Mounting human data coupled with extensive animal data supports the assertion that CSD is not only a marker in response to severe brain injury, but in fact, plays a causal role in injury propagation(8). Animal data is fairly definitive in this assertion, in that CSD can be studied in uninjured brain and inducing CSD leads to neuronal death, particularly with repeated events. Note the progressive loss of brain electrical activity with repeated CSD in the figure to the right. In animal models, CSD clearly leads to expansion of injury, particularly in ischemic stroke models. Human data is unavoidably observational to this point, however by observing multiple physiologic modalities, the deleterious effects become clear. A spectrum of local blood flow responses to CSD have been observed, ranging from a wave of hyperemia (termed the normal hemodynamic response) to a wave of ischemia (termed the inverse hemodynamic response(9, 10)). The factors that determine the response likely have to do with the availability of substrate (glucose, oxygen) and delivery (blood flow) coupled with the baseline metabolic state of the tissue (depressed metabolic state may be more resistant). When the inverse hemodynamic response is observed, an associated wave of tissue hypoxia is observed, which becomes linearly more hypoxic with repeated CSD in a short interval(11). Brain metabolism also can be measured during CSD, and consistent metabolic challenge is noted, with increased micro dialysis lactate and decreased glucose(12). In the case of repeated events, this glucose depletion becomes progressive due to inadequate time for the tissue to recover between these massive events leading to progressive ischemia(12).