| Migraine is a common multifactorial brain disorder, with disabling attacks of headache, vomiting, and transient focal neurological deficits (aura), sometimes leading to brain lesions. The migraine aura is caused by cortical spreading depression (CSD), a propagating chemical wave of neuronal depolarization. Familial hemiplegic migraine (FHM1) is a monogenic severe subtype of migraine caused by mutations in the CACNA1A calcium channel gene. FHM1 is an established model to study the pathogenesis of the common types of migraine. I have access to transgenic knock-in mouse models that carry two different human FHM1 mutations. I want to study CSD and associated mechanisms in these mouse models by using a novel MRI technique (MEMRI) that maps calcium channel functionality in vivo through Mn2+ uptake during neuronal excitation. Working hypotheses are: 1. The calcium channel mutations lower the trigger threshold, and thereby the propagation, speed, and extent of CSD. 2. CSD disrupts the blood-brain-barrier and, thereby, may lead to brain lesions. 3. CSD is associated with cytotoxic oedema and, therefore, MEMRI will closely correlate to MRI diffusion measurements, which are also applicable in humans. 4. Migraine triggers induce both CSD and migraine-like attacks in the mouse models. I propose, firstly, to characterize CSD, and secondly, to monitor in vivo migraine-like attacks that can be induced by specific triggers. To this end I will analyse the mouse models in vivo, before, during and after exposure to CSD or migraine triggers. I will use our ultra-high field MRI systems to develop fast protocols to track CSD progression in real time with MEMRI and compare the results with real-time diffusion measurements and biochemical analyses. Ultimately, a better understanding of the role of calcium channels in migraine may identify new targets for prophylactic treatment; finding correlations between MEMRI and diffusion imaging will allow translation of the results to human diffusion studies. |
