In this study, using wildtype and transgenic hemiplegic migraine mutant mice, we showed that three CSD events induced in a minimally invasive manner by optogenetics, evoke a temporary headache-relevant (i.e. increased mouse grimace scale (MGS) scores and the presence of oculotemporal strokes) and brain neuroinflammation (i.e. HMGB1 release) phenotypes within 30 min. The gene discussed is HMGB1; the disease is Headache.