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Estimated brain age from magnetic resonance image (MRI) and its deviation from chronological age can provide early insights into potential neurodegenerative diseases, supporting early detection and implementation of prevention strategies. Diffusion MRI (dMRI) presents an opportunity to build an earlier biomarker for neurodegenerative disease prediction because it captures subtle microstructural changes that precede more perceptible macrostructural changes. However, the coexistence of macro- and micro-structural information in dMRI raises the question of whether current dMRI-based brain age estimation models are leveraging the intended microstructural information or if they inadvertently rely on the macrostructural information. To develop a microstructure-specific brain age, we propose a method for brain age identification from dMRI that mitigates the model's use of macrostructural information by non-rigidly registering all images to a standard template. Imaging data from 13,398 participants across 12 datasets were used for the training and evaluation. We compare our brain age models, trained with and without macrostructural information mitigated, with an architecturally similar T1-weighted (T1w) MRI-based brain age model and two recent, popular, openly available T1w MRI-based brain age models that primarily use macrostructural information. We observe difference between our dMRI-based brain age and T1w MRI-based brain age across stages of neurodegeneration, with dMRI-based brain age being older than T1w MRI-based brain age in participants transitioning from cognitively normal (CN) to mild cognitive impairment (MCI), but younger in participants already diagnosed with Alzheimer's disease (AD). Furthermore, dMRI-based brain age may offer advantages over T1w MRI-based brain age in predicting the transition from CN to MCI up to five years before diagnosis.

Preclinical diffusion MRI (dMRI) has proven value in methods development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages that facilitate high spatial resolution and high signal-to-noise ratio (SNR) images, cutting-edge diffusion contrasts, and direct comparison with histological data as a methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with many decisions that not only differ dramatically from in vivo imaging of small animals, but ultimately affect what questions can be answered using the data. This work concludes a 3-part series of recommendations and considerations for preclinical dMRI. Herein, we describe best practices for dMRI of ex vivo tissue, with a focus on image pre-processing, data processing and model fitting, and tractography. In each section, we attempt to provide guidelines and recommendations, but also highlight areas for which no guidelines exist (and why), and where future work should lie. We end by providing guidelines on code sharing and data sharing, and point towards open-source software and databases specific to small animal and ex vivo imaging., Comment: Part 3 of 3 in "Considerations and recommendations for preclinical diffusion MRI"

Purpose: Diffusion weighted MRI (dMRI) and its models of neural structure provide insight into human brain organization and variations in white matter. A recent study by McMaster, et al. showed that complex graph measures of the connectome, the graphical representation of a tractogram, vary with spatial sampling changes, but biases introduced by anisotropic voxels in the process have not been well characterized. This study uses microstructural measures (fractional anisotropy and mean diffusivity) and white matter bundle properties (bundle volume, length, and surface area) to further understand the effect of anisotropic voxels on microstructure and tractography. Methods: The statistical significance of the selected measures derived from dMRI data were assessed by comparing three white matter bundles at different spatial resolutions with 44 subjects from the Human Connectome Project Young Adult dataset scan/rescan data using the Wilcoxon Signed Rank test. The original isotropic resolution (1.25 mm isotropic) was explored with six anisotropic resolutions with 0.25 mm incremental steps in the z dimension. Then, all generated resolutions were upsampled to 1.25 mm isotropic and 1 mm isotropic. Results: There were statistically significant differences between at least one microstructural and one bundle measure at every resolution (p less than or equal to 0.05, corrected for multiple comparisons). Cohen's d coefficient evaluated the effect size of anisotropic voxels on microstructure and tractography. Conclusion: Fractional anisotropy and mean diffusivity cannot be recovered with basic up sampling from low quality data with gold standard data. However, the bundle measures from tractogram become more repeatable when voxels are resampled to 1 mm isotropic.

