KEYWORDS: Diffusion tensor imaging, Image segmentation, Data modeling, Scanners, Brain, Neuroimaging, Motion models, Signal to noise ratio, Matrices, Head
PurposeAs large analyses merge data across sites, a deeper understanding of variance in statistical assessment across the sources of data becomes critical for valid analyses. Diffusion tensor imaging (DTI) exhibits spatially varying and correlated noise, so care must be taken with distributional assumptions. Here, we characterize the role of physiology, subject compliance, and the interaction of the subject with the scanner in the understanding of DTI variability, as modeled in the spatial variance of derived metrics in homogeneous regions.ApproachWe analyze DTI data from 1035 subjects in the Baltimore Longitudinal Study of Aging, with ages ranging from 22.4 to 103 years old. For each subject, up to 12 longitudinal sessions were conducted. We assess the variance of DTI scalars within regions of interest (ROIs) defined by four segmentation methods and investigate the relationships between the variance and covariates, including baseline age, time from the baseline (referred to as “interval”), motion, sex, and whether it is the first scan or the second scan in the session.ResultsCovariate effects are heterogeneous and bilaterally symmetric across ROIs. Inter-session interval is positively related (p≪0.001) to FA variance in the cuneus and occipital gyrus, but negatively (p≪0.001) in the caudate nucleus. Males show significantly (p≪0.001) higher FA variance in the right putamen, thalamus, body of the corpus callosum, and cingulate gyrus. In 62 out of 176 ROIs defined by the Eve type-1 atlas, an increase in motion is associated (p<0.05) with a decrease in FA variance. Head motion increases during the rescan of DTI (Δμ=0.045 mm per volume).ConclusionsThe effects of each covariate on DTI variance and their relationships across ROIs are complex. Ultimately, we encourage researchers to include estimates of variance when sharing data and consider models of heteroscedasticity in analysis. This work provides a foundation for study planning to account for regional variations in metric variance.
PurposeIn brain diffusion magnetic resonance imaging (dMRI), the volumetric and bundle analyses of whole-brain tissue microstructure and connectivity can be severely impeded by an incomplete field of view (FOV). We aim to develop a method for imputing the missing slices directly from existing dMRI scans with an incomplete FOV. We hypothesize that the imputed image with a complete FOV can improve whole-brain tractography for corrupted data with an incomplete FOV. Therefore, our approach provides a desirable alternative to discarding the valuable brain dMRI data, enabling subsequent tractography analyses that would otherwise be challenging or unattainable with corrupted data.ApproachWe propose a framework based on a deep generative model that estimates the absent brain regions in dMRI scans with an incomplete FOV. The model is capable of learning both the diffusion characteristics in diffusion-weighted images (DWIs) and the anatomical features evident in the corresponding structural images for efficiently imputing missing slices of DWIs in the incomplete part of the FOV.ResultsFor evaluating the imputed slices, on the Wisconsin Registry for Alzheimer’s Prevention (WRAP) dataset, the proposed framework achieved PSNRb0=22.397, SSIMb0=0.905, PSNRb1300=22.479, and SSIMb1300=0.893; on the National Alzheimer’s Coordinating Center (NACC) dataset, it achieved PSNRb0=21.304, SSIMb0=0.892, PSNRb1300=21.599, and SSIMb1300=0.877. The proposed framework improved the tractography accuracy, as demonstrated by an increased average Dice score for 72 tracts (p<0.001) on both the WRAP and NACC datasets.ConclusionsResults suggest that the proposed framework achieved sufficient imputation performance in brain dMRI data with an incomplete FOV for improving whole-brain tractography, thereby repairing the corrupted data. Our approach achieved more accurate whole-brain tractography results with an extended and complete FOV and reduced the uncertainty when analyzing bundles associated with Alzheimer’s disease.
