Evaluation of mixed effects in event-related fMRI studies: impact of first-level design and filtering.

With the introduction of event-related designs in fMRI, it has become crucial to optimize design efficiency and temporal filtering to detect activations at the 1st level with high sensitivity. We investigate the relevance of these issues for fMRI population studies, that is, 2nd-level analysis, for a set of event-related fMRI (er-fMRI) designs with different 1st-level efficiencies, adopting three distinct 1st-level filtering strategies as implemented in SPM99, SPM2, and FSL3.0. By theory, experiments, and simulations using physiological fMRI noise, we show that both design and filtering impact the outcome of the statistical analysis, not only at the 1st but also at the 2nd level. There are several reasons behind this finding. First, sensitivity is affected by both design and filtering, since the scan-to-scan variance, that is the fixed effect, is not negligible with respect to the between-subject variance, that is the random effect, in er-fMRI population studies. The impact of the fixed effects error on the sensitivity of the mixed effects analysis can be mitigated by an optimal choice of er-fMRI design and filtering. Moreover, the accuracy of the 1st- and 2nd-level parameter estimates also depend on design and filtering; especially, we show that inaccuracies caused by the presence of residual noise autocorrelations can be constrained by designs that have hemodynamic responses with a Gaussian distribution. In conclusion, designs with both good efficiency and decorrelating properties, for example, such as the geometric or Latin square probability distributions, combined with the "whitening" filters of SPM2 and FSL3.0, give the best result, both for 1st- and 2nd-level analysis of er-fMRI studies.