What do you think ________ troubles him most from time to time?
A.it is thatB.that isC.which isD.it is在线课程A
解析：
do you think在这里是插入语，这是一句强调句，Do you think it is sth that troubles him most from time to time．而这里的sth正是trouble的主语，也是强调句的被强调部分，因此用what提问。