Proper quality control (QC) is time consuming when working with large-scale medical imaging datasets, yet necessary, as poor-quality data can lead to erroneous conclusions or poorly trained machine learning models. Most efforts to reduce data QC time rely on outlier detection, which cannot capture every instance of algorithm failure. Thus, there is a need to visually inspect every output of data processing pipelines in a scalable manner. We design a QC pipeline that allows for low time cost and effort across a team setting for a large database of diffusion weighted and structural magnetic resonance images. Our proposed method satisfies the following design criteria: 1.) a consistent way to perform and manage quality control across a team of researchers, 2.) quick visualization of preprocessed data that minimizes the effort and time spent on the QC process without compromising the condition or caliber of the QC, and 3.) a way to aggregate QC results across pipelines and datasets that can be easily shared. In addition to meeting these design criteria, we also provide information on what a successful output should be and common occurrences of algorithm failures for various processing pipelines. Our method reduces the time spent on QC by a factor of over 20 when compared to naively opening outputs in an image viewer and demonstrate how it can facilitate aggregation and sharing of QC results within a team. While researchers must spend time on robust visual QC of data, there are mechanisms by which the process can be streamlined and efficient., Comment: 22 pages, 12 figures, 1 table, 6 supplemental figures

An incomplete field-of-view (FOV) in diffusion magnetic resonance imaging (dMRI) can severely hinder the volumetric and bundle analyses of whole-brain white matter connectivity. Although existing works have investigated imputing the missing regions using deep generative models, it remains unclear how to specifically utilize additional information from paired multi-modality data and whether this can enhance the imputation quality and be useful for downstream tractography. To fill this gap, we propose a novel framework for imputing dMRI scans in the incomplete part of the FOV by integrating the learned diffusion features in the acquired part of the FOV to the complete brain anatomical structure. We hypothesize that by this design the proposed framework can enhance the imputation performance of the dMRI scans and therefore be useful for repairing whole-brain tractography in corrupted dMRI scans with incomplete FOV. We tested our framework on two cohorts from different sites with a total of 96 subjects and compared it with a baseline imputation method that treats the information from T1w and dMRI scans equally. The proposed framework achieved significant improvements in imputation performance, as demonstrated by angular correlation coefficient (p < 1E-5), and in downstream tractography accuracy, as demonstrated by Dice score (p < 0.01). Results suggest that the proposed framework improved imputation performance in dMRI scans by specifically utilizing additional information from paired multi-modality data, compared with the baseline method. The imputation achieved by the proposed framework enhances whole brain tractography, and therefore reduces the uncertainty when analyzing bundles associated with neurodegenerative., Comment: 20 pages; 8 figures

While typical qualitative T1-weighted magnetic resonance images reflect scanner and protocol differences, quantitative T1 mapping aims to measure T1 independent of these effects. Changes in T1 in the brain reflect structural changes in brain tissue. Magnetization-prepared two rapid acquisition gradient echo (MP2RAGE) is an acquisition protocol that allows for efficient T1 mapping with a much lower scan time per slab compared to multi-TI inversion recovery (IR) protocols. We collect and register B1-corrected MP2RAGE acquisitions with an additional inversion time (MP3RAGE) alongside multi-TI selective inversion recovery acquisitions for four subjects. We use a maximum a posteriori (MAP) T1 estimation method for both MP2RAGE and compare to typical point estimate MP2RAGE T1 mapping, finding no bias from MAP MP2RAGE but a sensitivity to B1 inhomogeneities with MAP MP3RAGE. We demonstrate a tissue-dependent bias between MAP MP2RAGE T1 estimates and the multi-TI inversion recovery T1 values. To correct this bias, we train a patch-based ResNet-18 to calibrate the MAP MP2RAGE T1 estimates to the multi-TI IR T1 values. Across four folds, our network reduces the RMSE significantly (white matter: from 0.30 +/- 0.01 seconds to 0.11 +/- 0.02 seconds, subcortical gray matter: from 0.26 +/- 0.02 seconds to 0.10 +/- 0.02 seconds, cortical gray matter: from 0.36 +/- 0.02 seconds to 0.17 +/- 0.03 seconds). Using limited paired training data from both sequences, we can reduce the error between quantitative imaging methods and calibrate to one of the protocols with a neural network., Comment: \c{opyright} 2025. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/. 27 pages, 12 figures

