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Significance Diffusion-weighted MRI (DWI) tractography is widely used to map structural connections of the human brain in vivo and has been adopted by large-scale initiatives such as the human connectome project. Our results indicate that, even with high-quality data, DWI tractography alone is unlikely to provide an anatomically accurate map of the brain connectome. It is crucial to complement tractography results with a combination of histological or neurophysiological methods to map structural connectivity accurately. Our findings, however, do not diminish the importance of diffusion MRI as a noninvasive tool that offers important quantitative measures related to brain tissue microstructure and white matter architecture. Tractography based on diffusion-weighted MRI (DWI) is widely used for mapping the structural connections of the human brain. Its accuracy is known to be limited by technical factors affecting in vivo data acquisition, such as noise, artifacts, and data undersampling resulting from scan time constraints. It generally is assumed that improvements in data quality and implementation of sophisticated tractography methods will lead to increasingly accurate maps of human anatomical connections. However, assessing the anatomical accuracy of DWI tractography is difficult because of the lack of independent knowledge of the true anatomical connections in humans. Here we investigate the future prospects of DWI-based connectional imaging by applying advanced tractography methods to an ex vivo DWI dataset of the macaque brain. The results of different tractography methods were compared with maps of known axonal projections from previous tracer studies in the macaque. Despite the exceptional quality of the DWI data, none of the methods demonstrated high anatomical accuracy. The methods that showed the highest sensitivity showed the lowest specificity, and vice versa. Additionally, anatomical accuracy was highly dependent upon parameters of the tractography algorithm, with different optimal values for mapping different pathways. These results suggest that there is an inherent limitation in determining long-range anatomical projections based on voxel-averaged estimates of local fiber orientation obtained from DWI data that is unlikely to be overcome by improvements in data acquisition and analysis alone.

There has been growing attention on the effect of COVID‐19 on white‐matter microstructure, especially among those that self‐isolated after being infected. There is also immense scientific interest and potential clinical utility to evaluate the sensitivity of single‐shell diffusion magnetic resonance imaging (MRI) methods for detecting such effects. In this work, the performances of three single‐shell‐compatible diffusion MRI modeling methods are compared for detecting the effect of COVID‐19, including diffusion‐tensor imaging, diffusion‐tensor decomposition of orthogonal moments and correlated diffusion imaging. Imaging was performed on self‐isolated patients at the study initiation and 3‐month follow‐up, along with age‐ and sex‐matched controls. We demonstrate through simulations and experimental data that correlated diffusion imaging is associated with far greater sensitivity, being the only one of the three single‐shell methods to demonstrate COVID‐19‐related brain effects. Results suggest less restricted diffusion in the frontal lobe in COVID‐19 patients, but also more restricted diffusion in the cerebellar white matter, in agreement with several existing studies highlighting the vulnerability of the cerebellum to COVID‐19 infection. These results, taken together with the simulation results, suggest that a significant proportion of COVID‐19 related white‐matter microstructural pathology manifests as a change in tissue diffusivity. Interestingly, different b‐values also confer different sensitivities to the effects. No significant difference was observed in patients at the 3‐month follow‐up, likely due to the limited size of the follow‐up cohort. To summarize, correlated diffusion imaging is shown to be a viable single‐shell diffusion analysis approach that allows us to uncover opposing patterns of diffusion changes in the frontal and cerebellar regions of COVID‐19 patients, suggesting the two regions react differently to viral infection. We used simulations and experimental data to demonstrate the feasibility of the novel correlated diffusion imaging for detecting microstructural changes in human white matter. We demonstrate in the case of mild COVID‐19, correlated diffusion imaging is superior to diffusion tensor imaging when only single‐shell data are available. Moreover, correlated diffusion imaging may exhibit sensitivities to different pathologies at different b‐values.

