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Background and purpose: Structural magnetic resonance techniques have been widely applied in neurological disorders to better understand tissue changes, probing characteristics such as volume, iron deposition and diffusion. Dystonia is a hyperkinetic movement disorder, resulting in abnormal postures and pain. Its pathophysiology is poorly understood, with normal routine clinical imaging in idiopathic forms. More advanced tools provide an opportunity to identify smaller scale structural changes which may underpin pathophysiology. This review aims to provide an overview of methodological approaches undertaken in structural brain imaging of dystonia cohorts, and to identify commonly identified pathways, networks or regions that are implicated in pathogenesis. Methods: Structural magnetic resonance imaging studies of idiopathic and genetic forms of dystonia were systematically reviewed. Adhering to strict inclusion and exclusion criteria, PubMed and Embase databases were searched up to January 2022, with studies reviewed for methodological quality and key findings. Results: Seventy‐seven studies were included, involving 1945 participants. The majority of studies employed diffusion tensor imaging (DTI) (n = 45) or volumetric analyses (n = 37), with frequently implicated areas of abnormality in the brainstem, cerebellum, basal ganglia and sensorimotor cortex and their interconnecting white matter pathways. Genotypic and motor phenotypic variation emerged, for example fewer cerebello‐thalamic tractography streamlines in genetic forms than idiopathic and higher grey matter volumes in task‐specific than non‐task‐specific dystonias. Discussion: Work to date suggests microstructural brain changes in those diagnosed with dystonia, although the underlying nature of these changes remains undetermined. Employment of techniques such as multiple diffusion weightings or multi‐exponential relaxometry has the potential to enhance understanding of these differences.

Purpose\ud The use of high-performance gradient systems (i.e., high gradient strength and/or high slew rate) for human MRI is limited by physiological effects (including the elicitation of magnetophosphenes and peripheral nerve stimulation (PNS)). These effects, in turn, depend on the interaction between time-varying magnetic fields and the body, and thus on the participant’s position with respect to the scanner’s isocenter. This study investigated the occurrence of magnetophosphenes and PNS when scanning participants on a high-gradient (300 mT/m) system, for different gradient amplitudes, ramp times, and participant positions.\ud \ud Methods\ud Using a whole-body 300 mT/m gradient MRI system, a cohort of participants was scanned with the head, heart, and prostate at magnet isocenter and a train of trapezoidal bipolar gradient pulses, with ramp times from 0.88 to 4.20 ms and gradient amplitudes from 60 to 300 mT/m. Reports of magnetophosphenes and incidental reports of PNS were obtained. A questionnaire was used to record any additional subjective effects.\ud \ud Results\ud Magnetophosphenes were strongly dependent on participant position in the scanner. 87% of participants reported the effect with the heart at isocenter, 33% with the head at isocenter, and only 7% with the prostate at isocenter. PNS was most widely reported by participants for the vertical gradient axis (67% of participants), and was the dominant physiological effect for ramp times below 2 ms.\ud \ud Conclusion\ud This study evaluates the probability of eliciting magnetophosphenes during whole-body imaging using an ultra-strong gradient MRI system. It provides empirical guidance on the use of high-performance gradient systems for whole-body human MRI.

Most diffusion magnetic resonance imaging studies of disease rely on statistical comparisons between large groups of patients and healthy participants to infer altered tissue states in the brain; however, clinical heterogeneity can greatly challenge their discriminative power. There is currently an unmet need to move away from the current approach of group-wise comparisons to methods with the sensitivity to detect altered tissue states at the individual level. This would ultimately enable the early detection and interpretation of microstructural abnormalities in individual patients, an important step towards personalized medicine in translational imaging. To this end, Detect was developed to advance diffusion magnetic resonance imaging tractometry towards single-patient analysis. By operating on the manifold of white-matter pathways and learning normative microstructural features, our framework captures idiosyncrasies in patterns along white-matter pathways. Our approach paves the way from traditional group-based comparisons to true personalized radiology, taking microstructural imaging from the bench to the bedside. The authors propose Detect, a browser-based anomaly detection framework for diffusion magnetic resonance imaging tractometry data. The tool leverages normative microstructural brain features derived from healthy participants using deep autoencoders to detect anomalies at the individual level.

