Quantitative MRI Preprocessing: Effects of Tissue-Specific Smoothing Approaches on Statistical inference

Background: Quantitative MRI (qMRI) provides voxel-wise measurements of tissue properties related to myelin, iron and water content, making it a powerful tool for studying brain aging and microstructural alterations in vivo. However, conventional spatial smoothing can introduce partial-volume effects and blur tissue boundaries, potentially affecting both statistical sensitivity and anatomical specificity. Several tissue-specific smoothing strategies have been proposed to address these limitations, yet their relative impact on voxel-wise statistical analyses remains insufficiently characterized. The present study aims (i) to systematically compare three tissue-specific smoothing strategies: a linear tissue-weighted compensated approach (TWS), a generalized version of nonlinear tissue-masked compensated smoothing approach (gTSPOON), and an intensity-weighted edge-preserving approach based on the Smallest Univalue Segment Assimilating Nucleus smoothing (SUSANs), and (ii) to investigate how smoothing approaches interact with statistical inference frameworks by comparing parametric and non-parametric voxel-wise analyse. Methods: Analyses were performed on a publicly available lifespan qMRI dataset comprising 138 healthy participants (19-75 years) and quantitative maps of MTsat, PD, R1, and R2*. The generalized TSPOON (gTSPOON) method was implemented using tissue-specific masks derived from probabilistic tissue segmentation. All three smoothing approaches (TWS, gTSPOON and SUSANs) were parameterized to achieve comparable nominal spatial smoothing. Age-related effects were investigated separately in GM and WM using voxel-wise general linear models following a previously published framework. Statistical inference was assessed using multiple complementary approaches, including parametric Random Field Theory (RFT), under both stationarity and non-stationarity assumptions, as well as non-parametric permutation-based inference. In addition to conventional thresholded statistical parametric maps, voxel-wise log-likelihood (LL) maps were computed to quantify general linear model (GLM) goodness-of-fit independently of statistical thresholding. Bland-Altman analyses and spatial agreement metrics were subsequently used to compare smoothing strategies. Results: TWS and gTSPOON produced highly similar spatial distributions of age-related effects across all qMRI parameters and tissue classes. However, TWS consistently yielded a larger number of significant voxels and clusters, reflecting slightly higher sensitivity, from slightly wider effective smoothness and reduced RESEL counts. By contrast, SUSANs generated substantially fewer significant voxels and clusters, associated with approximately half the effective smoothness and a markedly larger number of RESELs. Despite these differences in statistical sensitivity, voxel-wise LL analyses revealed distinct anatomical preferences for each smoothing strategy. TWS provided the best model fit predominantly within GM, whereas gTSPOON showed superior performance in homogeneous WM regions. Conversely, SUSANs achieved the highest LL values at GM-WM interfaces, particularly within sulcal and gyral transitions, indicating improved preservation of sharp anatomical gradients. These spatial patterns were consistently observed across MTsat, PD, R1 and R2* maps. Comparisons across stationary and non-stationary RFT assumptions revealed only minor differences, while non-parametric inference produced highly concordant results, indicating that the primary source of variability originated from the smoothing procedure itself rather than the inference framework. Conclusions: Tissue-specific smoothing strategies substantially influence both statistical sensitivity and voxel-wise model fitting in qMRI analyses. While TWS and gTSPOON provide highly consistent results, the edge-preserving SUSANs approach preferentially enhances model fit at tissue boundaries. Importantly, voxel-wise log-likelihood mapping revealed that no smoothing strategy is uniformly optimal throughout the brain; instead, each method exhibits anatomically preferential regions where model fit is maximized. These findings suggest that smoothing should be viewed as a region-dependent optimization problem and highlight voxel-wise LL mapping as a principled framework for selecting or developing adaptive smoothing strategies tailored to specific neuroanatomical structures and biological processes, including age-related brain changes.