Empirical assessment of the assumptions of ComBat with diffusion tensor imaging.

Purpose: Diffusion 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. Approach: As 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) ßAGE, the linear regression coefficient of the relationship between FA and age; (ii) Î³/f*, the ComBat-estimated site-shift; and (iii) Î´/f*, 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. Results: ComBat remains well behaved for ßAGE 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. Conclusion: Prior 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.

Deep conditional generative model for longitudinal single-slice abdominal computed tomography harmonization.

Purpose: Two-dimensional single-slice abdominal computed tomography (CT) provides a detailed tissue map with high resolution allowing quantitative characterization of relationships between health conditions and aging. However, longitudinal analysis of body composition changes using these scans is difficult due to positional variation between slices acquired in different years, which leads to different organs/tissues being captured. Approach: To address this issue, we propose C-SliceGen, which takes an arbitrary axial slice in the abdominal region as a condition and generates a pre-defined vertebral level slice by estimating structural changes in the latent space. Results: Our experiments on 2608 volumetric CT data from two in-house datasets and 50 subjects from the 2015 Multi-Atlas Abdomen Labeling Challenge Beyond the Cranial Vault (BTCV) dataset demonstrate that our model can generate high-quality images that are realistic and similar. We further evaluate our method's capability to harmonize longitudinal positional variation on 1033 subjects from the Baltimore longitudinal study of aging dataset, which contains longitudinal single abdominal slices, and confirmed that our method can harmonize the slice positional variance in terms of visceral fat area. Conclusion: This approach provides a promising direction for mapping slices from different vertebral levels to a target slice and reducing positional variance for single-slice longitudinal analysis. The source code is available at: https://github.com/MASILab/C-SliceGen.

DeepN4: Learning N4ITK Bias Field Correction for T1-weighted Images.

T1-weighted (T1w) MRI has low frequency intensity artifacts due to magnetic field inhomogeneities. Removal of these biases in T1w MRI images is a critical preprocessing step to ensure spatially consistent image interpretation. N4ITK bias field correction, the current state-of-the-art, is implemented in such a way that makes it difficult to port between different pipelines and workflows, thus making it hard to reimplement and reproduce results across local, cloud, and edge platforms. Moreover, N4ITK is opaque to optimization before and after its application, meaning that methodological development must work around the inhomogeneity correction step. Given the importance of bias fields correction in structural preprocessing and flexible implementation, we pursue a deep learning approximation / reinterpretation of the N4ITK bias fields correction to create a method which is portable, flexible, and fully differentiable. In this paper, we trained a deep learning network "DeepN4" on eight independent cohorts from 72 different scanners and age ranges with N4ITK-corrected T1w MRI and bias field for supervision in log space. We found that we can closely approximate N4ITK bias fields correction with naïve networks. We evaluate the peak signal to noise ratio (PSNR) in test dataset against the N4ITK corrected images. The median PSNR of corrected images between N4ITK and DeepN4 was 47.96 dB. In addition, we assess the DeepN4 model on eight additional external datasets and show the generalizability of the approach. This study establishes that incompatible N4ITK preprocessing steps can be closely approximated by naïve deep neural networks, facilitating more flexibility. All code and models are released at https://github.com/MASILab/DeepN4 .

Robust fiber orientation distribution function estimation using deep constrained spherical deconvolution for diffusion-weighted magnetic resonance imaging.

Purpose: Diffusion-weighted magnetic resonance imaging (DW-MRI) is a critical imaging method for capturing and modeling tissue microarchitecture at a millimeter scale. A common practice to model the measured DW-MRI signal is via fiber orientation distribution function (fODF). This function is the essential first step for the downstream tractography and connectivity analyses. With recent advantages in data sharing, large-scale multisite DW-MRI datasets are being made available for multisite studies. However, measurement variabilities (e.g., inter- and intrasite variability, hardware performance, and sequence design) are inevitable during the acquisition of DW-MRI. Most existing model-based methods [e.g., constrained spherical deconvolution (CSD)] and learning-based methods (e.g., deep learning) do not explicitly consider such variabilities in fODF modeling, which consequently leads to inferior performance on multisite and/or longitudinal diffusion studies. Approach: In this paper, we propose a data-driven deep CSD method to explicitly constrain the scan-rescan variabilities for a more reproducible and robust estimation of brain microstructure from repeated DW-MRI scans. Specifically, the proposed method introduces a three-dimensional volumetric scanner-invariant regularization scheme during the fODF estimation. We study the Human Connectome Project (HCP) young adults test-retest group as well as the MASiVar dataset (with inter- and intrasite scan/rescan data). The Baltimore Longitudinal Study of Aging dataset is employed for external validation. Results: From the experimental results, the proposed data-driven framework outperforms the existing benchmarks in repeated fODF estimation. By introducing the contrastive loss with scan/rescan data, the proposed method achieved a higher consistency while maintaining higher angular correlation coefficients with the CSD modeling. The proposed method is assessing the downstream connectivity analysis and shows increased performance in distinguishing subjects with different biomarkers. Conclusion: We propose a deep CSD method to explicitly reduce the scan-rescan variabilities, so as to model a more reproducible and robust brain microstructure from repeated DW-MRI scans. The plug-and-play design of the proposed approach is potentially applicable to a wider range of data harmonization problems in neuroimaging.

