Principal Investigator: Melissa Cortez
Keywords: Headache , Migraine , Migraine with Aura , Concussion , Post Traumatic Headache , Post-concussive syndrome , autonomic dysfunction , Trigeminal Cephalgia , POTS , Postural Orthostatic Tachycardic Syndrome Department: Neurology
IRB Number: 00085309
Specialty: Neurology, Neurology, Neurology
Sub Specialties: Traumatic Brain Injury, Migraine, Headache
Recruitment Status: Recruiting

Contact Information

Leah Millsap

Brief Summary

Headache disorders are clinically heterogeneous groups, often with overlapping symptom complements that are difficult to link to currently accepted pathophysiology of specific headache types. Key potential distinguishing mediators include sensory, affective, and autonomic dysfunction, which have been well recognized in these headache varieties, though the most clinically relevant distinguishing differences remain unknown.

This project proposes to characterize autonomic function and sensory thresholds in headache disorders compared to normal controls. To accomplish this, we will employ a battery of clinical, physiological, and psychometric measures to each group.  Specifically, we will non-invasively assess cardiovascular and facial autonomic function, sensory thresholds to touch, photophobia, and neuropsychometric testing in the following subject groups: non-headache control (NH), episodic migraine (EM), chronic migraine (CM), trigeminal autonomic cephalgias (TAC), post-traumatic headache (PTH), those at risk for development of PTH (AR), orthostatic intolerance with headache (OIH), orthostatic intolerance without headache (OI), Chiari malformation with headache (CHMH), and Chiari malformation without headache (CHM). Our multiple data streams should provide new information on headache physiology and potential comparative measures between clinically overlapping groups.

Our specific aims are:

Prospectively confirm and further validate differences in autonomic function and sensory thresholds between clinically defined headache groups and normal controls. Alterations in autonomic and sensory function have been described in episodic migraine (EM) headache [1-4], though less is known about whether these changes persist in chronic migraine (CM) and/or whether they differ from other pathophysiologically distinct headache subtypes (post-traumatic headache (PTH), trigeminal autonomic cephalgias (TAC)). Our previous work has demonstrated preliminary evidence that craniofacial autonomic function and sensory thresholds differ between episodic migraine and non-headache controls using similar methodologies (unpublished; Characterization of Migraine Endophenotypes, IRB_00064447), though follow-up studies are needed to confirm and further characterize these differences.
We hypothesize that these parameters will differ significantly in headache subgroups compared to NH subjects and perhaps most markedly, in EM as previously demonstrated. Also, these parameters may also significantly differ in CM, PTH and TAC (the latter two being recurrent headache subtypes that are viewed as pathophysiologically distinct from migraine).

To test this, we will add standardized autonomic testing (tilt-table, sudomotor, cardiovascular reflex and catecholamine testing) and additional non-invasive investigational parameters (quantitative frequency analysis of optically measured hemodynamic changes and dynamic pupillometry) to our previous craniofacial battery. Symptom burden, headache characterization, and medical history, will be assessed by written questionnaire and headache/medication diary.

To evaluate replicability within individuals, we will re-test each individual at baseline, and again at 2 weeks and 1 month.

Test autonomic measures and sensory thresholds as disease biomarkers.
In addition to evaluating replicability, as in Aim 1, we will also follow perform follow-up measures to follow disease progression and treatment response in episodic migraine (EM), chronic migraine (CM), trigeminal autonomic cephalgias (TAC), post-traumatic headache (PTH), and those at risk for development of PTH (AR), ), orthostatic intolerance with headache (OIH), orthostatic intolerance without headache (OI), Chiari malformation with headache (CHMH), and Chiari malformation without headache (CHM). Additional measures of long-term replicability will be obtained in non-headache controls (NH). To do this, we will utilize the same testing battery described above for follow-up testing points at 2 and 3 months. Subjects will be followed observationally only, and will complete standard of care treatment recommendations as prescribed by their clinical providers.

We hypothesize that 1) development of PTH in the AR group will be accompanied by changes in physiological measures and symptom burden compared to baseline, and 2) clinical treatment response in those who experience headache resolution with clinically driven treatment will correlate with normalization in autonomic physiological markers and improved symptom scores. 