Gradient nonlinearities in magnetic resonance imaging (MRI) cause spatially varying mismatches between the imposed and the effective gradients and can cause significant biases in rotationally invariant diffusion MRI measures derived from, for example, diffusion tensor imaging. The estimation of the orientational organization of fibrous tissue, which is nowadays frequently performed with spherical deconvolution techniques ideally using higher diffusion weightings, can likewise be biased by gradient nonlinearities. We explore the sensitivity of two established spherical deconvolution approaches to gradient nonlinearities, namely constrained spherical deconvolution (CSD) and damped Richardson‐Lucy (dRL). Additionally, we propose an extension of dRL to take into account gradient imperfections, without the need of data interpolation. Simulations show that using the effective b‐matrix can improve dRL fiber orientation estimation and reduces angular deviations, while CSD can be more robust to gradient nonlinearity depending on the implementation. Angular errors depend on a complex interplay of many factors, including the direction and magnitude of gradient deviations, underlying microstructure, SNR, anisotropy of the effective response function, and diffusion weighting. Notably, angular deviations can also be observed at lower b‐values in contrast to the perhaps common assumption that only high b‐value data are affected. In in vivo Human Connectome Project data and acquisitions from an ultrastrong gradient (300 mT/m) scanner, angular differences are observed between applying and not applying the effective gradients in dRL estimation. As even small angular differences can lead to error propagation during tractography and as such impact connectivity analyses, incorporating gradient deviations into the estimation of fiber orientations should make such analyses more reliable., Gradient nonlinearities cause spatially varying mismatches between the imposed and the effective gradients in diffusion magnetic resonance imaging. We explore the sensitivity of spherical deconvolution approaches, including constrained spherical deconvolution and damped Richardson‐Lucy (dRL), to gradient nonlinearity artifacts. Additionally, we propose an extension of the dRL method to take into account gradient imperfections without the need of data interpolation. As even small angular differences can lead to error propagation during fiber tractography, incorporating gradient deviations into the estimation of the fiber orientation distributions should make such analyses more reliable.

Recent advances in diffusion magnetic resonance imaging (dMRI) analysis techniques have improved our understanding of fibre-specific variations in white matter microstructure. Increasingly, studies are adopting multi-shell dMRI acquisitions to improve the robustness of dMRI-based inferences. However, the impact of b-value choice on the estimation of dMRI measures such as apparent fibre density (AFD) derived from spherical deconvolution is not known. Here, we investigate the impact of b-value sampling scheme on estimates of AFD. First, we performed simulations to assess the correspondence between AFD and simulated intra-axonal signal fraction across multiple b-value sampling schemes. We then studied the impact of sampling scheme on the relationship between AFD and age in a developmental population (n=78) aged 8-18 (mean=12.4, SD=2.9 years) using hierarchical clustering and whole brain fixel-based analyses. Multi-shell dMRI data were collected at 3.0T using ultra-strong gradients (300 mT/m), using 6 diffusion-weighted shells ranging from 0 – 6000 s/mm2. Simulations revealed that the correspondence between estimated AFD and simulated intra-axonal signal fraction was improved with high b-value shells due to increased suppression of the extra-axonal signal. These results were supported by in vivo data, as sensitivity to developmental age-relationships was improved with increasing b-value (b=6000 s/mm2, median R2 = .34; b=4000 s/mm2, median R2 = .29; b=2400 s/mm2, median R2 = .21; b=1200 s/mm2, median R2 = .17) in a tract-specific fashion. Overall, estimates of AFD and age-related microstructural development were better characterised at high diffusion-weightings due to improved correspondence with intra-axonal properties.

