Fearn,
You raise a very good point. Disease would be my other argument against extended contact. There wasn't enough newcomers (and their livestock) to be vectors of disease. Or if there a large settlement, it was so long ago that the epidemics ran their courses and the population rebounded.
Also, the depopulation continued well after the 16th Century. Take the Mandans for example. In 1719 Bernard Le Harpe visited an area of Wichita villages in eastern Oklahoma that had a population of around 6,000 people if I remember correctly. Later, in the 1750's the Wichitas had a fortified village on the Red River on the OK/TX border where they defeated a Spanish expedition with cannons, and probably a few of those lancers with leather armor. If I remember correctly, by the end of the 19th Century, there were only 332 Wichitas left. Today there are around 2,000, about 1/3rd of what one group them had in the 18th Century.
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