Migraine affects 12% of the world population. Chronic migraine, which completely disrupts the lives of sufferers, affects close to 3%, and is extremely difficult to treat. It appears that there is an evolution or 'kindling' from an episodic to a chronc migraine state. Migraine is a pain disorder, but more fundamentally it is a disorder of brain excitability, whose fundamental manifestation is an increase in the 'volume' of sensory input. We have identified changes in brain sensory responses after cortical spreading depression (CSD), a wave of brain activity that is thought to underlie the migraine aura. Remarkably, these changes resemble what is seen in the brain during plasticity - i.e. during learning. Our core hypothesis is that CSD and other migraine-related events co-opt the normal learning machinery of the sensory brain to cause a form of dysfunctional learning - or malignant plasticity. We suspect that the development of an acute migraine attack, and the progression of migraine, is driven by this negative plasticity process. We will use imaging and electrical recordings in mice expressing genes found in migraine patients to test this hypothesis.
Our first aim focuses on the changes in individual cellular function caused by CSD, which is thought to underlie the migraine aura. We have identified structural and functional changes in neurons, astrocytes, and blood vessels after CSD, each of which might explain the change in sensory network response we observed.
Our second aim broadens our approach to look at larger neural networks disrupted by CSD. In addition to pain, migraine also involves changes in perception of light; photophobia or aversion to light is extremely common. We will image the visual cortex of awake mice as they decide on their preference for light levels, before and after CSD.
Our third aim will try to apply the insighs we have gained to the development of migraine treatments. Sensory map sharpening - one of the markers of sensory learning we identified after CSD - may be identifiable in humans using fMRI. We will test whether sharpening of sensory maps occurs on chronic CSD stimulation, and thus might serve as a biomarker of migraine progression. Finally, on the basis of our cellular findings, we will test two clinically-relevant medications whose mechanism may be suppression of excessive calcium activity after CSD. Overall, our experiments should uncover basic mechanisms underlying the development of a migraine attack and the progression of migraine, and point to treatment strategies that arrest the 'malignant learning' that takes place in this disease.

Public Health Relevance

Migraine affects more than one in ten people in the US. It is a disorder of amplified sensation, than can evolve into a permanent state. This proposal aims to study how migraine evolves, explicitly treating it as a disorder of sensory plasticity. We will usea combination of imaging and electrophysiology to examine the sensory network response disrupted by cortical spreading depression, the physiological correlate of the migraine aura.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS085413-03
Application #
8914056
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Oshinsky, Michael L
Project Start
2013-09-26
Project End
2018-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
3
Fiscal Year
2015
Total Cost
$325,938
Indirect Cost
$107,188
Name
University of Utah
Department
Neurology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Cortez, Melissa M; Rea, Natalie A; Hunter, Lindsay A et al. (2017) Altered pupillary light response scales with disease severity in migrainous photophobia. Cephalalgia 37:801-811
Hartings, Jed A; Shuttleworth, C William; Kirov, Sergei A et al. (2017) The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy. J Cereb Blood Flow Metab 37:1571-1594
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Hoggan, Ryan N; Subhash, Amith; Blair, Steve et al. (2016) Thin-film optical notch filter spectacle coatings for the treatment of migraine and photophobia. J Clin Neurosci 28:71-6
Kaufmann, Dan; Theriot, Jeremy J; Zyuzin, Jekaterina et al. (2016) Heterogeneous incidence and propagation of spreading depolarizations. J Cereb Blood Flow Metab :271678X16659496
Minen, Mia; Shome, Ashna; Halpern, Audrey et al. (2016) A migraine management training program for primary care providers: An overview of a survey and pilot study findings, lessons learned, and considerations for further research. Headache 56:725-40
Kaufmann, Dan; Bates, Emily A; Yagen, Boris et al. (2016) sec-Butylpropylacetamide (SPD) has antimigraine properties. Cephalalgia 36:924-35

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