When investigating connectivity and microstructure of white matter pathways of the brain using diffusion tractography bundle segmentation, it is important to understand potential confounds and sources of variation in the process. While cross-scanner and cross-protocol effects on diffusion microstructure measures are well described (in particular fractional anisotropy and mean diffusivity), it is unknown how potential sources of variation effect bundle segmentation results, which features of the bundle are most affected, where variability occurs, nor how these sources of variation depend upon the method used to reconstruct and segment bundles. In this study, we investigate six potential sources of variation, or confounds, for bundle segmentation: variation (1) across scan repeats, (2) across scanners, (3) across vendors (4) across acquisition resolution, (5) across diffusion schemes, and (6) across diffusion sensitization. We employ four different bundle segmentation workflows on two benchmark multi-subject cross-scanner and cross-protocol databases, and investigate reproducibility and biases in volume overlap, shape geometry features of fiber pathways, and microstructure features within the pathways. We find that the effects of acquisition protocol, in particular acquisition resolution, result in the lowest reproducibility of tractography and largest variation of features, followed by vendor-effects, scanner-effects, and finally diffusion scheme and b-value effects which had similar reproducibility as scan-rescan variation. However, confounds varied both across pathways and across segmentation workflows, with some bundle segmentation workflows more (or less) robust to sources of variation. Despite variability, bundle dissection is consistently able to recover the same location of pathways in the deep white matter, with variation at the gray matter/ white matter interface. Next, we show that differences due to the choice of bundle segmentation workflows are larger than any other studied confound, with low-to-moderate overlap of the same intended pathway when segmented using different methods. Finally, quantifying microstructure features within a pathway, we show that tractography adds variability over-and-above that which exists due to noise, scanner effects, and acquisition effects. Overall, these confounds need to be considered when harmonizing diffusion datasets, interpreting or combining data across sites, and when attempting to understand the successes and limitations of different methodologies in the design and development of new tractography or bundle segmentation methods.

Characterizing and understanding the limitations of diffusion MRI fiber tractography\udis a prerequisite for methodological advances and innovations which will allow these\udtechniques to accurately map the connections of the human brain. The so-called\ud“crossing fiber problem” has received tremendous attention and has continuously\udtriggered the community to develop novel approaches for disentangling distinctly oriented fiber populations. Perhaps an even greater challenge occurs when multiple\udwhite matter bundles converge within a single voxel, or throughout a single brain\udregion, and share the same parallel orientation, before diverging and continuing\udtowards their final cortical or sub-cortical terminations. These so-called “bottleneck”\udregions contribute to the ill-posed nature of the tractography process, and lead to\udboth false positive and false negative estimated connections. Yet, as opposed to the\udextent of crossing fibers, a thorough characterization of bottleneck regions has not\udbeen performed. The aim of this study is to quantify the prevalence of bottleneck\udregions. To do this, we use diffusion tractography to segment known white matter\udbundles of the brain, and assign each bundle to voxels they pass through and to specific orientations within those voxels (i.e. fixels). We demonstrate that bottlenecks\udoccur in greater than 50-70% of fixels in the white matter of the human brain. We find that all projection, association, and commissural fibers contribute to, and are\udaffected by, this phenomenon, and show that even regions traditionally considered\ud“single fiber voxels” often contain multiple fiber populations. Together, this study\udshows that a majority of white matter presents bottlenecks for tractography which\udmay lead to incorrect or erroneous estimates of brain connectivity or quantitative\udtractography (i.e., tractometry), and underscores the need for a paradigm shift in the\udprocess of tractography and bundle segmentation for studying the fiber pathways of\udthe human brain.

