Neuronal circuitry in migraine pain generation. Cortical spreading depression (CSD) triggers plasma protein extravasation from dural blood vessels, which in turn activates trigeminal (TG) afferents. Multiple mutations have been found in familial and sporadic migraine that could reduce the threshold for firing of TG neurons, either directly by affecting neuronal excitability or indirectly by modulating local glia activity. Signals are transduced to the trigeminal nucleus caudalis (TNC), which receives several modulatory inputs from other areas of the brainstem, such as the periaqueductal gray (PAG), the locus coeruleus (LC) and the raphe nuclei (RN). These areas have been proposed as sites of dysfunction in migraine. The TNC projects to rostral brain areas, where the perception of pain is generated.