Characterizing patterns of DTI variance in aging brains.

Background: As 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. Purpose: We characterize the role of physiology, subject compliance, and the interaction of subject with the scanner in the understanding of DTI variability, as modeled in spatial variance of derived metrics in homogeneous regions. Methods: We analyze DTI data from 1035 subjects in the Baltimore Longitudinal Study of Aging (BLSA), with ages ranging from 22.4 to 103 years old. For each subject, up to 12 longitudinal sessions were conducted. We assess 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. Results: Covariate 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 millimeters per volume). Conclusions: The 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.

DeepN4: Learning N4ITK Bias Field Correction for T1-weighted Images.

T1-weighted (T1w) MRI has low frequency intensity artifacts due to magnetic field inhomogeneities. Removal of these biases in T1w MRI images is a critical preprocessing step to ensure spatially consistent image interpretation. N4ITK bias field correction, the current state-of-the-art, is implemented in such a way that makes it difficult to port between different pipelines and workflows, thus making it hard to reimplement and reproduce results across local, cloud, and edge platforms. Moreover, N4ITK is opaque to optimization before and after its application, meaning that methodological development must work around the inhomogeneity correction step. Given the importance of bias fields correction in structural preprocessing and flexible implementation, we pursue a deep learning approximation / reinterpretation of the N4ITK bias fields correction to create a method which is portable, flexible, and fully differentiable. In this paper, we trained a deep learning network "DeepN4" on eight independent cohorts from 72 different scanners and age ranges with N4ITK-corrected T1w MRI and bias field for supervision in log space. We found that we can closely approximate N4ITK bias fields correction with naïve networks. We evaluate the peak signal to noise ratio (PSNR) in test dataset against the N4ITK corrected images. The median PSNR of corrected images between N4ITK and DeepN4 was 47.96 dB. In addition, we assess the DeepN4 model on eight additional external datasets and show the generalizability of the approach. This study establishes that incompatible N4ITK preprocessing steps can be closely approximated by naïve deep neural networks, facilitating more flexibility. All code and models are released at https://github.com/MASILab/DeepN4.

White matter tract microstructure, macrostructure, and associated cortical gray matter morphology across the lifespan.

Characterizing how, when and where the human brain changes across the lifespan is fundamental to our understanding of developmental processes of childhood and adolescence, degenerative processes of aging, and divergence from normal patterns in disease and disorders. We aimed to provide detailed descriptions of white matter pathways across the lifespan by thoroughly characterizing white matter microstructure, white matter macrostructure, and morphology of the cortex associated with white matter pathways. We analyzed 4 large, high-quality, publicly-available datasets comprising 2789 total imaging sessions, and participants ranging from 0 to 100 years old, using advanced tractography and diffusion modeling. We first find that all microstructural, macrostructural, and cortical features of white matter bundles show unique lifespan trajectories, with rates and timing of development and degradation that vary across pathways - describing differences between types of pathways and locations in the brain, and developmental milestones of maturation of each feature. Second, we show cross-sectional relationships between different features that may help elucidate biological changes occurring during different stages of the lifespan. Third, we show unique trajectories of age-associations across features. Finally, we find that age associations during development are strongly related to those during aging. Overall, this study reports normative data for several features of white matter pathways of the human brain that will be useful for studying normal and abnormal white matter development and degeneration.

Whole-brain, gray, and white matter time-locked functional signal changes with simple tasks and model-free analysis.