We present a new software package with a library of standardised tractography protocols devised for the robust automated extraction of white matter tracts both in the human and the macaque brain. Using in vivo data from the Human Connectome Project (HCP) and the UK Biobank and ex vivo data for the macaque brain datasets, we obtain white matter atlases, as well as atlases for tract endpoints on the white-grey matter boundary, for both species. We illustrate that our protocols are robust against data quality, generalisable across two species and reflect the known anatomy. We further demonstrate that they capture inter-subject variability by preserving tract lateralisation in humans and tract similarities stemming from twinship in the HCP cohort. Our results demonstrate that the presented toolbox will be useful for generating imaging-derived features in large cohorts, and in facilitating comparative neuroanatomy studies. The software, tractography protocols, and atlases are publicly released through FSL, allowing users to define their own tractography protocols in a standardised manner, further contributing to open science. •A new software package for standardised and automated cross-species tractography.•Homologous white matter bundles in the human and macaque brain.•Human white matter tract atlases generated from large datasets (1000 subjects).•Tractography protocols are standardised, but preserve individual variability.•Generalisability across datasets shown using the HCP and the UK Biobank data.

Diffusion tensor imaging (DTI) is a well-established magnetic resonance imaging (MRI) technique used for studying microstructural changes in the white matter. As with many other imaging modalities, DTI images suffer from technical between-scanner variation that hinders comparisons of images across imaging sites, scanners and over time. Using fractional anisotropy (FA) and mean diffusivity (MD) maps of 205 healthy participants acquired on two different scanners, we show that the DTI measurements are highly site-specific, highlighting the need of correcting for site effects before performing downstream statistical analyses. We first show evidence that combining DTI data from multiple sites, without harmonization, may be counter-productive and negatively impacts the inference. Then, we propose and compare several harmonization approaches for DTI data, and show that ComBat, a popular batch-effect correction tool used in genomics, performs best at modeling and removing the unwanted inter-site variability in FA and MD maps. Using age as a biological phenotype of interest, we show that ComBat both preserves biological variability and removes the unwanted variation introduced by site. Finally, we assess the different harmonization methods in the presence of different levels of confounding between site and age, in addition to test robustness to small sample size studies. •Significant site and scanner effects exist in DTI scalar maps.•Several multi-site harmonization methods are proposed.•ComBat performs the best at removing site effects in FA and MD.•Voxels associated with age in FA and MD are more replicable after ComBat.•ComBat is generalizable to other imaging modalities.

ObjectivesPreoperative, noninvasive prediction of the meningioma grade is important because it influences the treatment strategy. The purpose of this study was to evaluate the role of radiomics features of postcontrast T1-weighted images (T1C), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) maps, based on the entire tumor volume, in the differentiation of grades and histological subtypes of meningiomas.MethodsOne hundred thirty-six patients with pathologically diagnosed meningiomas (108 low-grade [benign], 28 high-grade [atypical and anaplastic]), who underwent T1C and diffusion tensor imaging, were included in the discovery set. The T1C image, ADC, and FA maps were analyzed to derive volume-based data of the entire tumor. Radiomics features were correlated with meningioma grades and histological subtypes. Various machine learning classifiers were trained to build classification models to predict meningioma grades. We tested the model in a validation set (58 patients; 46 low-grade; 12 high-grade).ResultsThe machine learning classifiers showed variable performances depending on the machine learning algorithms. The best classification system for the prediction of meningioma grades had an area under the curve of 0.86 (95% confidence interval [CI], 0.74–0.98) in the validation set. The accuracy, sensitivity, and specificity of the best classifier were 89.7, 75.0, and 93.5% in the validation set, respectively. Various texture parameters differed significantly between fibroblastic and non-fibroblastic subtypes.ConclusionsRadiomics feature-based machine learning classifiers of T1C images, ADC, and FA maps are useful for differentiating meningioma grades.Key Points• Preoperative, noninvasive differentiation of the meningioma grade is important because it influences the treatment strategy.• Radiomics feature-based machine learning classifiers of T1C images, ADC, and FA maps are useful for differentiating meningioma grades.• In benign meningiomas, there were significant differences in the various texture parameters between fibroblastic and non-fibroblastic meningioma subtypes.

