Adjusting for global effects in voxel-based morphometry: gray matter decline in normal aging

Results from studies that have examined age-related changes in gray matter based on structural MRI scans have not always been consistent. Reasons for this variability likely include small or unevenly-distributed samples, different methods for tissue class segmentation and spatial normalization, and the use of different statistical models. Particularly relevant to the latter is the method of adjusting for global (total) gray matter when making inferences about regionally-specific changes. In the current study, we use voxel-based morphometry (VBM) to explore the impact of these methodological choices in assessing age-related changes in gray matter volume in a sample of 420 adults evenly distributed between the ages of 18-77 years. At a broad level, we replicate previous findings, showing age-related gray matter decline in nearly all parts of the brain, with particularly rapid decline in inferior regions of frontal cortex (e.g., insula and left inferior frontal gyrus) and the central sulcus. Segmentation was improved by increasing the number of tissue classes and using less age-biased templates, and registration was improved by using a diffeomorphic flow-based algorithm (DARTEL) rather than a "constrained warp" approach. Importantly, different approaches to adjusting for global effects--not adjusting, Local Covariation, Global Scaling, and Local Scaling--significantly affected regionally-specific estimates of age-related decline, as demonstrated by ranking age effects across anatomical ROIs. Split-half cross-validation showed that, on average, Local Covariation explained a greater proportion of age-related variance across these ROIs than did Global Scaling. Nonetheless, the appropriate choice for global adjustment depends on one's assumptions and specific research questions. More generally, these results emphasize the importance of being explicit about the assumptions underlying key methodological choices made in VBM analyses and the inferences that follow.