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Integrating the underlying brain circuit's structural and functional architecture is required to explore the functional organization of cognitive networks properly. In that regard, we recently introduced the Functionnectome. This structural-functional method combines an fMRI acquisition with tractography-derived white matter connectivity data to map cognitive processes onto the white matter. However, this multimodal integration faces three significant challenges: 1) the definition of the interface between grey and white matter, as the tractography streamlines may fail to reach the grey matter properly; 2) the scrambling effect of crossing fibers on functional signal, as a single voxel in such regions can be structurally connected to several cognitive networks with heterogeneous functional signals; and 3) the difficulty of interpretation of the resulting cognitive maps, as crossing and overlapping white matter tracts can obscure the organization of the studied network. In the present study, we tackled these problems by developing a streamline-extension procedure and dividing the white matter anatomical priors between association, commissural, and projection fibers. This approach significantly improved the characterization of the white matter involvement in the studied cognitive processes. The new Functionnectome priors produced are now readily available, and the analysis workflow highlighted here should also be generalizable to other structural-functional approaches.

Assessing the consistency of quantitative MRI measurements is critical for inclusion in longitudinal studies and clinical trials. Intraclass coefficient correlation and coefficient of variation were used to evaluate the different consistency aspects of diffusion- and myelinbased MRI measures. Multi-shell diffusion and inhomogeneous magnetization transfer datasets were collected from twenty healthy adults at a high-frequency of five MRI sessions. The consistency was evaluated across whole bundles and the track-profile along the bundles. The impact of the fiber populations on the consistency was also evaluated using the number of fiber orientations map. For whole and profile bundles, moderate to high reliability of diffusion and myelin measures were observed. We report higher reliability of measures for multiple fiber populations than single. The overall portrait of the most consistent measurements and bundles drawn from a wide range of MRI techniques presented here will be particularly useful for identifying reliable biomarkers capable of detecting, monitoring and predicting white matter changes in clinical applications and has the potential to inform patient-specific treatment strategies.Key pointsReliability and variability are excellent to good for DWI measurements, and good to moderate for MT measures for whole bundles and along the bundles.The number of fiber populations affects the reliability and variability of the MRI measurements.The reliability and variability of MRI measurements are also bundle dependent.

Modern tractography algorithms such as anatomically-constrained tractography (ACT) are based on segmentation maps of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF). These maps are generally estimated from a T1-weighted (T1w) image and then registered in diffusion weighted images (DWI) space. Registration of T1w to diffusion space and partial volume estimation are challenging and rarely voxel-perfect. Diffusion-based segmentation would, thus, potentially allow not to have higher quality anatomical priors injected in the tractography process. On the other hand, even if FA-based tractography is possible without T1 registration, the literature shows that this technique suffers from multiple issues such as holes in the tracking mask and a high proportion of generated broken and anatomically implausible streamlines. Therefore, there is an important need for a tissue segmentation algorithm that works directly in the native diffusion space. We propose DORIS, a DWI-based deep learning segmentation algorithm. DORIS outputs 10 different tissue classes including WM, GM, CSF, ventricles, and 6 other subcortical structures (putamen, pallidum, hippocampus, caudate, amygdala, and thalamus). DORIS was trained and validated on a wide range of subjects, including 1,000 individuals from 22 to 90 years old from clinical and research DWI acquisitions, from 5 public databases. In the absence of a “true” ground truth in diffusion space, DORIS used a silver standard strategy from Freesurfer output registered onto the DWI. This strategy is extensively evaluated and discussed in the current study. Segmentation maps provided by DORIS are quantitatively compared to Freesurfer and FSL-fast and the impacts on tractography are evaluated. Overall, we show that DORIS is fast, accurate, and reproducible and that DORIS-based tractograms produce bundles with a longer mean length and fewer anatomically implausible streamlines.

TractoInferno is the world’s largest open-source multi-site tractography database, including both research- and clinical-like human acquisitions, aimed specifically at machine learning tractography approaches and related ML algorithms. It provides 284 datasets acquired from 3T scanners across 6 different sites. Available data includes T1-weighted images, single-shell diffusion MRI (dMRI) acquisitions, spherical harmonics fitted to the dMRI signal, fiber ODFs, and reference streamlines for 30 delineated bundles generated using 4 tractography algorithms, as well as masks needed to run tractography algorithms. Manual quality control was additionally performed at multiple steps of the pipeline. We showcase TractoInferno by benchmarking the learn2track algorithm and 5 variations of the same recurrent neural network architecture. Creating the TractoInferno database required approximately 20,000 CPU-hours of processing power, 200 man-hours of manual QC, 3,000 GPU-hours of training baseline models, and 4 Tb of storage, to produce a final database of 350 Gb. By providing a standardized training dataset and evaluation protocol, TractoInferno is an excellent tool to address common issues in machine learning tractography.

