Migraine headache afflicts 20% of the population and causes major economic losses. Despite its high prevalence and serious economic consequences, its physiological, metabolic and molecular basis remains poorly understood and under-investigated. This application represents a joint effort by basic and clinical neuroscientists to understand the biological basis of migraine headache.
Aimi ng to achieve a greater understanding of the neural substrate of migraine aura and headache, our program comprises 3 multidisciplinary Projects, plus a Scientific and an Administrative Core. Project 1 proposes to examine cortical spreading depression (CSD) in normal and genetically modified mice and expand upon a recent novel finding that prophylactic antimigraine drugs suppress the susceptibility to CSD. Suppression of CSD is the first identified coherent physiological action for these pharmacologically distinct drugs, and emphasizes the importance of CSD to migraine pathophysiology. Project 1 will also expand upon our recent preliminary findings that thresholds for CSD become reduced during estrogen withdrawal as a mechanism to explain enhanced susceptibility in females to migraine headaches during menses. Project 2 will determine whether CSD is capable of activating meningeal nociceptors and central trigeminovascular neurons, and whether such activation depends upon the activation and degranulation of local mast cell or mediated by local activation of parasympathetic fibers originating in the sphenopalatine ganglion. Project 3 will examine the similarities and differences between patients with migraine (with and without aura), and test the hypothesis that CSD is the pathophysiological mechanism underlying both types of migraine. It will study the role of the cerebellum in migraine, and will build on preliminary findings showing long-term anatomical changes in the cortex and white matter of migraineurs to address the question: Is migraine a progressive disease? Taken together our 3 projects are mechanistically driven, multi-disciplinary, clinically relevant, molecular in orientation, and incorporate state of the art imaging. ? ? PROJECT 1 ? ? PI: Michael Moskowitz ? ? Title: Migraine Drug Prophylaxis ? ? Description (provided by applicant): Migraine headache afflicts 20% of the population and causes major economic losses. Despite its high prevalence and serious economic consequences, its physiological, metabolic and molecular basis remains poorly understood and under-investigated. This application represents a joint effort by basic and clinical neuroscientists to understand the biological basis of migraine headache.
Aimi ng to achieve a greater understanding of the neural substrate of migraine aura and headache, our program comprises 3 multidisciplinary Projects, plus a Scientific and an Administrative Core. Project 1 proposes to examine cortical spreading depression (CSD) in normal and genetically modified mice and expand upon a recent novel finding that prophylactic antimigraine drugs suppress the susceptibility to CSD. Suppression of CSD is the first identified coherent physiological action for these pharmacologically distinct drugs, and emphasizes the importance of CSD to migraine pathophysiology. Project 1 will also expand upon our recent preliminary findings that thresholds for CSD become reduced during estrogen withdrawal as a mechanism to explain enhanced susceptibility in females to migraine headaches during menses. Project 2 will determine whether CSD is capable of activating meningeal nociceptors and central trigeminovascular neurons, and whether such activation depends upon the activation and degranulation of local mast cell or mediated by local activation of parasympathetic fibers originating in the sphenopalatine ganglion. Project 3 will examine the similarities and differences between patients with migraine (with and without aura), and test the hypothesis that CSD is the pathophysiological mechanism underlying both types of migraine. It will study the role of the cerebellum in migraine, and will build on preliminary findings showing long-term anatomical changes in the cortex and white matter of migraineurs to address the question: Is migraine a progressive disease? Taken together our 3 projects are mechanistically driven, multi-disciplinary, clinically relevant, molecular in orientation, and incorporate state of the art imaging. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS035611-12
Application #
7472436
Study Section
Special Emphasis Panel (ZNS1-SRB-K (48))
Program Officer
Porter, Linda L
Project Start
1997-07-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
12
Fiscal Year
2008
Total Cost
$1,354,144
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Eikermann-Haerter, Katharina; Lee, Jeong Hyun; Yalcin, Nilufer et al. (2015) Migraine prophylaxis, ischemic depolarizations, and stroke outcomes in mice. Stroke 46:229-36
Ayata, Cenk; Lauritzen, Martin (2015) Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. Physiol Rev 95:953-93
Hadjikhani, Nouchine; Ward, Noreen; Boshyan, Jasmine et al. (2013) The missing link: enhanced functional connectivity between amygdala and visceroceptive cortex in migraine. Cephalalgia 33:1264-8
Burstein, Rami; Strassman, Andrew; Moskowitz, Michael (2012) Can cortical spreading depression activate central trigeminovascular neurons without peripheral input? Pitfalls of a new concept. Cephalalgia 32:509-11
Eikermann-Haerter, Katharina; Lee, Jeong Hyun; Yuzawa, Izumi et al. (2012) Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations. Circulation 125:335-45
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Cenik, Can; Chua, Hon Nian; Zhang, Hui et al. (2011) Genome analysis reveals interplay between 5'UTR introns and nuclear mRNA export for secretory and mitochondrial genes. PLoS Genet 7:e1001366
Noseda, Rodrigo; Burstein, Rami (2011) Advances in understanding the mechanisms of migraine-type photophobia. Curr Opin Neurol 24:197-202

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