Put your arm straight out like you’re about to shake someone’s hand. Now twist your arm so your palm is facing down, and notice how you can feel that twist all the way up your forearm and even past your elbow. It just feels more tense.
If you experience wrist or arm pain from using a mouse in the palm-down position, Evoluent’s VerticalMouse offers a more natural, more ergonomic position that may help. But the change in position means a change in gestures, too, and that takes getting used to.