Recent studies have revealed the production of time-locked blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals throughout the entire brain in response to tasks, challenging the existence of sparse and localized brain functions and highlighting the pervasiveness of potential false negative fMRI findings. "Whole-brain" actually refers to gray matter, the only tissue traditionally studied with fMRI. However, several reports have demonstrated reliable detection of BOLD signals in white matter, which have previously been largely ignored. Using simple tasks and analyses, we demonstrate BOLD signal changes across the whole brain, in both white and gray matters, in similar manner to previous reports of whole brain studies. We investigated whether white matter displays time-locked BOLD signals across multiple structural pathways in response to a stimulus in a similar manner to the cortex. We find that both white and gray matter show time-locked activations across the whole brain, with a majority of both tissue types showing statistically significant signal changes for all task stimuli investigated. We observed a wide range of signal responses to tasks, with different regions showing different BOLD signal changes to the same task. Moreover, we find that each region may display different BOLD responses to different stimuli. Overall, we present compelling evidence that, just like all gray matter, essentially all white matter in the brain shows time-locked BOLD signal changes in response to multiple stimuli, challenging the idea of sparse functional localization and the prevailing wisdom of treating white matter BOLD signals as artifacts to be removed.

Spatiospectral image processing workflow considerations for advanced MR spectroscopy of the brain.

Magnetic resonance spectroscopy (MRS) is one of the few non-invasive imaging modalities capable of making neurochemical and metabolic measurements in vivo. Traditionally, the clinical utility of MRS has been narrow. The most common use has been the "single-voxel spectroscopy" variant to discern the presence of a lactate peak in the spectra in one location in the brain, typically to evaluate for ischemia in neonates. Thus, the reduction of rich spectral data to a binary variable has not classically necessitated much signal processing. However, scanners have become more powerful and MRS sequences more advanced, increasing data complexity and adding 2 to 3 spatial dimensions in addition to the spectral one. The result is a spatially- and spectrally-variant MRS image ripe for image processing innovation. Despite this potential, the logistics for robustly accessing and manipulating MRS data across different scanners, data formats, and software standards remain unclear. Thus, as research into MRS advances, there is a clear need to better characterize its image processing considerations to facilitate innovation from scientists and engineers. Building on established neuroimaging standards, we describe a framework for manipulating these images that generalizes to the voxel, spectral, and metabolite level across space and multiple imaging sites while integrating with LCModel, a widely used quantitative MRS peak-fitting platform. In doing so, we provide examples to demonstrate the advantages of such a workflow in relation to recent publications and with new data. Overall, we hope our characterizations will lower the barrier of entry to MRS processing for neuroimaging researchers.

UNesT: Local spatial representation learning with hierarchical transformer for efficient medical segmentation.

Transformer-based models, capable of learning better global dependencies, have recently demonstrated exceptional representation learning capabilities in computer vision and medical image analysis. Transformer reformats the image into separate patches and realizes global communication via the self-attention mechanism. However, positional information between patches is hard to preserve in such 1D sequences, and loss of it can lead to sub-optimal performance when dealing with large amounts of heterogeneous tissues of various sizes in 3D medical image segmentation. Additionally, current methods are not robust and efficient for heavy-duty medical segmentation tasks such as predicting a large number of tissue classes or modeling globally inter-connected tissue structures. To address such challenges and inspired by the nested hierarchical structures in vision transformer, we proposed a novel 3D medical image segmentation method (UNesT), employing a simplified and faster-converging transformer encoder design that achieves local communication among spatially adjacent patch sequences by aggregating them hierarchically. We extensively validate our method on multiple challenging datasets, consisting of multiple modalities, anatomies, and a wide range of tissue classes, including 133 structures in the brain, 14 organs in the abdomen, 4 hierarchical components in the kidneys, inter-connected kidney tumors and brain tumors. We show that UNesT consistently achieves state-of-the-art performance and evaluate its generalizability and data efficiency. Particularly, the model achieves whole brain segmentation task complete ROI with 133 tissue classes in a single network, outperforming prior state-of-the-art method SLANT27 ensembled with 27 networks. Our model performance increases the mean DSC score of the publicly available Colin and CANDI dataset from 0.7264 to 0.7444 and from 0.6968 to 0.7025, respectively. Code, pre-trained models, and use case pipeline are available at: https://github.com/MASILab/UNesT.

