IIRC you can get a 60 day visa issued via a consulate in US. That would save the first visa run @:-) Don't remember if there is cost involved with this.

Yep, and the expat boards will have stories if people get turned back or a particular immigration post is bad. Lack of consistency has been a common complaint. But the purpose is to target those who just kept going in and out to keep renewing the visa and to make them get whatever longer-term visa would apply to their situation (work, student, retiree, etc.). So while I'd say the odds are that you won't get hassled for 2-3 entries on the same trip (e.g. using BKK as a base and flying LCCs to other countries and back), I can't 100% guarantee it.

Isaan can really be delightful, but I think you need at least a trip or two under your belt to start to appreciate it. Otherwise it may seem a bit boring. Phi Mai and Phanom Rung are good for Angkor-era ruins, there's that candle festival for the Buddhist Lent in Ubon, and Udon Thani has the lotus lake in winter. But some of the best experiences are "found" ones with food, Isaan music at live venues, or things like that. Nakhon Phanom was even peaceful enough that I could ride a bike around, take the 5 p.m. cruise to nowhere on the Mekong for B50, and get a wide-eyed look or two from a kid who'd never seen a farang before.

There's a specialized website that might be useful to the OP: ajarn.com. It's basically for foreign expat teachers in Thailand teaching English or in English. They talk about visa runs extensively and also generally have good information about budget to moderate travel in Thailand for foreigners who stay more than a few days.

Definitely one of the few quality areas that has yet to ruined by tourism but absolutely correct that its not for a first time visitor. excepting the main cities (Udon, Ubon, Korat, Khon Kaen.... but they can be boring too). Some language skill helps immensely with Issan too, especially for food.