Curating, processing, and combining large-scale medical imaging datasets from national studies is a non-trivial task due to the intense computation and data throughput required, variability of acquired data, and associated financial overhead. Existing platforms or tools for large-scale data curation, processing, and storage have difficulty achieving a viable cost-to-scale ratio of computation speed for research purposes, either being too slow or too expensive. Additionally, management and consistency of processing large data in a team-driven manner is a non-trivial task. We design a BIDS-compliant method for an efficient and robust data processing pipeline of large-scale diffusion-weighted and T1-weighted MRI data compatible with low-cost, high-efficiency computing systems. Our method accomplishes automated querying of data available for processing and process running in a consistent and reproducible manner that has long-term stability, while using heterogenous low-cost computational resources and storage systems for efficient processing and data transfer. We demonstrate how our organizational structure permits efficiency in a semi-automated data processing pipeline and show how our method is comparable in processing time to cloud-based computation while being almost 20 times more cost-effective. Our design allows for fast data throughput speeds and low latency to reduce the time for data transfer between storage servers and computation servers, achieving an average of 0.60 Gb/s compared to 0.33 Gb/s for using cloud-based processing methods. The design of our workflow engine permits quick process running while maintaining flexibility to adapt to newly acquired data.

To date, there has been no comprehensive study characterizing the effect of diffusion-weighted magnetic resonance imaging voxel resolution on the resulting connectome for high resolution subject data. Similarity in results improved with higher resolution, even after initial down-sampling. To ensure robust tractography and connectomes, resample data to 1 mm isotropic resolution.

Diffusion MRI (dMRI) streamline tractography, the gold standard for in vivo estimation of brain white matter (WM) pathways, has long been considered indicative of macroscopic relationships with WM microstructure. However, recent advances in tractography demonstrated that convolutional recurrent neural networks (CoRNN) trained with a teacher-student framework have the ability to learn and propagate streamlines directly from T1 and anatomical contexts. Training for this network has previously relied on high-resolution dMRI. In this paper, we generalize the training mechanism to traditional clinical resolution data, which allows generalizability across sensitive and susceptible study populations. We train CoRNN on a small subset of the Baltimore Longitudinal Study of Aging (BLSA), which better resembles clinical protocols. Then, we define a metric, termed the epsilon ball seeding method, to compare T1 tractography and traditional diffusion tractography at the streamline level. Under this metric, T1 tractography generated by CoRNN reproduces diffusion tractography with approximately two millimeters of error.

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 age-matched, 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., Comment: 11 pages, 5 figures, to be published in SPIE Medical Imaging 2024: Image Processing

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 MRI data has become an important 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. The second applies 3D residual neural networks (ResNets) to learn features directly from the images, which are non-linearly 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 years for cognitively normal participants and MAE of 6.62 years for cognitively impaired participants, while the second method achieves MAE of 4.69 years for cognitively normal participants and MAE of 4.96 years for cognitively impaired participants. We find that the ResNet model captures subtler, non-macrostructural features for brain age prediction., Comment: SPIE Medical Imaging: Image Processing. San Diego, CA. February 2024 (accepted as poster presentation)

This work presents BundleSeg, a reliable, reproducible, and fast method for extracting white matter pathways. The proposed method combines an iterative registration procedure with a recently developed precise streamline search algorithm that enables efficient segmentation of streamlines without the need for tractogram clustering or simplifying assumptions. We show that BundleSeg achieves improved repeatability and reproducibility than state-of-the-art segmentation methods, with significant speed improvements. The enhanced precision and reduced variability in extracting white matter connections offer a valuable tool for neuroinformatic studies, increasing the sensitivity and specificity of tractography-based studies of white matter pathways.

The value of preclinical diffusion MRI (dMRI) is substantial. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages including higher signal-to-noise ratio and spatial resolution compared to in vivo studies, and enabling more advanced diffusion contrasts. Another major advantage of ex vivo dMRI is the direct comparison with histological data as a methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with decisions that not only differ dramatically from in vivo imaging of small animals, but ultimately affect what questions can be answered using the data. This work represents "Part 2" of a 3-part series of recommendations and considerations for preclinical dMRI. We describe best practices for dMRI of ex vivo tissue, with a focus on the value that ex vivo imaging adds to the field of dMRI and considerations in ex vivo image acquisition. We give general considerations and foundational knowledge that must be considered when designing experiments. We describe differences in specimens and models and discuss why some may be more or less appropriate for different studies. We then give guidelines for ex vivo protocols, including tissue fixation, sample preparation, and MR scanning. In each section, we attempt to provide guidelines and recommendations, but also highlight areas for which no guidelines exist (and why), and where future work should lie. An overarching goal herein is to enhance the rigor and reproducibility of ex vivo dMRI acquisitions and analyses, and thereby advance biomedical knowledge., Comment: Part 2 of 3 in "Considerations and recommendations for preclinical diffusion MRI"