Mapping the Impact of Approximate Gradient Nonlinearity Fields Correction on Tractography.

Nonlinear gradients impact diffusion weighted MRI by introducing spatial variation in estimated diffusion tensors. Recent studies have shown that increasing signal-to-noise ratios and the use of ultra-strong gradients may lead to clinically significant impacts on analyses due to these nonlinear gradients in microstructural measures. These effects can potentially bias tractography results and cause misinterpretation of data. Herein, we characterize the impact of an "approximate" gradient nonlinearity correction technique in tractography using empirically derived gradient nonlinear fields. This technique scales the diffusion signal by the change in magnitude due to the gradient nonlinearities, without concomitant correction of gradient direction errors. The impact of this correction on tractography is assessed through white matter bundle segmentation and connectomics via bundle-wise volume, fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, primary eigenvector, and length; as well as the modularity, global efficiency, and characteristic path length connectomics graph measures. We investigate the differences between (1) these measures directly and (2) the within session variability of these measures before and after approximate correction in 61 subjects from the MASiVar pediatric reproducibility dataset. We find approximate correction results is little to no differences on the population level, but large differences on the subject-specific level for both the measures directly and their within session variability. Thus, this study suggests though approximate correction of gradient nonlinearities may not change tractography findings on the population level, subject-specific interpretations may exhibit large fluctuations. A limitation is the lack of comparison with the empirical voxel-wise gradient table correction.

Distortion correction of functional MRI without reverse phase encoding scans or field maps.

Functional magnetic resonance images (fMRI) acquired using echo planar sequences typically suffer from spatial distortions due to susceptibility induced off-resonance fields, which may cause geometric mismatch with structural images and affect subsequent quantification and localization of brain function. State-of-the art distortion correction methods (for example, using FSL's topup or AFNI's 3dQwarp algorithms) require the collection of additional scans - either field maps or images with reverse phase encoding directions (i.e., blip-up/blip-down acquisitions) - to estimate and correct distortions. However, not all imaging protocols acquire these additional data and thus cannot take advantage of these post-acquisition corrections. In this study, we aim to enable state-of-the art processing of historical or limited datasets that do not include specific sequences for distortion correction by using only the acquired functional data and a single commonly acquired structural image. To achieve this, we synthesize an undistorted image with contrast similar to the fMRI data and use the non-distorted synthetic image as an anatomical target for distortion correction. We evaluate the efficacy of this approach, named SynBOLD-DisCo (Synthetic BOLD contrast for Distortion Correction), and show that this distortion correction process yields fMRI data that are geometrically similar to non-distorted structural images, with distortion correction virtually equivalent to acquisitions that do contain both blip-up/blip-down images. Our method is available as a Singularity container, source code, and an executable trained model to facilitate evaluation and integration into existing fMRI preprocessing pipelines.

SynBOLD-DisCo: Synthetic BOLD images for distortion correction of fMRI without additional calibration scans.

The blood oxygen level dependent (BOLD) signal from functional magnetic resonance imaging (fMRI) is a noninvasive technique that has been widely used in research to study brain function. However, fMRI suffers from susceptibility-induced off resonance fields which may cause geometric distortions and mismatches with anatomical images. State-of-the-art correction methods require acquiring reverse phase encoded images or additional field maps to enable distortion correction. However, not all imaging protocols include these additional scans and thus cannot take advantage of these susceptibility correction capabilities. As such, in this study we aim to enable state-of-the-art distortion correction with FSL's topup algorithm of historical and/or limited fMRI data that include only a structural image and single phase encoded fMRI. To do this, we use 3D U-net models to synthesize undistorted fMRI BOLD contrast images from the structural image and use this undistorted synthetic image as an anatomical target for distortion correction with topup. We evaluate the efficacy of this approach, named SynBOLD-DisCo (synthetic BOLD images for distortion correction), and show that BOLD images corrected using our approach are geometrically more similar to structural images than the distorted BOLD data and are practically equivalent to state-of-the-art correction methods which require reverse phase encoded data. Future directions include additional validation studies, integration with other preprocessing operations, retraining with broader pathologies, and investigating the effects of spin echo versus gradient echo images for training and distortion correction. In summary, we demonstrate SynBOLD-DisCo corrects distortion of fMRI when reverse phase encoding scans or field maps are not available.

