If you put someone in an unfamiliar car and ask them to drive it somewhere, the most trouble they're likely to have is if they need to figure out how to turn on the wipers in the dark. The controls may vary but they're close enough that people figure it out.

Put that same person in front of their work computer, but rearrange all the desktop icons and change the color scheme. There's a non-zero chance that they immediately freeze up and act like there's no possible way for them to do anything. They act like human macros, any slight change throws everything off.