Background and Purpose\ud Diffusion MRI of the brain enables to quantify white matter fiber orientations noninvasively. Several approaches have been proposed to estimate such characteristics from diffusion MRI data with spherical deconvolution being one of the most widely used methods. Spherical deconvolution requires to define––or derive from the data––a response function, which is used to compute the fiber orientation distribution (FOD). Different characteristics of the response function are expected to affect the FOD computation and the subsequent fiber tracking.\ud \ud Methods\ud In this work, we explored the effects of inaccuracies in the shape factors of the response function on the FOD characteristics.\ud \ud Results\ud With simulations, we show that the apparent fiber density could be doubled in the presence of underestimated shape factors in the response functions, whereas the overestimation of the shape factor will cause more spurious peaks in the FOD, especially when the signal-to-noise ratio is below 15. Moreover, crossing fiber populations with a separation angle smaller than 60° were more sensitive to inaccuracies in the response function than fiber populations with more orthogonal separation angles. Results with in vivo data demonstrate angular deviations in the FODs and spurious peaks as a result of modified shape factors of the response function, while the reconstruction of the main parts of fiber bundles is well preserved.\ud \ud Conclusions\ud This work sheds light on how specific aspects of the response function shape can affect the estimated FODs, and highlights the importance of a proper calibration/definition of the response function.

Short association fibres (SAF) of the human brain are estimated to represent over a half of the total white matter volume, and their involvement has been implicated in a range of neurological and psychiatric conditions. This population of fibres, however, remains relatively understudied in the neuroimaging literature. Some of the challenges pertinent to the mapping of SAF include their variable anatomical course and close proximity to the cortical mantle, leading to partial volume effects and exacerbating the influence of the gyral bias. This work considers the choice of scanner, acquisition, voxel size, seeding strategy and filtering techniques to propose a whole-brain, surface-based tractography approach with the aim of providing a method for investigating SAF ≤30-40 mm. The framework is designed to: (1) ensure a greater cortical surface coverage through spreading streamline seeds more uniformly; (2) introduce precise filtering mechanics which are particularly important when dealing with small, morphologically diverse structures; and (3) allow the use of surface-based registration for dataset comparisons which can be superior to volume-based registration in the cortical vicinity. The indexation of surface vertices at each streamline end enables direct interfacing between streamlines and the cortical surface without dependence on the voxel grid. SAF tractograms generated using recent test- retest data from our institution are carefully characterised and measures of consistency using streamline-, voxel- and surface-wise comparisons calculated to inform researchers and serve as a benchmark for future methodological developments.

Most diffusion MRI (dMRI) studies of disease rely on statistical comparisons between large groups of patients and healthy controls to infer altered tissue state. Such studies often require data from a significant number of patients before robust inferences can be made, and clinical heterogeneity can greatly challenge their discriminative power. Moreover, for clinicians and researchers studying small datasets, rare cases, or individual patients, this approach is clearly inappropriate. There is a clear and unmet need to shift away from the current standard approach of group-wise comparisons to methods with the sensitivity for detection of altered tissue states at the individual level. This would ultimately enable the early detection and interpretation of microstructural abnormalities in individual patients, an important step towards personalised-medicine in translational imaging. To this end, Detect was developed to advance dMRI-based Tractometry towards single-subject analysis. By: 1) operating on the manifold of white matter pathways; and 2) learning normative microstructural features to better discriminate patients from controls, our framework captures idiosyncrasies in patterns along brain white matter pathways in the individual. This novel approach paves the way from traditional group-based comparisons to true personalised radiology, taking microstructural imaging from the bench to the bedside.