The ability to perceive speech in noise (SPiN) declines with age. Although the etiology of SPiN decline is not well understood, accumulating evidence suggests a role for the dorsal speech stream. While age‐related decline within the dorsal speech stream would negatively affect SPiN performance, experience‐induced neuroplastic changes within the dorsal speech stream could positively affect SPiN performance. Here, we investigated the relationship between SPiN performance and the structure of the arcuate fasciculus (AF), which forms the white matter scaffolding of the dorsal speech stream, in aging singers and non‐singers. Forty‐three non‐singers and 41 singers aged 20 to 87 years old completed a hearing evaluation and a magnetic resonance imaging session that included High Angular Resolution Diffusion Imaging. The groups were matched for sex, age, education, handedness, cognitive level, and musical instrument experience. A subgroup of participants completed syllable discrimination in the noise task. The AF was divided into 10 segments to explore potential local specializations for SPiN. The results show that, in carefully matched groups of singers and non‐singers (a) myelin and/or axonal membrane deterioration within the bilateral frontotemporal AF segments are associated with SPiN difficulties in aging singers and non‐singers; (b) the structure of the AF is different in singers and non‐singers; (c) these differences are not associated with a benefit on SPiN performance for singers. This study clarifies the etiology of SPiN difficulties by supporting the hypothesis for the role of aging of the dorsal speech stream., The arcuate fasciculus (AF) was divided into ten segments to explore potential local specializations for speech perception in noise (SPiN) in young and older singers and non‐singers. Our results show that the structure of the AF differs in young and older adults, especially in frontotemporal segments, and that these differences affect SPiN performance. The structure of the AF was also different in singers and non‐singers, but these differences were not associated with a better SPiN performance.

ObjectiveTo characterize microstructural white matter changes related to relapsing-remitting multiple sclerosis using advanced diffusion MRI modeling and tractography. The association between imaging data and patient’s cognitive performance, fatigue severity and depressive symptoms is also explored.MethodsIn this cross-sectional study, 24 relapsing-remitting multiple sclerosis patients and 11 healthy controls were compared using high angular resolution diffusion imaging (HARDI). The imaging method includes a multi-shell scheme, free water correction to obtain tissue-specific measurements, probabilistic tracking algorithm robust to crossing fibers and white matter lesions, automatic streamlines and bundle dissection and tract-profiling with tractometry. The neuropsychological evaluation included the Symbol Digit Modalities Test, Paced Auditory Serial Addition Test, Modified Fatigue Impact Scale and Beck Depression Inventory-II.ResultsBundle-wise analysis by tractometry revealed a difference between patients and controls for 11 of the 14 preselected white matter bundles. In patients, free water corrected fractional anisotropy was significantly reduced while radial and mean diffusivities were increased, consistent with diffuse demyelination. The fornix and left inferior fronto-occipital fasciculus exhibited a higher free water fraction. Eight bundles showed an increase in total apparent fiber density and four bundles had a higher number of fiber orientations, suggesting axonal swelling and increased organization complexity, respectively. In the association study, depressive symptoms were associated with diffusion abnormalities in the right superior longitudinal fasciculus.ConclusionTissue-specific diffusion measures showed abnormalities along multiple cerebral white matter bundles in patients with relapsing-remitting multiple sclerosis. The proposed methodology combines free-water imaging, advanced bundle dissection and tractometry, which is a novel approach to investigate cerebral pathology in multiple sclerosis. It opens a new window of use for HARDI-derived measures and free water corrected diffusion measures. Advanced diffusion MRI provides a better insight into cerebral white matter changes in relapsing-remitting multiple sclerosis, namely diffuse demyelination, edema and increased fiber density and complexity.