Large-scale longitudinal neuroimaging studies with diffusion imaging techniques are necessary to test and validate models of white matter neurophysiological processes that change in time, both in healthy and diseased brains. The predictive power of such longitudinal models will always be limited by the reproducibility of repeated measures acquired during different sessions. At present, there is limited quantitative knowledge about the across-session reproducibility of standard diffusion metrics in 3T multi-centric studies on subjects in stable conditions, in particular when using tract based spatial statistics and with elderly people. In this study we implemented a multi-site brain diffusion protocol in 10 clinical 3T MRI sites distributed across 4 countries in Europe (Italy, Germany, France and Greece) using vendor provided sequences from Siemens (Allegra, Trio Tim, Verio, Skyra, Biograph mMR), Philips (Achieva) and GE (HDxt) scanners. We acquired DTI data (2×2×2mm3, b=700s/mm2, 5 b0 and 30 diffusion weighted volumes) of a group of healthy stable elderly subjects (5 subjects per site) in two separate sessions at least a week apart. For each subject and session four scalar diffusion metrics were considered: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial (AD) diffusivity. The diffusion metrics from multiple subjects and sessions at each site were aligned to their common white matter skeleton using tract-based spatial statistics. The reproducibility at each MRI site was examined by looking at group averages of absolute changes relative to the mean (%) on various parameters: i) reproducibility of the signal-to-noise ratio (SNR) of the b0 images in centrum semiovale, ii) full brain test–retest differences of the diffusion metric maps on the white matter skeleton, iii) reproducibility of the diffusion metrics on atlas-based white matter ROIs on the white matter skeleton. Despite the differences of MRI scanner configurations across sites (vendors, models, RF coils and acquisition sequences) we found good and consistent test–retest reproducibility. White matter b0 SNR reproducibility was on average 7±1% with no significant MRI site effects. Whole brain analysis resulted in no significant test–retest differences at any of the sites with any of the DTI metrics. The atlas-based ROI analysis showed that the mean reproducibility errors largely remained in the 2–4% range for FA and AD and 2–6% for MD and RD, averaged across ROIs. Our results show reproducibility values comparable to those reported in studies using a smaller number of MRI scanners, slightly different DTI protocols and mostly younger populations. We therefore show that the acquisition and analysis protocols used are appropriate for multi-site experimental scenarios. •We implement a multi-site 3T MRI protocol for brain DTI on 10 EU sites.•We acquire across-session test–retest data on 50 healthy elderly subjects.•We use full brain TBSS and ROI analysis to calculate FA, MD, RD and AD.•Reproducibility errors are in the 2–6% range.•Reproducibility errors tended to be lower in sites with shorter acquisitions.

Diffusion tensor magnetic resonance imaging (DTI) is unsurpassed in its ability to map tissue microstructure and structural connectivity in the living human brain. Nonetheless, the angular sampling requirement for DTI leads to long scan times and poses a critical barrier to performing high-quality DTI in routine clinical practice and large-scale research studies. In this work we present a new processing framework for DTI entitled DeepDTI that minimizes the data requirement of DTI to six diffusion-weighted images (DWIs) required by conventional voxel-wise fitting methods for deriving the six unique unknowns in a diffusion tensor using data-driven supervised deep learning. DeepDTI maps the input non-diffusion-weighted (b ​= ​0) image and six DWI volumes sampled along optimized diffusion-encoding directions, along with T1-weighted and T2-weighted image volumes, to the residuals between the input and high-quality output b = 0 image and DWI volumes using a 10-layer three-dimensional convolutional neural network (CNN). The inputs and outputs of DeepDTI are uniquely formulated, which not only enables residual learning to boost CNN performance but also enables tensor fitting of resultant high-quality DWIs to generate orientational DTI metrics for tractography. The very deep CNN used by DeepDTI leverages the redundancy in local and non-local spatial information and across diffusion-encoding directions and image contrasts in the data. The performance of DeepDTI was systematically quantified in terms of the quality of the output images, DTI metrics, DTI-based tractography and tract-specific analysis results. We demonstrate rotationally-invariant and robust estimation of DTI metrics from DeepDTI that are comparable to those obtained with two b ​= ​0 images and 21 DWIs for the primary eigenvector derived from DTI and two b ​= ​0 images and 26–30 DWIs for various scalar metrics derived from DTI, achieving 3.3–4.6 × ​acceleration, and twice as good as those of a state-of-the-art denoising algorithm at the group level. The twenty major white-matter tracts can be accurately identified from the tractography of DeepDTI results. The mean distance between the core of the major white-matter tracts identified from DeepDTI results and those from the ground-truth results using 18 ​b ​= ​0 images and 90 DWIs measures around 1–1.5 ​mm. DeepDTI leverages domain knowledge of diffusion MRI physics and power of deep learning to render DTI, DTI-based tractography, major white-matter tracts identification and tract-specific analysis more feasible for a wider range of neuroscientific and clinical studies. •A new processing framework for DTI using data-driven supervised deep learning.•DeepDTI minimizes the data requirement of DTI to one b=0 and six DWI volumes.•The DeepDTI framework maps both scalar and orientational DTI metrics.•Enables DTI-based tractography and tract-specific analysis using a 30-60 second scan.•Comparable to fully-sampled DTI scan and better than benchmark denoising algorithm.

