The clinical problem and the need for a simple diagnostic test

Migraine is a common, disabling, episodic brain disorder, typically characterised by recurring, usually incapacitating attacks of severe head pain and associated symptoms of autonomic and neurological dysfunction (migraine without aura). Migraine attacks last between 4-72 hours (median one day). In one-third of patients attacks are associated with neurological aura symptoms (migraine with aura). Some migraineurs may experience only a few attacks in their life, but the vast majority will get hit over and over again by ever recurring migraines. The individual attack frequency and severity may fluctuate due to factors such as hormonal changes, misuse of acute headache medication, stress, sleep-deprivation, intercurrent diseases, mood swings, and other unknown factors. By and large, half of all migraineurs experience two or more attacks per month, and a quarter one or more per week. One in ten patients will progress from episodic to chronic migraine, experiencing headaches on 15 or more days per month (= chronification). Such patients may easily experience several hundreds to thousands of attacks.

Chronic migraine is considered the most severe and most difficult-to-treat form of migraine. The chronification process may start spontaneously but is usually triggered by overuse of acute headache medication and/or caffeine7, in particular in patients with overweight and/or depression.

There is a huge unmet need of effective and well tolerated treatments for migraine. Although the acute treatment options for attacks have significantly improved with the advent of triptans, more than half of the patients are still dissatisfied. And although widely accepted validated and accurate diagnostic clinical criteria are available, migraine patients often are misdiagnosed and consequently undertreated. A simple, yet reliable diagnostic test for migraine would improve patient care.

The scientific problem – Towards prevention of the triggering, initiation, recurrence and chronification of migraine attacks

Although the mechanisms for the migraine headache and aura are reasonably well understood1, much less is known about: (i) why migraine patients are predisposed to migraine attacks? (ii) how migraine attacks are triggered; (iii) why attacks recur? (iv) why the attack-frequency may progress so dramatically to chronic migraine. The absence of a good understanding of how migraine attacks may begin has hampered the development of prophylactic treatments to prevent migraine attacks and chronification.

Human and animal studies have shown that glutamatergic-mediated cerebral hyperexcitability leading to increased susceptibility to spreading depression (SD) is pivotal to the initiation of attacks of familial hemiplegic migraine and other monogenic migraine subtypes. Whether similar mechanisms are involved in common migraines, is uncertain. In analogy to other chronic pain syndromes, central sensitisation of pain-signalling pathways is believed to be at the core of the chronification process leading to chronic migraine. How sensitisation in migraine might begin and progress is unknown. Studies to understand what makes the migraine brain different and predisposed to chronification are desperately needed.

Work packages

Interictal and pre-ictal biomarkers and pathways for episodic and chronic migraine


  1. To identify and validate interictal biochemical, neuroimaging, and neurophysiological biomarkers to establish objective diagnostic tests for migraine.
  2. To stratify migraine patients for treatment based on biomarker profiles.
  3. To identify patients that are at risk for chronification.
  4. To identify subgroup specific pathways for migraine pain.
  5. To identify novel migraine prophylactic treatment targets.


Partners involved

LUMC, ULG (Leader)  and UKE

Genetic biomarkers and molecular pathways for episodic and chronic migraine


  1. To obtain genotypic data from EUROHEADPAIN and IHGC patient collections.
  2. To identify novel genetic risk factors for migraine pain and subgroups of migraine, including patients with frequent attacks.
  3. To understand the genetic structure of migraine subgroups by patient stratification.
  4. To mine pain- and migraine-relevant pathway information from available genotype data sets.


Partners involved

UH-FIMM (Leader) and QIMR

Predictive brain changes and mechanisms for the triggering and initiation of migraine attacks


  1. To identify neurophysiological brain changes relevant for the prediction of migraine attacks.
  2. To elucidate neurobiological network mechanisms and modulatory factors in mice relevant to attack initiationin patients.
  3. To build computational models for predicting brain network stability in migraine.


Partners involved

LUMC (Leader) and UKE

Understanding the neurobiological mechanisms of migraine pain


  1. To dissect brain stem and hypothalamic circuitries and molecular mechanisms relevant to trigeminal processing of pain signals, to find out the relative contribution of peripheral and central neurons to sensitization.
  2. To validate and manipulate these structures to understand episodic and chronic migraine pain.
  3. To explore, by manipulating mechanisms relevant to migraine pain, the therapeutic potential of novel targets against migraine pain.


Partners involved


Effects and mode of action of pharmacological and neuro-modulation treatment options for migraine


  1. To test several novel classes of drug targets for their ability to provoke migraine headaches in double-blind, placebo-controlled, cross-over studies.
  2. To elucidate modes of action of these drug targets in an experimental rat model of migraine.
  3. To test existing, and develop novel, non-invasive magnetic or direct current stimulation devices for their potential to change brain changes, connectivity, and metabolism, and efficacy to reduce pain.


Partners involved

ULG, REGIONH (Leader), Cefaly Technology, USZ