Migraine Endophenotypes

Principal Investigator: Kevin Brennan
Keywords: Headache , Migraine , endophenotypes Department: Neurology
IRB Number: 00064447 Co Investigator:  
Specialty: Neurology, Neurology, Neurology
Sub Specialties: General Neurology, Headache
Recruitment Status: Active, not recruiting

Contact Information

Matthew Halverson
matt.halverson@hsc.utah.edu
801-587-8581

Brief Summary

Migraine and post-traumatic headache are clinically heterogeneous groups, often with complex symptom complements that are difficult to link to currently accepted pathophysiology of headache. This project proposes to investigate endophenotypes within migraine and post-traumatic headache compared to normal controls. To accomplish this, we will employ a battery of clinical, imaging, physiological, and psychometric measures to each group.  Specifically, we will non-invasively assess fMRI, cortical motion perception, cardiovascular and facial autonomic function, allodynia, photophobia, and neuropsychometric testing in the following subject groups: non-headache control (NH), migraine with aura (MA), migraine without aura (MO), migrainous vertigo (MV), chronic migraine (CM), trigeminal cephalgia (TC), and post-traumatic headache (PTH).

We anticipate that our work will aid in the understanding and classification of headache disorders by physiologically characterizing endophenotypes within migraine and other chronic headache disorders. This approach, if successful, can serve as a model for characterization of other headache subtypes. Additionally, our multiple data streams should provide new information on migraine and chronic headache physiology and potential comparative measures between clinically overlapping groups. Finally, our proposal has the potential to generate physiologically defined measures of treatment, which in turn could help in the testing of rationally generated headache treatment. This project is part of a larger multifaceted effort to define, understand, and subsequently treat migraine and chronic headache disorders. These methods can be applied to other subsets of headache to aid in identifying other physiologically definable endophenotypes. 

Our specific aims are:

1. Determine whether the anatomy and physiology of motion sensitive cortex is altered in MV and PTH patients.

Primary visual (V1) cortex is hyperexcitable in MA patients. We suspect that motion sensitive (V5/MT+) cortex will be similarly excitable in MV and PTH. We will use functional magnetic resonance imaging (fMRI) to map these cortices. We will compare area of activation (fMRI) and perform connectivity mapping (fMRI). We hypothesize that V5/MT+ activation will be larger in area, have a larger amplitude response, and show greater functional connectivity to other regions, in MV and PTH patients compared to MAsV and controls.

2. Determine whether MV and PTH patients have altered cortical motion perception compared to MAsV and controls.

We suspect that patients with MV and PTH will have inter-ictal alterations in motion perception. We will determine the threshold for coherent motion detection using random dot kinematograms (RDK) in MV compared to MAsV patients and controls. Our hypothesis is that MV and PTH patients will have a lowered threshold for motion detection compared to MA and controls.

3. Determine whether migraine and PTH patients have altered autonomic function and sensory thresholds compared to controls.

We suspect that both migraine (with and without vertigo) and PTH patients will have inter-ictal alterations in facial autonomic function and sensory thresholds. We will determine the pattern of autonomic facial response to trigeminal stimulation and sensitivity to odor, thermal and mechanical stimulation in headache groups compared to controls, and whether these changes correlate with changes in heart rate or blood pressure (autonomically mediated parameters that are not limited to the face). Our hypothesis is that those with headache will have a differing pattern of facial trigeminovascular autonomic and sensory activation from normal controls.

4. Determine whether migraine and PTH patients have altered photophobia thresholds.

We suspect that both migraine (with and without vertigo) and PTH patients will have inter-ictal alterations in photophobia thresholds. We will determine the threshold of light sensitivity in headache groups compared to controls and will also test thresholds when blocking certain colors of light. Our hypothesis is that those with headache w ill have a greater light sensitivity, especially to blue-green light, and thus lower thresholds on photophobia testing, from normal controls.

5. Determine whether improvement or worsening of physiological measures correlates with clinical and neuropsychological endpoints in headache syndromes, thus serving as biomarkers of disease.

We suspect that improvement or worsening in clinical headache symptoms and neuropsychological correlates of chronic pain will correlate with attenuated physiological and psychophysical measurements, including cortical motion perception, photophobia, facial autonomic response, osmosensitivity, and/or allodynia.

Inclusion Criteria

A total of 300 participants will be recruited, divided among the following groups: MV, MA, migraine without aura (MO), post-traumatic headache (PTH), chronic migraine, trigeminal cephalgia, and age and sex-matched controls. All participants will be evaluated by a headache provider. Patients will be screened using a standard clinical questionnaire; diagnostic characterization is determined based on this questionnaire. Symptoms and relevant comorbidities are also obtained via the questionnaire. 

Inclusion criteria for each group will be MV (as defined above), migraine with aura without vertigo, migraine without aura, post-traumatic headache, chronic migraine, and trigeminal cephalgia (each as defined by the recently updated ICHD-III beta diagnostic criteria, summarized in brief below), and normal, non-headache controls.

The criteria for the diagnosis of migraine are as follows:

  1. Migraine with aura (MA): At least 2 episodes of aura symptoms including visual disturbances prior to the onset of headache and fulfilling criteria for migraine, as in migraine without aura below.
  2. Migraine without aura (MO):  At least 5 episodes of moderate to severe headache with all of the following:
    1. Pulsating or one-sided headache
    2. Associated with nausea and/or vomiting and/or hypersensitivity to light or sound
    3. Headache exacerbated by movement or similar physical activity
    4. Headache lasting 4-72 hours
  3. Probable Migraine (MP). At least 5 episodes of moderate to severe headache with only 3 of the features listed above under 2a-d.
  4. Other headaches (OH). Recurrent headaches that do not fulfill the criteria for any form of migraine.
  5. No recurrent headaches (NH).
  6. Chronic migraine (CM). Those meeting diagnostic criteria for #1 or #2 above, with headache occurring >15 days per month.
  7. Trigeminal cephalgia: headache or facial pain occurring with at least one or more craniofacial autonomic symptom ipsilateral to the head pain.

Post-traumatic headache as follows:

  1. Headache fulfilling criteria 2 and/or 3, no typical characteristics required
  2. Head trauma with all the following:
    1. Either no loss of consciousness, or loss of consciousness of less than 30 minutes’ duration
  3. Symptoms and/or signs diagnostic of concussion
  4. Headache develops within 7 days after head trauma
  5. One or other of the following:
    1. Headache resolves within 3 months after head trauma
    2. Headache persists but 3 months have not yet passed since head trauma

For complete diagnostic criteria, we will refer to the following published guideline: Headache Classification Committee of the IHS. ICHD 3rd edition, beta version. Cephalgia (2013). 33(9) 629-808.

Exclusion Criteria

Exclusion criteria will be age under 18 years, conditions which could increase the risk of fMRI procedures, or those with medical conditions or who are on medications (that cannot be safely held for 48 hours prior to autonomic testing) that may confound test outcomes. Subjects will be permitted to use acute migraine or vertigo treatment up to 48 hours prior to study, but testing will take place at least 48 hours after an acute attack, as this is an inter-ictal study. Subjects will be asked to keep a headache and/or vertigo diary for the period of study.