This paper describes a novel approach to in-vivo measurement of brain surface folding in clinically acquired neonatal MR image data. Specifically it addresses the problem of comparing folding of surfaces of arbitrary area. Most of the current measures of folding are not independent of the area of the surface from which they are derived. Therefore, applying them to whole brains or subregions of different sizes result in differences which may or may not reflect true differences in folding. In this paper we describe alternative approaches to deriving area independent measures. The measures were applied to twelve premature infants (age 28-37 weeks) from which cortical gray and white surfaces were extracted. Experimental results show that previous folding measures are sensitive to the size of the surface patch, and that the area independent measures proposed here provide significant improvements. Such a system provides a tool to allow the study of structural development in the neonatal brain within specific functional subregions, which may be critical in identifying later neurological impairment.