Diffusion MRI techniques are used widely to study the characteristics of the human brain connectome in vivo. However, to resolve and characterise white matter (WM) fibres in heterogeneous MRI voxels remains a challenging problem typically approached with signal models that rely on prior information and constraints. We have recently introduced a 5D relaxation–diffusion correlation framework wherein multidimensional diffusion encoding strategies are used to acquire data at multiple echo‐times to increase the amount of information encoded into the signal and ease the constraints needed for signal inversion. Nonparametric Monte Carlo inversion of the resulting datasets yields 5D relaxation–diffusion distributions where contributions from different sub‐voxel tissue environments are separated with minimal assumptions on their microscopic properties. Here, we build on the 5D correlation approach to derive fibre‐specific metrics that can be mapped throughout the imaged brain volume. Distribution components ascribed to fibrous tissues are resolved, and subsequently mapped to a dense mesh of overlapping orientation bins to define a smooth orientation distribution function (ODF). Moreover, relaxation and diffusion measures are correlated to each independent ODF coordinate, thereby allowing the estimation of orientation‐specific relaxation rates and diffusivities. The proposed method is tested on a healthy volunteer, where the estimated ODFs were observed to capture major WM tracts, resolve fibre crossings, and, more importantly, inform on the relaxation and diffusion features along with distinct fibre bundles. If combined with fibre‐tracking algorithms, the methodology presented in this work has potential for increasing the depth of characterisation of microstructural properties along individual WM pathways., Diffusion MRI techniques designed to resolve fibre crossings within a given white matter (WM) voxel typically assume that the voxel‐level microstructural features can be represented by a single signal response function; this precludes the investigation of microscopic differences between the sub‐voxel fibre populations. In this work, we build on a recently introduced 5D relaxation–diffusion correlation MRI framework and present an analysis protocol for deriving and visualising metrics informing on the relaxation rates and diffusivities of distinct fibres. Experiments on a healthy volunteer demonstrate that the presented approach can capture crossings between distinct WM tracts of the human brain and inform on their individual relaxation–diffusion properties.

We provide a rich multi-contrast microstructural MRI dataset acquired on an ultra-strong gradient 3T Connectom MRI scanner comprising 5 repeated sets of MRI microstructural contrasts in 6 healthy human participants. The availability of data sets that support comprehensive simultaneous assessment of test-retest reliability of multiple microstructural contrasts (i.e., those derived from advanced diffusion, multi-component relaxometry and quantitative magnetisation transfer MRI) in the same population is extremely limited. This unique dataset is offered to the imaging community as a test-bed resource for conducting specialised analyses that may assist and inform their current and future research. The Microstructural Image Compilation with Repeated Acquisitions (MICRA) dataset includes raw data and computed microstructure maps derived from multi-shell and multi-direction encoded diffusion, multi-component relaxometry and quantitative magnetisation transfer acquisition protocols. Our data demonstrate high reproducibility of several microstructural MRI measures across scan sessions as shown by intra-class correlation coefficients and coefficients of variation. To illustrate a potential use of the MICRA dataset, we computed sample sizes required to provide sufficient statistical power a priori across different white matter pathways and microstructure measures for different statistical comparisons. We also demonstrate whole brain white matter voxel-wise repeatability in several microstructural maps. The MICRA dataset will be of benefit to researchers wishing to conduct similar reliability tests, power estimations or to evaluate the robustness of their own analysis pipelines.

The anisotropic microstructure of white matter is reflected in various MRI contrasts. Transverse relaxation rates can be probed as a function of fibre-orientation with respect to the main magnetic field, while diffusion properties are probed as a function of fibre-orientation with respect to an encoding gradient. While the latter is easy to obtain by varying the orientation of the gradient, as the magnetic field is fixed, obtaining the former requires re-orienting the head. In this work we deployed a tiltable RF-coil to study$$T_2$$T2- and diffusional anisotropy of the brain white matter simultaneously in diffusion-$$T_2$$T2correlation experiments.

Diffusion magnetic resonance imaging is a technique which has long been used to study white matter microstructure in vivo. Recent advancements in hardware and modelling techniques have opened up interest in disentangling tissue compartments in the grey matter. In this study, we evaluate the repeatability of soma and neurite density imaging in a sample of six healthy adults scanned five times on an ultra-strong gradient magnetic resonance scanner (300 mT/m). Repeatability was expressed as an intraclass correlation coefficient (ICC). Our findings reveal that measures of soma density (mean ICC \(=\) 0.976), neurite density (mean ICC \(=\) 0.959) and apparent soma size (mean ICC \(=\) 0.923) are highly reliable across multiple cortical and subcortical networks. Overall, we demonstrate the promise of moving advanced grey matter microstructural imaging towards applications of development, ageing, and disease.

