Migraine aura, which precedes the headache phase in about one out of three patients, has a range of neurological symptoms and can last for anywhere between five minutes to one hour. The underlying neurological mechanisms of the spontaneous start of the aura phase, and its relation with subsequent headache, are yet to be elucidated as the diverse range of involved brain systems necessitates a multidisciplinary approach. Researchers with expertise in functional neurobiology conducted several multidisciplinary experiments under the aegis of the UNDERNEATH MIGRAINE (Underneath the attack: cortical network function in migraine) project. To study factors contributing to migraine susceptibility, they used migraine mouse models with human pathogenic mutations. Researchers first set up in vivo electrophysiology systems to record brain activity in freely behaving mice. Through this, they could monitor neuronal activity as well as behaviour with emphasis on the phenomenon cortical spreading depression (CSD). CSD has been associated with migraine aura, a condition where blurry vision or increased sensitivity to light are some of the common symptoms. Project members made several exciting discoveries. The freely behaving migraine mice occasionally displayed CSD events in the absence of chemical or electrical triggers. Enhanced cortical excitability was seen in areas beyond the visual cortex, the suspected site of origin for migraine auras. They validated the utility of visual evoked potentials to detect cortical excitability. A first, research outcomes provided evidence of predictive neuronal activity changes prior to CSD. The stress hormone corticosterone enhanced CSD susceptibility in migraine mice but not wild-type mice. Using behavioural allodynia measurements, pre-treatment with the migraine drug sumatriptan normalised migraine mice that had previously displayed enhanced sensitisation. Using optogenetics, researchers successfully and non-invasively induced CSD by shining blue light on the skull of anesthetised and freely behaving transgenic mice. As useful tool to study metabolic changes, the team also developed an ion-sensitive electrode prototype for in vivo brain recordings of pH and K+ during CSD in living mice. Experiments revealed CSD-related migraine-specific neurobiological changes by monitoring metabolic, inflammatory and neuroplasticity markers in migraine mice. Study outcomes led to further collaborations with epilepsy researchers and the awarding of a US CURE SUDEP fellowship. Despite the end of the project, the research team is currently studying neuronal excitation-inhibition balance in specific brain regions to dissect migraine network mechanisms using optogenetic techniques. Results are expected to provide novel insight into the co-morbidity of migraine and epilepsy. Outcomes should help improve therapeutic strategies for migraine.
Migraine, functional neurobiology, electrophysiology, CSD, sumatriptan, prototype, marker, epilepsy, optogenetic