Isaac builds up rage every time he clears a room, which is indicated by the patch of skin that spreads around his face, as well as the four sections of the horn lighting up red one at a time.
After four rooms, Isaac's head will start to flash red; upon entering a room with enemies, he will fire a large Brimstone laser for ~3.33 seconds.
The laser deals Isaac's damage per tick (15x Isaac's damage per second).