Influence of the normalization template on the outcome of statistical parametric mapping of PET scans J.D. Gispert, a J. Pascau, a S. Reig, a R. Martı ´nez-La ´zaro, a V. Molina, b P. Garcı ´a-Barreno, a and M. Desco a, * a Medical Imaging Laboratory, Hospital Universitario “Gregorio Maran ˜o ´n,” Madrid, Spain b Department of Psychiatry, Hospital Doce de Octubre, Madrid, Spain Received 30 April 2002; revised 4 December 2002; accepted 23 December 2002 Abstract Spatial normalization is an essential preprocessing step in statistical parametric mapping (SPM)-based analysis of PET scans. The standard template provided with the SPM99 software package was originally constructed using 15 O-H 2 O PET scans and is commonly applied regardless of the tracer actually used in the scans being analyzed. This work studies the effect of using three different normalization templates in the outcome of the statistical analysis of PET scans: (1) the standard SPM99 PET template; (2) an 18 F-FDG PET template, constructed by averaging PET scans previously normalized to the standard template; and (3) an MRI-aided 18 F-FDG PET template, constructed by averaging PET scans normalized according to the deformation parameters obtained from MRI scans. A strictly anatomical MRI normalization of each PET was used as a reference, under the rationale that a normalization based only upon MRI should provide higher spatial accuracy. The potential bias involved in the normalization process was estimated in a clinical SPM study comparing schizophrenic patients with control subjects. For each between-group comparison, three SPM maps were obtained, one for each template. To evaluate the influence of the template, these SPM maps were compared to the reference SPM map achieved using the anatomical normalization. SPMs obtained by MRI-aided normalization showed the highest spatial specificity, and also higher sensitivity when compared to the standard normalization using the SPM99 15 O-H 2 O template. These results show that the use of the standard template under inappropriate conditions (different tracer or mental state) may lead to inconsistent interpretations of the statistical analysis. © 2003 Elsevier Science (USA). All rights reserved. Introduction Statistical parametric mapping (SPM) is a method con- ceived to perform voxel-by-voxel statistical analysis of functional images (Friston et al., 1995). Spatial normaliza- tion is a required preprocessing step in intersubject statisti- cal analysis that consists of applying the nonlinear defor- mations required to force every particular PET scan to match a reference template study. The algorithm minimizes the residual squared difference between the images being normalized and the template image (Ashburner and Friston, 1999). The main disadvantage of this approach lies in the total loss of natural or pathological variability in brain morphology. This problem might be of particular relevance when studying diseases like schizophrenia, known to in- volve changes in brain morphology (Lawrie and Abukmeil, 1998). Normalization can be performed directly by deforming the PET scans until they match the PET template or indi- rectly by using an additional MRI template. In this latter case, the deformation parameters are determined from struc- tural images from the same subjects and then applied to the PET scans. This MRI-aided spatial normalization is alleg- edly more accurate than the one performed by using only functional images, given the better anatomical information and higher spatial resolution of MRI images (Ashburner and Friston, 1999). However, when MR images of the subjects under study are not available, it is only possible to perform a normal- * Corresponding author. Unidad de Medicina y Cirugı ´a Experimental, Hospital General Universitario “Gregorio Maran ˜o ´n,” Dr. Esquerdo, 46, E-28007 Madrid, Spain. Fax: +34-426-51-08. E-mail address: desco@mce.hggm.es (M. Desco). NeuroImage 19 (2003) 601– 612 www.elsevier.com/locate/ynimg 1053-8119/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1053-8119(03)00072-7