Diffusion-weighted magnetic resonance imaging (dMRI) allows for the in-vivo assessment of anatomical white matter in the brain, thus allowing the depiction of structural connectivity. Using structural processing techniques and related methods, a growing body of literature has illustrated that connectomics is a crucial aspect to assessing the brain in health and disease. The Pediatric Imaging Neurocognition and Genetics (PING) dataset was collected and released openly to contribute to the assessment of typical brain development in a pediatric sample. This current work details the processing of diffusion-weighted images from the PING dataset, including rigorous quality assessment and fine-tuning of parameters at every step, to increase the accessibility of these data for connectomic analysis. This processing provides state-of-the-art diffusion measures, both classical diffusion tensor imaging (DTI) and more advanced HARDI-based metrics, enabling the evaluation not only of structural white matter but also of integrated multimodal analyses, i.e. combining structural information from dMRI with functional or gray matter analyses.

Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer’s disease (AD), are believed to spread through connected regions. Combining diffusion imaging and positron emission tomography, we investigated associations between Aβ, tau and white matter microstructure specifically in bundles connecting brain regions in which AD pathology accumulates. In 126 cognitively normal elderly at risk of AD, we focussed on free-water corrected diffusion measures in the cingulum, posterior cingulum, fornix and uncinate fasciculus. We found higher tissue fractional anisotropy and lower mean and radial diffusivity related to increased Aβ at the cortical endpoints of the cingulum and fornix. We observed similar but stronger associations in the uncinate fasciculus, but with increased Aβ and tau at the endpoints of this bundle. This consistent pattern of associations, with opposite directionality to the usual degeneration pattern in symptomatic individuals, suggests more restricted diffusion in bundles vulnerable to preclinical AD pathology.

Referral to hematology for anemia is common. In paroxysmal nocturnal hemoglobinuria (PNH), cells deficient in the glycosylphosphatidyl inositol (GPI) anchor are lysed by complement. Eculizumab improves overall survival and quality of life while reducing hemolysis, transfusion requirements, and thrombosis. We evaluated the frequency of screening for PNH in patients with unexplained anemia. Key clinical features, laboratory data, and investigations were recorded for patients referred for anemia since 2010, without a specific cause found. PNH testing was done by flow cytometry. 540 patients had: anemia not yet diagnosed (NYD, n=318 (including unexplained iron deficiency, n=92; DAT-negative hemolysis, n=9)); anemia of chronic disease, n=173; and pancytopenia NYD, n=49. 82.4% had LDH testing done; 85.0% total bilirubin; 78.7% reticulocyte counts; and 40.6% haptoglobin level; 131 (24.2%) had possible hemolysis. PNH testing was done in 56 (10.4%). Those screened for PNH were more likely to have: younger age (P=0.04); a history of thrombosis (P

Subconcussive hits to the head and physical fitness both have been associated with alterations in white matter (WM) microstructure in partly overlapping areas of the brain. The aim of the present study was to determine whether WM damage associated with repeated exposure to subconcussive hits to the head in university level contact sports athletes is modulated by high levels of fitness. To this end, 72 students were recruited: 24 athletes practicing a varsity contact sport (A-CS), 24 athletes practicing a varsity non-contact sport (A-NCS), and 24 healthy non-athletes (NA). Participants underwent a magnetic resonance imaging session that included diffusion-weighted imaging. Between-groups, statistical analyses were performed with diffusion tensor imaging measures extracted by tractometry of sections of the corpus callosum and the corticospinal tract. Most significant effects were found in A-NCS who exhibited higher fractional anisotropy (FA) values than A-CS in almost all segments of the corpus callosum and in the corticospinal tract. The A-NCS also showed higher FA compared with NA in the anterior regions of the corpus callosum and the corticospinal tracts. No group difference was found between the A-CS and the NA groups. These data suggest that repeated subconcussive hits to the head lead to anisotropic changes in the WM that may counteract the beneficial effects associated with high levels of fitness.

Investigative studies of white matter (WM) brain structures using diffusion MRI (dMRI) tractography frequently require manual WM bundle segmentation, often called “virtual dissection.” Human errors and personal decisions make these manual segmentations hard to reproduce, which have not yet been quantified by the dMRI community. It is our opinion that if the field of dMRI tractography wants to be taken seriously as a widespread clinical tool, it is imperative to harmonize WM bundle segmentations and develop protocols aimed to be used in clinical settings. The EADC‐ADNI Harmonized Hippocampal Protocol achieved such standardization through a series of steps that must be reproduced for every WM bundle. This article is an observation of the problematic. A specific bundle segmentation protocol was used in order to provide a real‐life example, but the contribution of this article is to discuss the need for reproducibility and standardized protocol, as for any measurement tool. This study required the participation of 11 experts and 13 nonexperts in neuroanatomy and “virtual dissection” across various laboratories and hospitals. Intra‐rater agreement (Dice score) was approximately 0.77, while inter‐rater was approximately 0.65. The protocol provided to participants was not necessarily optimal, but its design mimics, in essence, what will be required in future protocols. Reporting tractometry results such as average fractional anisotropy, volume or streamline count of a particular bundle without a sufficient reproducibility score could make the analysis and interpretations more difficult. Coordinated efforts by the diffusion MRI tractography community are needed to quantify and account for reproducibility of WM bundle extraction protocols in this era of open and collaborative science.