Batch size: go big or go home? Counterintuitive improvement in medical autoencoders with smaller batch size.

Batch size is a key hyperparameter in training deep learning models. Conventional wisdom suggests larger batches produce improved model performance. Here we present evidence to the contrary, particularly when using autoencoders to derive meaningful latent spaces from data with spatially global similarities and local differences, such as electronic health records (EHR) and medical imaging. We investigate batch size effects in both EHR data from the Baltimore Longitudinal Study of Aging and medical imaging data from the multimodal brain tumor segmentation (BraTS) challenge. We train fully connected and convolutional autoencoders to compress the EHR and imaging input spaces, respectively, into 32-dimensional latent spaces via reconstruction losses for various batch sizes between 1 and 100. Under the same hyperparameter configurations, smaller batches improve loss performance for both datasets. Additionally, latent spaces derived by autoencoders with smaller batches capture more biologically meaningful information. Qualitatively, we visualize 2-dimensional projections of the latent spaces and find that with smaller batches the EHR network better separates the sex of the individuals, and the imaging network better captures the right-left laterality of tumors. Quantitatively, the analogous sex classification and laterality regressions using the latent spaces demonstrate statistically significant improvements in performance at smaller batch sizes. Finally, we find improved individual variation locally in visualizations of representative data reconstructions at lower batch sizes. Taken together, these results suggest that smaller batch sizes should be considered when designing autoencoders to extract meaningful latent spaces among EHR and medical imaging data driven by global similarities and local variation.

Single slice thigh CT muscle group segmentation with domain adaptation and self-training.

Purpose: Thigh muscle group segmentation is important for assessing muscle anatomy, metabolic disease, and aging. Many efforts have been put into quantifying muscle tissues with magnetic resonance (MR) imaging, including manual annotation of individual muscles. However, leveraging publicly available annotations in MR images to achieve muscle group segmentation on single-slice computed tomography (CT) thigh images is challenging. Approach: We propose an unsupervised domain adaptation pipeline with self-training to transfer labels from three-dimensional MR to single CT slices. First, we transform the image appearance from MR to CT with CycleGAN and feed the synthesized CT images to a segmenter simultaneously. Single CT slices are divided into hard and easy cohorts based on the entropy of pseudo-labels predicted by the segmenter. After refining easy cohort pseudo-labels based on anatomical assumption, self-training with easy and hard splits is applied to fine-tune the segmenter. Results: On 152 withheld single CT thigh images, the proposed pipeline achieved a mean Dice of 0.888 (0.041) across all muscle groups, including gracilis, hamstrings, quadriceps femoris, and sartorius muscle. Conclusions: To our best knowledge, this is the first pipeline to achieve domain adaptation from MR to CT for thigh images. The proposed pipeline effectively and robustly extracts muscle groups on two-dimensional single-slice CT thigh images. The container is available for public use in GitHub repository available at: https://github.com/MASILab/DA_CT_muscle_seg.

Predicting Crohn's disease severity in the colon using mixed cell nucleus density from pseudo labels.

Crohn's disease (CD) is a debilitating inflammatory bowel disease with no known cure. Computational analysis of hematoxylin and eosin (H&E) stained colon biopsy whole slide images (WSIs) from CD patients provides the opportunity to discover unknown and complex relationships between tissue cellular features and disease severity. While there have been works using cell nuclei-derived features for predicting slide-level traits, this has not been performed on CD H&E WSIs for classifying normal tissue from CD patients vs active CD and assessing slide label-predictive performance while using both separate and combined information from pseudo-segmentation labels of nuclei from neutrophils, eosinophils, epithelial cells, lymphocytes, plasma cells, and connective cells. We used 413 WSIs of CD patient biopsies and calculated normalized histograms of nucleus density for the six cell classes for each WSI. We used a support vector machine to classify the truncated singular value decomposition representations of the normalized histograms as normal or active CD with four-fold cross-validation in rounds where nucleus types were first compared individually, the best was selected, and further types were added each round. We found that neutrophils were the most predictive individual nucleus type, with an AUC of 0.92 ± 0.0003 on the withheld test set. Adding information improved cross-validation performance for the first two rounds and on the withheld test set for the first three rounds, though performance metrics did not increase substantially beyond when neutrophils were used alone.

Semantic-Aware Contrastive Learning for Multi-Object Medical Image Segmentation.

