Migraine pain generation. Migraine triggers initiate the neuronal excitation that leads to clinical manifestations in children with a genetic vulnerability to migraine. Cortical spreading depression (CSD) triggers plasma protein extravasation from cerebral blood vessels, which in turn activates trigeminal (TG) afferents within the trigemino-vascular system (TVS). Gene mutations could reduce the threshold for firing of TG neurons. Signals are transduced to the trigeminal nucleus caudalis (TNC), which receives modulatory inputs from other brainstem nuclei (BN), such as the periaqueductal gray, the locus coeruleus and the raphe. The TNC projects to rostral brain areas, where the perception of pain is generated.