Small-animal diffusion MRI (dMRI) has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. The steps from animal setup and monitoring, to acquisition, analysis, and interpretation are complex, with many decisions that may ultimately affect what questions can be answered using the resultant data. This work aims to present selected recommendations and guidelines from the diffusion community, on best practices for preclinical dMRI of in vivo animals. We describe the general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss why some may be more or less appropriate for different studies. We then give guidelines for in vivo acquisition protocols, including decisions on hardware, animal preparation, and imaging sequences, followed by advice for data processing including pre-processing, model-fitting, and tractography. Finally, we provide an online resource which lists publicly available preclinical dMRI datasets and software packages, to promote responsible and reproducible research. In each section, we attempt to provide guides and recommendations, but also highlight areas for which no guidelines exist (and why), and where future work should focus. While we mainly cover the central nervous system (on which most preclinical dMRI studies are focused), we also provide, where possible and applicable, recommendations for other organs of interest. An overarching goal herein is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge., Comment: 47 pages, 5 figures, 1 table

Mild traumatic brain injury (mTBI) is a complex syndrome that affects up to 600 per 100,000 individuals, with a particular concentration among military personnel. About half of all mTBI patients experience a diverse array of chronic symptoms which persist long after the acute injury. Hence, there is an urgent need for better understanding of the white matter and gray matter pathologies associated with mTBI to map which specific brain systems are impacted and identify courses of intervention. Previous works have linked mTBI to disruptions in white matter pathways and cortical surface abnormalities. Herein, we examine these hypothesized links in an exploratory study of joint structural connectivity and cortical surface changes associated with mTBI and its chronic symptoms. Briefly, we consider a cohort of 12 mTBI and 26 control subjects. A set of 588 cortical surface metrics and 4,753 structural connectivity metrics were extracted from cortical surface regions and diffusion weighted magnetic resonance imaging in each subject. Principal component analysis (PCA) was used to reduce the dimensionality of each metric set. We then applied independent component analysis (ICA) both to each PCA space individually and together in a joint ICA approach. We identified a stable independent component across the connectivity-only and joint ICAs which presented significant group differences in subject loadings (p<0.05, corrected). Additionally, we found that two mTBI symptoms, slowed thinking and forgetfulness, were significantly correlated (p<0.05, corrected) with mTBI subject loadings in a surface-only ICA. These surface-only loadings captured an increase in bilateral cortical thickness., Comment: To be published in Proc SPIE Int Soc Opt Eng. 2021 Feb

Diffusion-weighted magnetic resonance imaging (DW-MRI) is the only non-invasive approach for estimation of intra-voxel tissue microarchitecture and reconstruction of in vivo neural pathways for the human brain. With improvement in accelerated MRI acquisition technologies, DW-MRI protocols that make use of multiple levels of diffusion sensitization have gained popularity. A well-known advanced method for reconstruction of white matter microstructure that uses multi-shell data is multi-tissue constrained spherical deconvolution (MT-CSD). MT-CSD substantially improves the resolution of intra-voxel structure over the traditional single shell version, constrained spherical deconvolution (CSD). Herein, we explore the possibility of using deep learning on single shell data (using the b=1000 s/mm2 from the Human Connectome Project (HCP)) to estimate the information content captured by 8th order MT-CSD using the full three shell data (b=1000, 2000, and 3000 s/mm2 from HCP). Briefly, we examine two network architectures: 1.) Sequential network of fully connected dense layers with a residual block in the middle (ResDNN), 2.) Patch based convolutional neural network with a residual block (ResCNN). For both networks an additional output block for estimation of voxel fraction was used with a modified loss function. Each approach was compared against the baseline of using MT-CSD on all data on 15 subjects from the HCP divided into 5 training, 2 validation, and 8 testing subjects with a total of 6.7 million voxels. The fiber orientation distribution function (fODF) can be recovered with high correlation (0.77 vs 0.74 and 0.65) as compared to the ground truth of MT-CST, which was derived from the multi-shell DW-MRI acquisitions. Source code and models have been made publicly available., Comment: 10 pages, 7 figures