PurposeDiffusion tensor imaging (DTI) is a magnetic resonance imaging technique that provides unique information about white matter microstructure in the brain but is susceptible to confounding effects introduced by scanner or acquisition differences. ComBat is a leading approach for addressing these site biases. However, despite its frequent use for harmonization, ComBat’s robustness toward site dissimilarities and overall cohort size have not yet been evaluated in terms of DTI.ApproachAs a baseline, we match N=358 participants from two sites to create a “silver standard” that simulates a cohort for multi-site harmonization. Across sites, we harmonize mean fractional anisotropy and mean diffusivity, calculated using participant DTI data, for the regions of interest defined by the JHU EVE-Type III atlas. We bootstrap 10 iterations at 19 levels of total sample size, 10 levels of sample size imbalance between sites, and 6 levels of mean age difference between sites to quantify (i) βAGE, the linear regression coefficient of the relationship between FA and age; (ii) γ^sf*, the ComBat-estimated site-shift; and (iii) δ^sf*, the ComBat-estimated site-scaling. We characterize the reliability of ComBat by evaluating the root mean squared error in these three metrics and examine if there is a correlation between the reliability of ComBat and a violation of assumptions.ResultsComBat remains well behaved for βAGE when N>162 and when the mean age difference is less than 4 years. The assumptions of the ComBat model regarding the normality of residual distributions are not violated as the model becomes unstable.ConclusionPrior to harmonization of DTI data with ComBat, the input cohort should be examined for size and covariate distributions of each site. Direct assessment of residual distributions is less informative on stability than bootstrap analysis. We caution use ComBat of in situations that do not conform to the above thresholds.
Imaging findings inconsistent with those expected at specific chronological age ranges may serve as early indicators of neurological disorders and increased mortality risk. Estimation of chronological age, and deviations from expected results, from structural magnetic resonance imaging (MRI) data has become an important proxy task for developing biomarkers that are sensitive to such deviations. Complementary to structural analysis, diffusion tensor imaging (DTI) has proven effective in identifying age-related microstructural changes within the brain white matter, thereby presenting itself as a promising additional modality for brain age prediction. Although early studies have sought to harness DTI’s advantages for age estimation, there is no evidence that the success of this prediction is owed to the unique microstructural and diffusivity features that DTI provides, rather than the macrostructural features that are also available in DTI data. Therefore, we seek to develop white-matter-specific age estimation to capture deviations from normal white matter aging. Specifically, we deliberately disregard the macrostructural information when predicting age from DTI scalar images, using two distinct methods. The first method relies on extracting only microstructural features from regions of interest (ROIs). The second applies 3D residual neural networks (ResNets) to learn features directly from the images, which are nonlinearly registered and warped to a template to minimize macrostructural variations. When tested on unseen data, the first method yields mean absolute error (MAE) of 6.11 ± 0.19 years for cognitively normal participants and MAE of 6.62 ± 0.30 years for cognitively impaired participants, while the second method achieves MAE of 4.69 ± 0.23 years for cognitively normal participants and MAE of 4.96 ± 0.28 years for cognitively impaired participants. We find that the ResNet model captures subtler, non-macrostructural features for brain age prediction.
Diffusion magnetic resonance imaging (dMRI) offers the ability to assess subvoxel brain microstructure through the extraction of biomarkers like fractional anisotropy, as well as to unveil brain connectivity by reconstructing white matter fiber trajectories. However, accurate analysis becomes challenging at the interface between cerebrospinal fluid and white matter, where the MRI signal originates from both the cerebrospinal fluid and the white matter partial volume. The presence of free water partial volume effects introduces a substantial bias in estimating diffusion properties, thereby limiting the clinical utility of DWI. Moreover, current mathematical models often lack applicability to single-shell acquisitions commonly encountered in clinical settings. Without appropriate regularization, direct model fitting becomes impractical. We propose a novel voxel-based deep learning method for mapping and correcting free-water partial volume contamination in DWI to address these limitations. This approach leverages data-driven techniques to reliably infer plausible free-water volumes across different diffusion MRI acquisition schemes, including single-shell acquisitions. Our evaluation demonstrates that the introduced methodology consistently produces more consistent and plausible results than previous approaches. By effectively mitigating the impact of free water partial volume effects, our approach enhances the accuracy and reliability of DWI analysis for single-shell dMRI, thereby expanding its applications in assessing brain microstructure and connectivity.