We predict that this multi-modal approach to autonomic and sensory threshold assessment will lend both localization (craniofacial vs global) and mechanistic (sympathetic- and/or parasympathetic-predominant dysfunction) insight to autonomic and sensory dysfunction in these groups.


1.         Mosek, A., et al., Autonomic dysfunction in migraineurs. Headache, 1999. 39(2): p. 108-17.

2.         Shechter, A., et al., Migraine and autonomic nervous system function: a population-based, case-control study. Neurology, 2002. 58(3): p. 422-7.

3.         Burstein, R., et al., An association between migraine and cutaneous allodynia. Ann Neurol, 2000. 47(5): p. 614-24.

4.         Digre, K.B. and K.C. Brennan, Shedding light on photophobia. J Neuroophthalmol, 2012. 32(1): p. 68-81.

Inclusion Criteria

A total of 420 pairwise participants, ages 12 year old to 65, will be recruited, divided among the following groups:

minimum of 30 each group:

  • episodic migraine with and without aura (EM)
  • chronic migraine (CM)
  • trigeminal autonomic cephalgias (TAC)
  • post-traumatic headache (PTH)
  • age and sex-matched non-headache controls (NH)
  • orthostatic intolerance with headache (OIH)
  • orthostatic intolerance without headache (OI)
  • Chiari malformation with headache (CHMH)
  • Chiari malformation without headache (CHM)

A minimum of 60 subjects at high risk (AR) for development of PTH meeting one of the following categories. Specifically, those who are at risk due to high-impact sport play or recent concussion as defined below.

Subjects 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 headache group are defined by the recently updated ICHD-III beta diagnostic criteria[5], summarized in brief below.

The criteria for the diagnosis of migraine are as follows:

  1. Episodic migraine (EM): either of the following allowed.
    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
  1. Chronic migraine (CM). Those meeting diagnostic criteria for #1 or #2 above, with headache occurring >15 days per month.

Trigeminal autonomic cephalgia (TAC): recurrent headache or facial pain occurring with at least one or more craniofacial autonomic symptom ipsilateral to the head pain.

Post-traumatic headache (PTH) 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

Orthostatic Intolerance with headache (OIH) criteria as follows [7]: OI is again defined as the inability to tolerate upright posture because of signs and symptoms which can be relieved upon lying down, but will explicitly include headache as one of the key recurrent symptoms. 

  1. Hypotension or hypertension upon change of upright posture during which BP 
  2. May or may not include reflex tachycardia upon change of upright posture 
  3. Headache with or without one or more of the following symptoms upon changing to an upright position:
    1. Lightheadedness upon change to upright posture. 
    2. Nausea or abdominal pain
    3. Sweating
    4. Tremulousness 
    5. Fatigue

Improvement of symptoms with recumbence to supine position.

Chiari malformation criteria as follows: Previously diagnosed with Chiari malformation type I or type II via MRI brain imaging. 

Inclusion criteria for the at-risk (AR) group will include:

  1. At-risk individuals (recreational sport participants)
  2. Acute concussion - individuals presenting for medical evaluation within 24 hours of concussion (can result from any mechanism, including sports related, fall, etc)
  3. Subacute, persistent post-concussive symptoms - individuals presenting for medical evaluation within 30-45 days of concussion (can result from any mechanism, including sports related, fall, etc)


5.         The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia, 2013. 33(9): p. 629-808.

7.         Stewart, Julian M. “Common Syndromes of Orthostatic Intolerance.” Pediatrics131.5 (2013): 968–980. PMC. Web. 28 Aug. 2018.


Exclusion Criteria

Subjects will be permitted to use acute headache-specific treatment up to 48 hours prior to study, but testing must take place at least 48 hours after an acute attack, as this is an inter-ictal study. 

Chronic headache related medications will be permitted for those enrolled. Subjects enrolled for Aim 2 do not have medication restrictions, though subjects will be asked to keep a headache and/or medication diary for the period of study.

Those who cannot provide consent, or where follow-up visits would not be feasible.