Veterans with mild traumatic brain injury (mTBI) have reported auditory and visual dysfunction that persists beyond the acute incident. The etiology behind these symptoms is difficult to characterize with current clinical imaging. These functional deficits may be caused by shear injury or micro-bleeds, which can be detected with special imaging modalities. We explore these hypotheses in a pilot study of multi-parametric MRI. We extract over 1,000 imaging and clinical metrics and project them to a low-dimensional space, where we can discriminate between healthy controls and patients with mTBI. We also show correlations between the metric representations and patient symptoms., Comment: SPIE Medical Imaging 2020

Confocal histology provides an opportunity to establish intra-voxel fiber orientation distributions that can be used to quantitatively assess the biological relevance of diffusion weighted MRI models, e.g., constrained spherical deconvolution (CSD). Here, we apply deep learning to investigate the potential of single shell diffusion weighted MRI to explain histologically observed fiber orientation distributions (FOD) and compare the derived deep learning model with a leading CSD approach. This study (1) demonstrates that there exists additional information in the diffusion signal that is not currently exploited by CSD, and (2) provides an illustrative data-driven model that makes use of this information., Comment: 2 pages, 4 figures. This work was accepted and published as an abstract at ISMRM 2018 held in Paris, France

Intra-voxel models of the diffusion signal are essential for interpreting organization of the tissue environment at micrometer level with data at millimeter resolution. Recent advances in data driven methods have enabled direct compari-son and optimization of methods for in-vivo data with externally validated histological sections with both 2-D and 3-D histology. Yet, all existing methods make limiting assumptions of either (1) model-based linkages between b-values or (2) limited associations with single shell data. We generalize prior deep learning models that used single shell spherical harmonic transforms to integrate the re-cently developed simple harmonic oscillator reconstruction (SHORE) basis. To enable learning on the SHORE manifold, we present an alternative formulation of the fiber orientation distribution (FOD) object using the SHORE basis while rep-resenting the observed diffusion weighted data in the SHORE basis. To ensure consistency of hyper-parameter optimization for SHORE, we present our Deep SHORE approach to learn on a data-optimized manifold. Deep SHORE is evalu-ated with eight-fold cross-validation of a preclinical MRI-histology data with four b-values. Generalizability of in-vivo human data is evaluated on two separate 3T MRI scanners. Specificity in terms of angular correlation (ACC) with the preclinical data improved on single shell: 0.78 relative to 0.73 and 0.73, multi-shell: 0.80 relative to 0.74 (p < 0.001). In the in-vivo human data, Deep SHORE was more consistent across scanners with 0.63 relative to other multi-shell methods 0.39, 0.52 and 0.57 in terms of ACC. In conclusion, Deep SHORE is a promising method to enable data driven learning with DW-MRI under conditions with varying b-values, number of diffusion shells, and gradient directions per shell.

Diffusion-weighted magnetic resonance imaging (DW-MRI) allows for non-invasive imaging of the local fiber architecture of the human brain at a millimetric scale. Multiple classical approaches have been proposed to detect both single (e.g., tensors) and multiple (e.g., constrained spherical deconvolution, CSD) fiber population orientations per voxel. However, existing techniques generally exhibit low reproducibility across MRI scanners. Herein, we propose a data-driven tech-nique using a neural network design which exploits two categories of data. First, training data were acquired on three squirrel monkey brains using ex-vivo DW-MRI and histology of the brain. Second, repeated scans of human subjects were acquired on two different scanners to augment the learning of the network pro-posed. To use these data, we propose a new network architecture, the null space deep network (NSDN), to simultaneously learn on traditional observed/truth pairs (e.g., MRI-histology voxels) along with repeated observations without a known truth (e.g., scan-rescan MRI). The NSDN was tested on twenty percent of the histology voxels that were kept completely blind to the network. NSDN significantly improved absolute performance relative to histology by 3.87% over CSD and 1.42% over a recently proposed deep neural network approach. More-over, it improved reproducibility on the paired data by 21.19% over CSD and 10.09% over a recently proposed deep approach. Finally, NSDN improved gen-eralizability of the model to a third in vivo human scanner (which was not used in training) by 16.08% over CSD and 10.41% over a recently proposed deep learn-ing approach. This work suggests that data-driven approaches for local fiber re-construction are more reproducible, informative and precise and offers a novel, practical method for determining these models., Comment: 10 pages, 5 figures