Diffusion-weighted MRI (DW-MRI) has been increasingly used in imaging neuroscience over the last decade. An early form of this technique, diffusion tensor imaging (DTI) was rapidly implemented by major MRI scanner companies as a scanner selling point. Due to the ease of use of such implementations, and the plausibility of some of their results, DTI was leapt on by imaging neuroscientists who saw it as a powerful and unique new tool for exploring the structural connectivity of human brain. However, DTI is a rather approximate technique, and its results have frequently been given implausible interpretations that have escaped proper critique and have appeared misleadingly in journals of high reputation. In order to encourage the use of improved DW-MRI methods, which have a better chance of characterizing the actual fiber structure of white matter, and to warn against the misuse and misinterpretation of DTI, we review the physics of DW-MRI, indicate currently preferred methodology, and explain the limits of interpretation of its results. We conclude with a list of ‘Do's and Don'ts’ which define good practice in this expanding area of imaging neuroscience.

We present distinct patterns of neurite distribution in the human cerebral cortex using diffusion magnetic resonance imaging (MRI). We analyzed both high-resolution structural (T1w and T2w images) and diffusion MRI data in 505 subjects from the Human Connectome Project. Neurite distributions were evaluated using the neurite orientation dispersion and density imaging (NODDI) model, optimized for gray matter, and mapped onto the cortical surface using a method weighted towards the cortical mid-thickness to reduce partial volume effects. The estimated neurite density was high in both somatosensory and motor areas, early visual and auditory areas, and middle temporal area (MT), showing a strikingly similar distribution to myelin maps estimated from the T1w/T2w ratio. The estimated neurite orientation dispersion was particularly high in early sensory areas, which are known for dense tangential fibers and are classified as granular cortex by classical anatomists. Spatial gradients of these cortical neurite properties revealed transitions that colocalize with some areal boundaries in a recent multi-modal parcellation of the human cerebral cortex, providing mutually supportive evidence. Our findings indicate that analyzing the cortical gray matter neurite morphology using diffusion MRI and NODDI provides valuable information regarding cortical microstructure that is related to but complementary to myeloarchitecture. •Neurite orientation dispersion and density imaging was applied to HCP diffusion MRI.•Cortical neurite density map showed strikingly similar distribution to myelin map.•Cortical neurite orientation dispersion was high in von Economo's granular cortex.

Various diffusion MRI (dMRI) measures have been proposed for characterising tissue microstructure over the last 15 years. Despite the growing number of experiments using different dMRI measures in assessments of white matter, there has been limited work on: 1) examining their covariance along specific pathways; and on 2) combining these different measures to study tissue microstructure. Indeed, it quickly becomes intractable for existing analysis pipelines to process multiple measurements at each voxel and at each vertex forming a streamline, highlighting the need for new ways to visualise or analyse such high-dimensional data. In a sample of 36 typically developing children aged 8–18 years, we profiled various commonly used dMRI measures across 22 brain pathways. Using a data-reduction approach, we identified two biologically-interpretable components that capture 80% of the variance in these dMRI measures. The first derived component captures properties related to hindrance and restriction in tissue microstructure, while the second component reflects characteristics related to tissue complexity and orientational dispersion. We then demonstrate that the components generated by this approach preserve the biological relevance of the original measurements by showing age-related effects across developmentally sensitive pathways. In summary, our findings demonstrate that dMRI analyses can benefit from dimensionality reduction techniques, to help disentangling the neurobiological underpinnings of white matter organisation. [Display omitted]