While the neural correlates of age-related episodic memory decline have been extensively studied, the precise involvement of the Posterior Cingulate Cortex (PCC) and posterior parietal cortex (the precuneus and the angular gyrus), remains unclear. The present study examined functional and structural neural correlates of age-related episodic memory change assessed over 12 years in 120 older adults (range 76-90 years). Episodic memory performance was measured using the Free and Cued Selective Reminding Test (FCSRT); functional connectivity metrics were computed from resting-state fMRI images and structural connectivity metrics were assessed through microstructural properties of reconstructed tract using a native space pipeline. We found that FCSRT change was significantly associated with the functional connectivity between the ventral PCC and three parietal regions, the ventral superior, the inferior part of the precuneus, and the rostro dorsal part of the angular gyrus. This association was independent of hippocampal volume. In addition, we found the that change in FCSRT scores was associated with fractional anisotropy of the tract connecting the ventral PCC and the ventral superior part of the precuneus. Change in episodic memory in aging was therefore related to a combination of high functional connectivity and low structural connectivity between the ventral PCC and the ventral superior part of the precuneus.

Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination improved the sensitivity of conventional DTI measures to detect associations between tissue-specific diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content measured along the cingulum was independently strongly associated with changes in verbal fluency. These observations suggest the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.

Primary brain tumors are notoriously hard to resect surgically. Due to their infiltrative nature, finding the optimal resection boundary without damaging healthy tissue can be challenging. One potential tool to help make this decision is diffusion-weighted magnetic resonance imaging (dMRI) tractography. dMRI exploits the diffusion of water molecule along axons to generate a 3D modelization of the white matter bundles in the brain. This feature is particularly useful to visualize how a tumor affects its surrounding white matter and plan a surgical path. This paper reviews the different ways in which dMRI can be used to improve brain tumor resection, its benefits and also its limitations. We expose surgical tools that can be paired with dMRI to improve its impact on surgical outcome, such as loading the 3D tractography in the neuronavigation system and direct electrical stimulation to validate the position of the white matter bundles of interest. We also review articles validating dMRI findings using other anatomical investigation techniques, such as postmortem dissections, manganese-enhanced MRI, electrophysiological stimulations, and phantom studies with known ground truth. We will be discussing the areas of the brain where dMRI performs well and where the future challenges are. We will conclude this review with suggestions and take home messages for neurosurgeons, tractographers, and vendors for advancing the field and on how to benefit from tractography's use in clinical practice.

A diffusion MRI (dMRI) tractography processing pipeline should be: i) reproducible in immediate test-test, ii) reproducible in time, iii) efficient and iv) easy to use. Two runs of the same processing pipeline with the same input data should give the same output today, tomorrow and in 2 years. However, processing dMRI data requires a large number of steps (20+ steps) that, at this time, may not be reproducible between runs or over time. If parameters such as the number of threads or the random number generator are not carefully set in the brain extraction, registration and fiber tracking steps, the end tractography results obtained can be far from reproducible and limit brain connectivity studies. Moreover, processing can take several hours to days of computation for a large database, even more so if the steps are running sequentially.To handle these issues, we presentTractoFlow, a fully automated pipeline that processes datasets from the raw diffusion weighted images (DWI) to tractography. It also outputs classical diffusion tensor imaging measures (fractional anisotropy (FA) and diffu-sivities) and several HARDI measures (Number of Fiber Orientation (NuFO), Apparent Fiber Density (AFD)). The pipeline requires a DWI and T1-weighted image as NIfTI files and b-values/b-vectors in FSL format. An optional reversed phase encoded b=0 image can also be used. This pipeline is based on two technologies:NextflowandSingularity, as well as recommended pre-processing and processing steps from the dMRI community. In this work, the TractoFlow pipeline is evaluated on three databases and shown to be efficient and reproducible from 98% to 100% depending on parameter choices. For example, 105 subjects from the Human Connectome Project (HCP) were fully ran in twenty-five (25) hours to produce, for each subject, a whole-brain tractogram with 4 million streamlines. The contribution of this paper is to introduce the importance of a robust pipeline in terms of runtime and reproducibility over time. In the era of open data and open science, efficiency and reproducibility is critical in neuroimaging projects. Our TractoFlow pipeline is publicly available for academic research and is an important step forward for better structural brain connectivity mapping.

