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So they have a mental condition that is inverting their perception of the X and/or Y axis? I've never heard of such a thing, let alone in two people within the same household.
There is surely a software solution, but the nerd in me wants to hack their brains using mirrors, or cameras or something so that what they see is opposite of what they're doing so that their actions are corrected with positive reinforcement. I know that there have been doctors who have used mirrors with amputees to help them eliminate phantom limb pain. I think there was also a doctor who helped a stroke victim to regain use of one side of her body with a similar technique.
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I don't see this as a mental issue at all and it does seem absurd that you know two people with the exact same problem. The mouse interface is a completely artificial and arbitrary one. In fact, apple recently completely reversed the scrolling interface (natural scrolling) so that vertical mouse movements work the opposite of the way they worked before. People adapt to the interface that's presented to them. Having the mouse go one way or the other to cause things to happen on the screen is arbitrary and something the human brain will adapt to. People may not like the change at first but after a while they forget about it.
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A few decades ago I had a chance to see some user testing video that Apple made where they had new customers unpack and setup a Mac II. There are two things that I always remembered from that.
1) Nobody could get the tape off of the plastic that wrapped the ADB keyboard cable.
2) Quite a few people were using the mouse rotated 180 degrees, they had never used a mouse before and didn't know how to hold it, some even found the way they were holding it to be unnatural when they moved it, but kept practicing, and at the end one was so proud to announce that she "finally got the knack of it" while holding it up in her hand still rotated 180 degrees.
I suppose that if someone just started off wrong and never knew what the right way was, they would learn to use it they way that the first started and would be opposed to any change. Much like some long time Mac users have been opposed to the scrolling direction changes introduced in Lion and beyond.
In this specific situation, it could be that one of the family members first learned how to use the mouse from the other one that was using it wrong, and then continued thinking that's the correct way until it because natural.