Connectivity matrices derived from diffusion MRI (dMRI) provide an interpretable and generalizable way of understanding the human brain connectome. However, dMRI suffers from inter-site and between-scanner variation, which impedes analysis across datasets to improve robustness and reproducibility of results. To evaluate different harmonization approaches on connectivity matrices, we compared graph measures derived from these matrices before and after applying three harmonization techniques: mean shift, ComBat, and CycleGAN. The sample comprises 168 agematched, sex-matched normal subjects from two studies: the Vanderbilt Memory and Aging Project (VMAP) and the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD). First, we plotted the graph measures and used coefficient of variation (CoV) and the Mann-Whitney U test to evaluate different methods’ effectiveness in removing site effects on the matrices and the derived graph measures. ComBat effectively eliminated site effects for global efficiency and modularity and outperformed the other two methods. However, all methods exhibited poor performance when harmonizing average betweenness centrality. Second, we tested whether our harmonization methods preserved correlations between age and graph measures. All methods except for CycleGAN in one direction improved correlations between age and global efficiency and between age and modularity from insignificant to significant with p-values less than 0.05.
Multi-site diffusion MRI data is often acquired on different scanners and with distinct protocols. Differences in hardware and acquisition result in data that contains site dependent information, which confounds connectome analyses aiming to combine such multi-site data. We propose a data-driven solution that isolates site-invariant information whilst maintaining relevant features of the connectome. We construct a latent space that is uncorrelated with the imaging site and highly correlated with patient age and a connectome summary measure. Here, we focus on network modularity. The proposed model is a conditional, variational autoencoder with three additional prediction tasks: one for patient age, and two for modularity trained exclusively on data from each site. This model enables us to 1) isolate site-invariant biological features, 2) learn site context, and 3) re-inject site context and project biological features to desired site domains. We tested these hypotheses by projecting 77 connectomes from two studies and protocols (Vanderbilt Memory and Aging Project (VMAP) and Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) to a common site. We find that the resulting dataset of modularity has statistically similar means (p-value ⪅0.05) across sites. In addition, we fit a linear model to the joint dataset and find that positive correlations between age and modularity were preserved.
Complex graph theory measures of brain structural connectomes derived from diffusion weighted images (DWI) provide insight into the network structure of the brain. Further, as the number of available DWI datasets grows, so does the ability to investigate associations in these measures with major biological factors, like age. However, one key hurdle that remains is the presence of scanner effects that can arise from different DWI datasets and confound multisite analyses. Two common approaches to correct these effects are voxel-wise and feature-wise harmonization. However, it is still unclear how to best leverage them for graph-theory analysis of an aging population. Thus, there is a need to better characterize the impact of each harmonization method and their ability to preserve age related features. We investigate this by characterizing four complex graph theory measures (modularity, characteristic path length, global efficiency, and betweenness centrality) in 48 participants aged 55 to 86 from Baltimore Longitudinal Study of Aging (BLSA) and Vanderbilt Memory and Aging Project (VMAP) before and after voxel- and feature-wise harmonization with the Null Space Deep Network (NSDN) and ComBat, respectively. First, we characterize across dataset coefficients of variation (CoV) and find the combination of NSDN, and ComBat causes the greatest reduction in CoV followed by ComBat alone then NSDN alone. Second, we reproduce published associations of modularity with age after correcting for other covariates with linear models. We find that harmonization with ComBat or ComBat and NSDN together improves the significance of existing age effects, reduces model residuals, and qualitatively reduces separation between datasets. These results reinforce the efficiency of statistical harmonization on the feature-level with ComBat and suggest that harmonization on the voxel-level is synergistic but may have reduced effect after running through the multiple layers of the connectomics pipeline. Thus, we conclude that feature-wise harmonization improves statistical results, but the addition of biologically informed voxel-based harmonization offers further improvement.
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