Investigative studies of white matter (WM) brain structures using diffusion MRI (dMRI) tractography frequently require manual WM bundle segmentation, often called "virtual dissection". Human errors and personal decisions make these manual segmentations hard to reproduce, which have not yet been quantified by the dMRI community. The contribution of this study is to provide the first large-scale, international, multi-center variability assessment of the "virtual dissection" of the pyramidal tract (PyT). Eleven (11) experts and thirteen (13) non-experts in neuroanatomy and "virtual dissection" were asked to perform 30 PyT segmentation and their results were compared using various voxel-wise and streamline-wise measures. Overall the voxel representation is always more reproducible 1. CC-BY-NC-ND 4.0 International license available under a not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint (which was this version posted April 30, 2019. ; https://doi.org/10.1101/623892 doi: bioRxiv preprint than streamlines (≈70% and ≈35% overlap respectively) and distances between segmen-tations are also lower for voxel-wise than streamline-wise measures (≈3mm and ≈6mm respectively). This needs to be seriously considered before using tract-based measures (e.g. bundle volume versus streamline count) for an analysis. We show and argue that future bundle segmentation protocols need to be designed to be more robust to human subjectivity. Coordinated efforts by the diffusion MRI tractography community are needed to quantify and account for reproducibility of WM bundle extraction techniques in this era of open and collaborative science.

International audience; Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination increased the ability of conventional DTI measures to detect associations between tissue diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content and mean diffusivity measured along the cingulum were independently associated with changes in verbal fluency. This suggests that both tissue modifications and an increase in interstitial isotropic water would contribute to cognitive decline. These observations reinforce the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.

Diffusion MRI fiber tractography is widely used to probe the structural connectivity of thebrain, with a range of applications in both clinical and basic neuroscience. Despite widespread use, tractography has well-known pitfalls that limits the anatomical accuracy of this technique. Numerous modern methods have been developed to address these shortcomings through advances in acquisition, modeling, and computation. To test whether these advances improve tractography accuracy, we organized the ISBI 2018 3D Validation of Tractography with Experimental MRI (3D-VoTEM) challenge. We made available three unique independent tractography validation datasets – a physical phantom and two ex vivo brain specimens - resulting in 176 distinct submissions from 9 research groups. By comparing results over a wide range of fiber complexities and algorithmic strategies, this challenge provides a more comprehensive assessment of tractography’s inherent limitations than has been reported previously. The central results were consistent across all sub-challenges in that, despite advances in tractography methods, the anatomical accuracy of tractography has not dramatically improved in recent years. Taken together, our results independently confirm findings from decades of tractography validation studies, demonstrate inherent limitations in reconstructing white matter pathways using diffusion MRI data alone, and highlight the need for alternative or combinatorial strategies to accurately map the fiber pathways of the brain.

Background: Mapping diffusion MRI tractography streamlines to the cortical surface facilitates the integration of white matter features onto gray matter, especially for connectivity analysis., Method: In this work, we present methods that combine cortical surface meshes with tractography reconstruction to improve endpoint precision and coverage. This cortical mapping also enables the study of structural measures from tractography along the cortex and subcortical structures. In addition to structural connectivity analysis, novel adaptive and dynamic surface seeding methods are proposed. These improvements are made by incorporating cortical maps such as endpoint density., Results: The proposed dynamic surface seeding increases the cortical coverage and reduces endpoint location biases. Our results suggest that the use of cortical and subcortical meshes together with a proper seeding strategy can reduce the variability in structural connectivity analysis., Conclusion: The proposed adaptive and dynamic seeding utilize cortical maps to better distribute tractography interconnections, thus increasing cortical coverage and reducing endpoint bias. This also facilitates the analysis of whitematter& diffusionMRI features along the cortex, combined with cortical measures or functional activation.