Medical image segmentation, or computing voxel-wise semantic masks, is a fundamental yet challenging task in medical imaging domain. To increase the ability of encoder-decoder neural networks to perform this task across large clinical cohorts, contrastive learning provides an opportunity to stabilize model initialization and enhances downstream tasks performance without ground-truth voxel-wise labels. However, multiple target objects with different semantic meanings and contrast level may exist in a single image, which poses a problem for adapting traditional contrastive learning methods from prevalent "image-level classification" to "pixel-level segmentation". In this article, we propose a simple semantic-aware contrastive learning approach leveraging attention masks and image-wise labels to advance multi-object semantic segmentation. Briefly, we embed different semantic objects to different clusters rather than the traditional image-level embeddings. We evaluate our proposed method on a multi-organ medical image segmentation task with both in-house data and MICCAI Challenge 2015 BTCV datasets. Compared with current state-of-the-art training strategies, our proposed pipeline yields a substantial improvement of 5.53% and 6.09% on Dice score for both medical image segmentation cohorts respectively (p-value 0.01). The performance of the proposed method is further assessed on external medical image cohort via MICCAI Challenge FLARE 2021 dataset, and achieves a substantial improvement from Dice 0.922 to 0.933 (p-value 0.01).

Deep Constrained Spherical Deconvolution for Robust Harmonization.

Diffusion weighted magnetic resonance imaging (DW-MRI) captures tissue microarchitecture at millimeter scale. With recent advantages in data sharing, large-scale multi-site DW-MRI datasets are being made available for multi-site studies. However, DW-MRI suffers from measurement variability (e.g., inter- and intra-site variability, hardware performance, and sequence design), which consequently yields inferior performance on multi-site and/or longitudinal diffusion studies. In this study, we propose a novel, deep learning-based method to harmonize DW-MRI signals for a more reproducible and robust estimation of microstructure. Our method introduces a data-driven scanner-invariant regularization scheme to model a more robust fiber orientation distribution function (FODF) estimation. We study the Human Connectome Project (HCP) young adults test-retest group as well as the MASiVar dataset (with inter- and intra-site scan/rescan data). The 8th order spherical harmonics coefficients are employed as data representation. The results show that the proposed harmonization approach maintains higher angular correlation coefficients (ACC) with the ground truth signals (0.954 versus 0.942), while achieves higher consistency of FODF signals for intra-scanner data (0.891 versus 0.826), as compared with the baseline supervised deep learning scheme. Furthermore, the proposed data-driven framework is flexible and potentially applicable to a wider range of data harmonization problems in neuroimaging.

Deep whole brain segmentation of 7T structural MRI.

7T magnetic resonance imaging (MRI) has the potential to drive our understanding of human brain function through new contrast and enhanced resolution. Whole brain segmentation is a key neuroimaging technique that allows for region-by-region analysis of the brain. Segmentation is also an important preliminary step that provides spatial and volumetric information for running other neuroimaging pipelines. Spatially localized atlas network tiles (SLANT) is a popular 3D convolutional neural network (CNN) tool that breaks the whole brain segmentation task into localized sub-tasks. Each sub-task involves a specific spatial location handled by an independent 3D convolutional network to provide high resolution whole brain segmentation results. SLANT has been widely used to generate whole brain segmentations from structural scans acquired on 3T MRI. However, the use of SLANT for whole brain segmentation from structural 7T MRI scans has not been successful due to the inhomogeneous image contrast usually seen across the brain in 7T MRI. For instance, we demonstrate the mean percent difference of SLANT label volumes between a 3T scan-rescan is approximately 1.73%, whereas its 3T-7T scan-rescan counterpart has higher differences around 15.13%. Our approach to address this problem is to register the whole brain segmentation performed on 3T MRI to 7T MRI and use this information to finetune SLANT for structural 7T MRI. With the finetuned SLANT pipeline, we observe a lower mean relative difference in the label volumes of ~8.43% acquired from structural 7T MRI data. Dice similarity coefficient between SLANT segmentation on the 3T MRI scan and the after finetuning SLANT segmentation on the 7T MRI increased from 0.79 to 0.83 with p<0.01. These results suggest finetuning of SLANT is a viable solution for improving whole brain segmentation on high resolution 7T structural imaging.

Comparing voxel- and feature-wise harmonization of complex graph measures from multiple sites for structural brain network investigation of aging.

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.