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Figure 1: Seizure generation based on cerebrovascular events. Traditionally, the main and leading hypothesis to explain seizures consisted of abnormal neuronal wiring and excitability. While evidence of this is undisputed, the alternative/complementary hypothesis also adds to the mix pre-existing leakage of the BBB, which generates a decrease in seizure threshold. According to this hypothesis BBB leakage decreases seizure threshold independent of the fact that such leakage is associated with or a result of the seizure itself (blue versus red idealized traces). In other words, and based on the results by Friedman’s Group, traumatically induced BBB disruption (BBBD) lowers seizure threshold. Others (e.g., Marchi et al.) have shown that BBBD alone is sufficient to provoke a seizure in a nonepileptic animal. While the contribution of BBB dysfunction to seizures has been demonstrated, the exact mechanisms (e.g., brain entry of peripherally circulating molecules, yellow dots in the cartoon) remain unclear.