Completed Research

Our researchers are hard at work on the projects you helped fund. Here are the final reports of the studies that have been completed.

F. Michael Cutrer, MD, The Mayo Clinic, Rochester, MN

Investigation of the Genetic Basis of Migraine: Building a DNA Library in Migraine Sufferers

Summary

In the application we proposed to establish a DNA library with samples from well characterized migraine sufferers and unrelated age/gender matched controls whose detailed clinical and diagnostic phenotype is carefully gathered and recorded in a searchable electronic database.  The first use of the library will be to carry out the first whole genome association study of migraine in a well characterized American population. Our proposal was not a specific study but rather the development of a DNA library that will serve as a resource for migraine research in the coming decades. 

We have accomplished our proposed goal in no small part due to the generosity of the Migraine Research Foundation.  We have established what is probably the largest migraine specific DNA repository in the world.  In the 12 months that we have received MRF support, we have sampled over 1400 migraine case and non-migraine controls subjects, bringing to the total samples to 2316.  Of those we have sampled 737 Migraine without aura subjects (MWO), 716 Migraine with aura (MWA) subjects and 863 non-Migraine controls (NMC) subjects.  Later this year, we will begin the application process for funding of the first migraine specific genome-wide association study of Migraine in the US. Because of the increasingly competitive environment especially as it pertains to NIH funding, we are increasing the number of sampled subjects that we will include in our proposal as we go forward. Our goal is to have sampled 4500 subjects for the GWAS (1500 MWO, 1500 MWA, 1500 NMC).  We have acquired funding which will hopefully carry us to the completion of this goal. Our work is on-going and progressing well.

Hypothesis vs. findings

Our hypotheses that establishment of such a repository was feasible and that we would have the capability to sample the large number of subjects required to carry out this research have been validated.

Unanswered questions

It is our hope and expectation that the library will form the basis of the first Genome Wide Association Study (GWAS) in the United States.  We will also use this repository to carry out migraine genetics research projects with a more limited scope as we continue to recruit and sample subjects for the GWAS. Two genetics projects are underway:

• We are currently Genotyping subjects to Assess the association of migraine with Serotonin receptor 2A and 2C and Serotonin transport gene polymorphisms.
• We are in the midst of developing a project assess the genotype phenotype correlation between candidate gene polymorphisms and Menstrually Associated migraine.  
  

In addition, we have begun to glean clinical data from the computerized repository of clinical phenotypic information to which the DNA genotypic data will be correlated.

Frank Porreca, PhD, University of Arizona, Tucson

Behavioral Model of Medication Overuse Headache

Published in Cephalalgia, Volume 29, Issue 12, December 2009

Summary

Medication overuse headache (MOH) is a disorder that develops from the frequent use of medications taken for the treatment of migraine headache pain. MOH affects an estimated 3-5% of the general population. The mechanisms underlying the development of MOH remain unknown. Among the medications associated with the development of MOH are opiates and triptans. While the effects of repeated opiate or triptan use for headache are unknown, it is possible that these medications may elicit neural adaptations in peripheral nociceptive fibers that innervate the dura that contribute to the increased frequency and occurrence of such headaches. Our preclinical studies were designed to explore possible neuroadaptive changes elicited by sustained exposure to morphine in order to give insight into possible causes of MOH. We found that morphine treatments elicited acute cutaneous allodynia of the facial regions that resolves after discontinuation.  Additionally, morphine increased the expression of calcitonin gene related peptide (CGRP) and nNOS in trigeminal primary afferent neurons identified with Flurogold to innervate the dura. Critically, these neuroadaptive changes persist for long periods of time and can result in different effects that occur even long after the discontinuation of the medication. Stimuli known to elicit migraine headache, such as NO donor or stress, produce facial allodynia, in morphine pre-treated rats while having no effects in vehicle treated animals. Such persistent neuroadaptive changes may be relevant to the processes that promote MOH. Acute and chronic blockade of nNOS did not prevent morphine-induced cutanoeus allodynia. More importantly blockade of CGRP fully reversed morphine-induced facial allodynia both during morphine infusion or after exposure to a stimulus known to elicit migraine headache, i.e. stress.

Hypothesis vs. findings

We began by investigating the peripheral sensory fibers within the trigeminal ganglia following sustained exposure to morphine, and we found a remarkable and persistent upregulation of CGRP and nNOS. This discovery was relevant to the known efficacy of CGRP antagonists in migraine pain.  Additionally, we found that assay of NGF in the skin was negative suggesting that our research would benefit from focus on of the role of CGRP and nNOS as potential mediators of medication overuse headache. For this reason, we believe that our hypothesis of NGF-dependency was not supported and we modified the experiments to fit the data observed. 

Unanswered questions

Additional studies will be necessary to better understad the mechanisms of medication overuse headache specifically related to opiates and to other medications such as triptans.  In particular, we are now poised to understand if initiating factors of headache (i.e., stress, NO donors or induction of CSD) are capable of producing activation of dural afferents in animals pre-exposed to morphine (but with normal sensory thresholds) and whether activation of afferents is dependent upon nNOS and results in release of CGRP.

Ann Scher, PhD, Uniformed Services University, Bethesda, MD

Migraine in Middle Age and Late Life: A Longitudinal Analysis of Factors Related to Migraine Prognosis in a Large Population-Based Cohort

Published in the Journal of the American Medical Association, Volume 301, Issue 24, June 2009

Summary

About one third of migraine sufferers experience transient neurological disturbances during or just before attacks (migraine with aura). There has been considerable interest in recent years regarding the evident increased risk of clinical and sub-clinical cardiovascular disease in migraine sufferers with aura. In this study, we were interested in whether adults with migraine in middle age were at increased risk of stroke-like lesions or white-matter lesions on MRI in later life. We were also interested in whether migraineurs with a certain genetic make-up were particularly at risk for these cardiovascular outcomes. Our study population is a unique population-based cohort of adults in Reykjavik, Iceland who have been followed for more than 25 years.
We have completed and published our first analysis related to the migraine and sub-clinical stroke-like lesions. We found that the migraineurs who reported aura symptoms in middle –age were more likely than others to have stroke-like lesions in the cerebellum.

Hypotheses vs. findings

Some of our findings were consistent with our hypotheses and some were not. For example, the only other study that considered this question (Kruit et al, JAMA 2005) also found that the relationship between migraine and these lesions was only evident for individuals with migraine with aura and was strongest for lesions located in the cerebellum. In addition to confirming these earlier results, we also found that the risk appeared to be evident only for women – which was interesting and needs to be confirmed in other studies. In secondary analyses, we also found a suggestion that migraine may be related to cortical lesions in men.

Unanswered questions

While the epidemiologic relationship between migraine with aura and clinical and sub-clinical cerebrovascular disease appears increasingly solid, the degree to which these infarct-like lesions have clinical consequences is uncertain. It is possible that people who experience migraine with aura over their lifetimes may have associated subtle problems with, for example, balance in their later years. It is also possible that these lesions are not at all associated with functional consequences. In either event, what these lesions – and even the migraine aura itself – represent is a question of scientific and public health interest.

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