I'm not a great player so I don't tend to make adjustments to make the game harder. But I do like to make adjustments that encourage me to play more of the game and get more out of it.
E.g., Dr Dude: set the Mix Master to require far more hits to spot Elements of Coolness. This eliminates the 'ramp all day' strategy and forces you to play the game properly.
One other thing I like to do is set the drop targets to have memory between balls. This means I actually shoot for them because I am more likely to see the rewards (but it is also not a safe shot). Without target memory they're not worth shooting for.