CSD is most often initiated in the occipital cortex of patients with visual migraine aura. It is believed that CSD is ignited by local elevation of extracellular K⁺ levels in pockets of intense excitatory transmission. When K⁺ levels reach a critical threshold of 10–12 mM, a self-propagating CSD wave is initiated and advances across the cortex with a slow velocity of 3 mm/min. The threshold for CSD initiation is reduced in FHM patients with mutations in the Ca_v2.1 Ca²⁺ channel because the higher Ca²⁺ level in dendrites facilitates glutamate release and thereby increases the likelihood that K⁺ levels will reach the CSD threshold. A combination of stress and food intake may be sufficient to ignite CSD in patients with FHM, whereas stronger stimulation is required in the rest of the population. The lower diagram depicts the cortical events linking CSD to migraine pain. The high extracellular K⁺ level at the edge of the CSD wavefront is key for wave propagation. K⁺ is normalized within minutes, but the restoration of normal membrane potential of neurons and glial cells is a high energy–demanding process. The cortical tissue experiences a minutes-lasting period of severe reduction of tissue O₂ tension (hypoxia) during CSD because O₂ consumption transiently exceeds the vascular supply of O₂. This hypoxia has several consequences: (a) Neurons exhibit severe morphological distortions, swelling, and transient loss of dendritic spines. Normal dendritic structures are reestablished 15–20 minutes later, coinciding with the reappearance of a normal EEG pattern. This hypoxic phase is followed by prolonged vasoconstriction and reduction of local blood flow. (b) The CSD wave activates MMP9, resulting in opening of the blood-brain barrier (BBB) and extravasation of plasma protein. The leakage of blood-borne factors activates nociceptive afferent neurons from trigeminal ganglion innervating meningeal arteries, connecting to trigeminal nucleus caudalis, triggering the migraine pain. (c) CSD triggers preconditioning — an endogenous mechanism of neuroprotection that raises ischemic tolerance.