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Underneath the attack: cortical network function in migraine

Final Report Summary - UNDERNEATH MIGRAINE (Underneath the attack: cortical network function in migraine)

In my Marie Curie (MC) project I investigated how sudden changes in brain physiology contribute to migraine attacks. This is important because migraine is a devastating brain disease affecting millions of European citizens, causing a large personal burden of migraine patients and an economic burden for society.

For my project, I implemented my functional neurobiology expertise for a range of multidisciplinary experiments to study mechanisms underlying migraine susceptibility by using unique migraine mouse models carrying human pathogenic mutations generated by the host team. The studies in this periodic report were carried out at the host institute under my supervision. During the MC project I set up and validated advanced in vivo electrophysiology systems for brain activity recordings in freely behaving mice. The systems enable monitoring of neuronal activity and behavior in relation to cortical spreading depression (CSD), the neurobiological correlate of the migraine aura.

The MC project yielded several relevant scientific results. My team discovered that migraine mice display spontaneous CSD events, and enhanced cortical excitability that was not restricted to the visual cortex where migraine auras are believed to originate. Using bright light as sensory trigger, we validated visual evoked potentials as useful readout of cortical excitability and obtained first evidence of predictive neuronal activity changes prior to CSD. Parallel behavioral studies showed that migraine mice displayed enhanced sensitization that was normalized by pre-treatment with the migraine drug sumatriptan. We demonstrated direct effects of external parameters on cortical excitability in a migraine-susceptible brain with the observation in anesthetized animals that stress hormone corticosterone enhances CSD susceptibility in migraine but not wild-type mice. For investigation of metabolic changes underlying CSD susceptibility we developed a prototype ion-sensitive electrode for in vivo brain recordings of pH and K+, and demonstrated its usage during CSD recordings in living mice. Recently, we successfully induced CSD in anesthetized and freely behaving transgenic mice in a non-invasive manner via optogenetic activation of cortical neurons, by shining light through the intact skull. Finally, we identified migraine-specific neurobiological changes related to CSD by demonstrating cortical and subcortical, as well as peripheral body fluid (i.e. blood plasma) changes in metabolic, inflammatory and neuroplasticity markers that were specifically altered upon CSD induction in migraine mice.

The MC grant promoted the development of my own research line and establishment of my position at the host institute as tenured senior researcher. The performed studies fit well those of EU MC BRAINPATH and FP7 EUROHEADPAIN projects that were granted during the MC period, to which I actively contribute as junior PI and co-coordinator of outreach activities. To further dissect migraine network mechanisms, my team is currently implementing optogenetics for modulation of neuronal excitation-inhibition balance in specific brain regions. Insight in these mechanisms likely uncovers mechanisms of the co-morbidity of migraine and epilepsy. To this end, my findings on cortical hyperexcitability in migraine mice inspired novel collaborations with epilepsy researchers at the LUMC and Dutch epilepsy institution SEIN, and contributed to a US CURE SUDEP fellowship that I was awarded during my MC project.