- The term spreading depolarization describes a mechanism of abrupt, massive ion translocation between neurons and the interstitial space, which leads to a cytotoxic edema in the gray matter of the brain. In energy-compromised tissue, spreading depolarization is preceded by a nonspreading silencing (depression of spontaneous activity) because of a neuronal hyperpolarization. By contrast, in tissue that is not energy compromised, spreading depolarization is accompanied by a spreading silencing (spreading depression) of spontaneous activity caused by a depolarization block. It is assumed that the nonspreading silencing translates into the initial clinical symptoms of ischemic stroke and the spreading silencing (spreading depression) into the symptoms of migraine aura. In energy-compromised tissue, spreading depolarization facilitates neuronal death, whereas, in healthy tissue, it is relatively innocuous. Therapies targeting spreading depolarization in metabolically compromised tissue may potentially treat conditions of acute cerebral injury such as aneurysmal subarachnoid hemorrhage.