Longitudinal neuroimaging (LNI) studies are rapidly becoming more prevalent and growing in size. Today, no standardized computational tools exist for the analysis of LNI data and widely used methods are sub-optimal for the types of data encountered in real-life studies. Linear Mixed Effects (LME) modeling, a mature approach well known in the statistics community, offers a powerful and versatile framework for analyzing real-life LNI data. This article presents the theory behind LME models, contrasts it with other popular approaches in the context of LNI, and is accompanied with an array of computational tools that will be made freely available through FreeSurfer – a popular Magnetic Resonance Image (MRI) analysis software package. Our core contribution is to provide a quantitative empirical evaluation of the performance of LME and competing alternatives popularly used in prior longitudinal structural MRI studies, namely repeated measures ANOVA and the analysis of annualized longitudinal change measures (e.g. atrophy rate). In our experiments, we analyzed MRI-derived longitudinal hippocampal volume and entorhinal cortex thickness measurements from a public dataset consisting of Alzheimer’s patients, subjects with mild cognitive impairment and healthy controls. Our results suggest that the LME approach offers superior statistical power in detecting longitudinal group differences.

We present an extension of the Linear Mixed Effects (LME) modeling approach to be applied to the mass-univariate analysis of longitudinal neuroimaging (LNI) data. The proposed method, called spatiotemporal LME or ST-LME, builds on the flexible LME framework and exploits the spatial structure in image data. We instantiated ST-LME for the analysis of cortical surface measurements (e.g. thickness) computed by FreeSurfer, a widely-used brain Magnetic Resonance Image (MRI) analysis software package. We validate the proposed ST-LME method and provide a quantitative and objective empirical comparison with two popular alternative methods, using two brain MRI datasets obtained from the Alzheimer’s disease neuroimaging initiative (ADNI) and Open Access Series of Imaging Studies (OASIS). Our experiments revealed that ST-LME offers a dramatic gain in statistical power and repeatability of findings, while providing good control of the false positive rate.