Four pixel-based methods for estimating regional activation in positron emission tomography (PET) images were implemented so as to allow the comparison of their performances in the same dataset. Change distribution analysis, Worsley's method, a pixelwise general linear model, a nonparametric method, and several methods derived from them were investigated. Important technical factors, including the degree of smoothing, stereotactic transform, coregistration algorithm, search volume, and the volumetric alpha level, were held constant. The dataset, which was obtained with a verb generation paradigm, was large enough to permit assessment of concordance between independent samples of conventional size, as well assessment of within-cohort replicability. (Eighteen normal subjects performed four GENERATE-READ pairs each.) Same-task (noise) images were also analyzed.In noise datasets, type I errors (false positives) occurred at the nominal rate (in 5% of datasets). Detected regions of activation were highly likely to be internally replicated (93%). The detected activations were a superset of activations previously reported using the same paradigm. The methods were chiefly distinguished by type 11 error rates and by the stability of the location of activation clusters. Those methods dependent on local variance estimates were less powerful with small sample sizes and less stable with respect to the attributed location of task-induced changes. The use of pooled variance (Worsley's method) reduced these problems, but variance was not stationary. Overall, the power of all analyses was modest with samples of conventional size (nine subjects x one or two task-pairs). Modeling of the sources of variance, particularly improvement of anatomical standardization, is likely to improve the power of pixel-based analyses.have been applied to numerous problems in cognitive neuroscience over the last decade. Progress in functional neuroimaging was greatly accelerated by the advent of computerized image analysis, especially the application of "pixel-based' methods of statistical analysis to activation images generated by positron emission tomography (PET). These methods, in which the fundamental unit of analysis is the pixel (picture element) rather than a region of intercst (ROI), were attractive because they did not require a priori anatomi-0 1996 Wiley-Liss, Inc.
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