Without further details it is difficult to know how exactly you would like to calculate it. A naive implementation that does exactly what your question asks and also gives you some possibilities is this one:
% im2double may or may not be needed depending of your goals
Frame1 = im2double(Frame1);
Frame2 = im2double(Frame2);
AverageDiff = mean(Frame1(:)-Frame2(:)); % This gives you the average difference. Use mean(abs(...)) for average absolute difference
