We present a general method-denoted MoDef-to help specify (or define) the model used to analyze brain imaging data. This method is based on the use of the multivariate linear model on a training data set. We show that when the a priori knowledge about the expected brain response is not too precise, the method allows for the specification of a model that yields a better sensitivity in the statistical results. This obviously relies on the validity of the a priori information, in our case the representativity of the training set, an issue addressed using a cross-validation technique. We propose a fast implementation that allows the use of the method on large data sets as found with functional Magnetic Resonance Images. An example of application is given on an experimental fMRI data set that includes nine subjects who performed a mental computation task. Results show that the method increases the statistical sensitivity of fMRI analyses.