challenges in an article in Lancet.

Study researchers have been able to identify 38 genomic loci that affect migraine risk, especially in genes expressed in tissues with vascular and smooth muscle cells. Others found that a high polygenic load is associated with increased migraine severity, presence in younger individuals, and migraine with aura.

They have also been able to identify the single gene associated with familial hemiplegic migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, and familial advanced sleep phase syndrome. Identifying which genes cause migraines is challenging because multiple variants may have small impacts, and other factors may be involved.

Human provocation models have found that calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), glyceryl trinitrate, and phosphodiesterase 3 and 5 inhibitors trigger migraine attacks in most patients with migraine via the second messenger systems of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). Induction rates reached 100% when patients received a KATP channel opener and 95% when they received a BKCa channel opener.

The origin of the migraines could be either peripheral or central. This research has been applied to developing drugs, such as those targeting CGRP or its receptor, that intercept trigger molecules, but such treatments have not always been successful. Human provocation models may be able to predict treatment response.

Study researchers have found conflicting results when studying whether CGRP plasma concentrations are elevated in peripheral blood during migraine attacks and whether interictal plasma concentrations of CGRP are elevated in individuals with episodic or chronic migraine. Two studies regarding PACAP indicated that spontaneous migraine attacks are associated with elevated PACAP-like immunoreactivity, while 2 studies did not find increases in PACAP in the interictal phase of migraines. Studies of whether CGRP is higher at baseline in migraine patients who benefited from treatment with onabotulinumtoxinA were also conflicting.

Additionally, magnetic resonance imaging (MRI) has shown conflicting results regarding whether white matter hyperintensities are associated with migraines with aura. One study found that women with migraine have thicker cortexes for visual areas than their peers while another study found structural changes in pain pathways that may be associated with thalamic changes.

Other studies have found that migraine patients’ brain structure is somewhat different compared with patients with tension-type headaches or headaches following traumatic brain injury. Functional MRI (fMRI) indicated that dorsal pons activity increases in the headache phase of migraine.

Ultimately, study researchers have been able to combine biomarker modalities. With neuroimaging via magnetic resonance angiography and human provocation models, they found that dilation of the middle cerebral artery and middle meningeal artery occurred in CGRP-induced migraine attacks. “Building on this foundation,” they concluded, “future research should investigate precision medicine approaches that improve the diagnosis and treatment of migraine.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Ashina M, Terwindt GM, Al-Karagholi MAM, et al. Migraine: disease characterisation, biomarkers, and precision medicine. Lancet. 2021;397(10283):1496-1504. doi:10.1016/S0140-6736(20)32162-0