Increasing evidence implicates white matter (WM) dynamics supporting learning in the mature brain. Recent MRI studies, mostly using diffusion tensor MRI (DT-MRI), have demonstrated learning-induced WM changes at the microstructural level. However, while DT-MRI-derived measures have sensitivity to general WM microstructural changes, they lack compartmental specificity, making them difficult to relate to underlying cellular mechanisms, stymying deeper understanding of mechanisms supporting training-induced gains in performance. Gaining a deeper understanding demands a more detailed characterization of changes in specific WM sub-components. To this end, four microstructural MRI techniques were employed to study alterations in rat brains after 5-days of water maze training: DT-MRI; Composite Hindered and Restricted Model of Diffusion (CHARMED); magnetization transfer (MT) imaging; quantitative susceptibility mapping and R2*.The hypothesis tested here was that microstructural changes would be: (i) observed in tracts supporting spatial navigation, i.e., fornix and corpus callosum (CC); and (ii) more pronounced in the myelin-specific measures.Medians and distributions of microstructural parameters were derived along the fornix, CC and cingulum (as a comparison tract) using the ‘tractometry’ approach. Summary measures were derived from different metrics using unsupervised data reduction. Significant pre-vs-post training differences were found in the medians of two principal components loading on: (i) anisotropy indices; and (ii) MT ratio. The most striking effect, however, was seen in the distributions of pre-vs-post training MT ratio in the fornix, consistent with the primary hypothesis, and highlighting the value of this alternative to the standard approach (i.e., comparing means/medians of DT-MRI parameters) for studying neuroplasticity in vivo.Significance statementRecent MRI-studies have demonstrated that white matter (WM) dynamics support learning, even in the mature brain. However, most studies are based on diffusion tensor MRI (DT-MRI) measures, which although providing sensitivity to WM microstructural changes, do not provide a direct translation to the underlying cellular mechanisms making interpretation difficult. Using alternative quantitative MRI approaches, this study provided more specific subcomponent microstructural insights into the brain’s WM response to water-maze training. We show that myelin-specific MR measures show more marked changes than axonal-specific and DT-MRI measures, in WM tracts responsible for spatial navigation. The results promote adoption of these alternative approaches to DT-MRI for studying neuroplasticity in vivo.

The anisotropy of brain white matter microstructure manifests itself in orientational-dependence of various MRI contrasts, and can result in significant quantification biases if ignored. Understanding the origins of this orientation-dependence could enhance the interpretation of MRI signal changes in development, ageing and disease and ultimately improve clinical diagnosis. Using a novel experimental setup, this work studies the contributions of the intra- and extra-axonal water to the orientation-dependence of one of the most clinically-studied parameters, apparent transverse relaxation T2. Specifically, a tiltable receive coil is interfaced with an ultra-strong gradient MRI scanner to acquire multidimensional MRI data with an unprecedented range of acquisition parameters. Using this setup, compartmental T2 can be disentangled based on differences in diffusional-anisotropy, and its orientation-dependence further elucidated by re-orienting the head with respect to the main magnetic field B→0. A dependence of (compartmental) T2 on the fibre orientation w.r.t. B→0 was observed, and further quantified using characteristic representations for susceptibility- and magic angle effects. Across white matter, anisotropy effects were dominated by the extra-axonal water signal, while the intra-axonal water signal decay varied less with fibre-orientation. Moreover, the results suggest that the stronger extra-axonal T2 orientation-dependence is dominated by magnetic susceptibility effects (presumably from the myelin sheath) while the weaker intra-axonal T2 orientation-dependence may be driven by a combination of microstructural effects. Even though the current design of the tiltable coil only offers a modest range of angles, the results demonstrate an overall effect of tilt and serve as a proof-of-concept motivating further hardware development to facilitate experiments that explore orientational anisotropy. These observations have the potential to lead to white matter microstructural models with increased compartmental sensitivity to disease, and can have direct consequences for longitudinal and group-wise T2- and diffusion-MRI data analysis, where the effect of head-orientation in the scanner is commonly ignored.