Traumatic brain injury (TBI) is particularly common in young people, generating healthcare costs that can span decades. The cellular processes activated in the first minutes following injury are poorly understood, and the 3-4 h following trauma are crucial for reducing subsequent injury. Spreading depression (SD) is a profound inactivation of neurons and glia lasting 1-2 min that arises focally and migrates outward across gray matter. In the hours following focal stroke, the metabolic stress of energy reduction and recurring SD-like events (peri-infarct depolarizations, PIDs) interact to promote neuronal injury. Similar recurring depolarizations might evolve immediately following TBI and exacerbate neuronal damage peripheral to the impact site. To test this possibility and examine if certain drugs might limit damage by inhibiting what we term traumatic spreading depression (tSD), we developed a technique whereby a small weight was dropped onto a live slice of rat neocortex while imaging changes in light transmittance (LT). Imaging revealed a propagating front of increased LT arising at the border of the impact site. Traumatic SD significantly expanded the region of ensuing damage. Both tSD and subsequent damage were blocked by the NMDA receptor antagonist MK-801 (100 microM) or the sigma-1 receptor (sigma1R) ligands dextromethorphan (30 microM) or BD-1063 (100 microM). Co-application of the sigma1R antagonist (+)3-PPP with DM reversed the block as did lowering temperature from 35 degrees C to 32 degrees C. This study provides evidence that an event similar to peri-infarct depolarization can arise from an injury site in neocortex within seconds following impact and act to expand the region of acute neuronal damage.