If I download a MIDI file and change the instrumental voicing via Synthesia to use it in my game - Is that considered a copyright infringement?
It can be, yes. The only way you'd be legally allowed to manipulate or change someone else's MIDI is if they gave you permission to do so.
That depends on whether the copyright allows for that. If it's one of the Creative Commons licenses, then it's probably okay. If it's the critical
All Rights Reserved, then it's probably not.