Axonal density and diameter are two fundamental properties of brain white matter. Recently, advanced diffusion MRI techniques have made these two parameters accessible in vivo. However, the ...techniques available to estimate such parameters are still under development. For example, current methods to map axonal diameters capture relative trends over different structures, but consistently over-estimate absolute diameters. Axonal density estimates are more accessible experimentally, but different modeling approaches exist and the impact of the experimental parameters has not been thoroughly quantified, potentially leading to incompatibility of results obtained in different studies using different techniques. Here, we characterise the impact of diffusion time on axonal density and diameter estimates using Monte Carlo simulations and STEAM diffusion MRI at 7T on 9 healthy volunteers. We show that axonal density and diameter estimates strongly depend on diffusion time, with diameters almost invariably overestimated and density both over and underestimated for some commonly used models. Crucially, we also demonstrate that these biases are reduced when the model accounts for diffusion time dependency in the extra-axonal space. For axonal density estimates, both upward and downward bias in different situations are removed by modeling extra-axonal time-dependence, showing increased accuracy in these estimates. For axonal diameter estimates, we report increased accuracy in ground truth simulations and axonal diameter estimates decreased away from high values given by earlier models and towards known values in the human corpus callosum when modeling extra-axonal time-dependence. Axonal diameter feasibility under both advanced and clinical settings is discussed in the light of the proposed advances.
Axonal degeneration is a central pathological feature of multiple sclerosis and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in ...vivo are limited in their specificity and clinical applicability, and by the lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls. AxCaliber is sensitive to acute axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the targeted tract, which correlated with neurofilament staining. Electron microscopy confirmed that increased mean axonal diameter is associated with acute axonal pathology. In humans with multiple sclerosis, we uncovered a diffuse increase in mean axonal caliber in most areas of the normal-appearing white matter, preferentially affecting patients with short disease duration. Our results demonstrate that MRI-based axonal diameter mapping is a sensitive and specific imaging biomarker that links noninvasive imaging contrasts with the underlying biological substrate, uncovering generalized axonal damage in multiple sclerosis as an early event.
•We generate a mouse brain atlas adapted for in vivo diffusion-weighted MRI.•The atlas features diffusion and anatomical contrasts, and the Allen annotation.•We demonstrate that using a single-sex ...atlas creates spurious sex effects.•Mean diffusivity correlated with microglia cell density from transcriptomic data.
Overcoming sex bias in preclinical research requires not only including animals of both sexes in the experiments, but also developing proper tools to handle such data. Recent work revealed sensitivity of diffusion-weighted MRI to glia morphological changes in response to inflammatory stimuli, opening up exciting possibilities to characterize inflammation in a variety of preclinical models of pathologies, the great majority of them available in mice. However, there are limited resources dedicated to mouse imaging, like those required for the data processing and analysis. To fill this gap, we build a mouse MRI template of both structural and diffusion contrasts, with anatomical annotation according to the Allen Mouse Brain Atlas, the most detailed public resource for mouse brain investigation. To achieve a standardized resource, we use a large cohort of animals in vivo, and include animals of both sexes. To prove the utility of this resource to integrate imaging and molecular data, we demonstrate significant association between the mean diffusivity from MRI and gene expression-based glia density. To demonstrate the need of equitable sex representation, we compared across sexes the warp fields needed to match a male-based template, and our template built with both sexes. Then, we use both templates for analysing mice imaging data obtained in animals of different ages, demonstrating that using a male-based template creates spurious significant sex effects, not present otherwise. All in all, our MouseX DW-ALLEN Atlas will be a widely useful resource getting us one step closer to equitable healthcare.
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The aim of this work was to understand biophysical substrate underpinning contrast in diffusional kurtosis imaging (DKI) in white matter, using the composite hindered and restricted model of ...diffusion (CHARMED).
Materials and methods
A theoretical relationship between the kurtosis function
K
and the CHARMED parameters, i.e., the restricted volume fraction
RF
and the axonal longitudinal diffusivity
D
was derived for the propagator used in the CHARMED model. Evidence for a similar correlation between these measures was then investigated in vivo across different WM regions in five healthy young subjects that underwent a CHARMED protocol at 3T.
Results
Our theoretical treatment shows that
K
has an increasing trend for both increasing
RF
values and increasing
D
. In vivo, a significant positive correlation (
P
< 0.001) was found between the kurtosis orthogonal to the fibre orientation
K
⊥
and
RF
. A multilinear regression showed that
K
⊥
values are better explained by a mixed contribution of both
RF
and
D
.
Conclusions
The CHARMED model was used to understand whether and where DKI contrast can be explained in terms of the underlying axonal geometry. This work demonstrates that the information contained in DKI overlaps with the information extracted by CHARMED in areas of higher intra-voxel directional coherence.
Adaptive working memory (WM) training may lead to cognitive benefits that are associated with white matter plasticity in parietofrontal networks, but the underlying mechanisms remain poorly ...understood. We investigated white matter microstructural changes after adaptive WM training relative to a nonadaptive comparison group. Microstructural changes were studied in the superior longitudinal fasciculus, the main parietofrontal connection, and the cingulum bundle as a comparison pathway. MRI-based metrics were the myelin water fraction and longitudinal relaxation rate R
from multicomponent relaxometry (captured with the mcDESPOT approach) as proxy metrics of myelin, the restricted volume fraction from the composite hindered and restricted model of diffusion as an estimate of axon morphology, and fractional anisotropy and radial diffusivity from diffusion tensor imaging. PCA was used for dimensionality reduction. Adaptive training was associated with benefits in a “WM capacity” component and increases in a microstructural component (increases in R
, restricted volume fraction, fractional anisotropy, and reduced radial diffusivity) that predominantly loaded on changes in the right dorsolateral superior longitudinal fasciculus and the left parahippocampal cingulum. In contrast, nonadaptive comparison activities were associated with the opposite pattern of reductions in WM capacity and microstructure. No group differences were observed for the myelin water fraction metric suggesting that R
was a more sensitive “myelin” index. These results demonstrate task complexity and location-specific white matter microstructural changes that are consistent with tissue alterations underlying myelination in response to training.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Non sempre è stata rivolta sufficiente attenzione al fatto che i tre più grandi interpreti figurativi della Commedia nell’Inghilterra tra Sette e Ottocento – Johann Heinrich Füssli (1741-1825), John ...Flaxman (1755-1826) e William Blake (1757-1827) – fossero in stretto contatto tra loro e reciprocamente legati da un solido e durevole vincolo di amicizia. Le illustrazioni dantesche di Blake vengono analizzate alla luce di questo dato fondamentale, ricostruendo le vicende biografiche che caratterizzarono l’amicizia fra i tre artisti e valutando le possibili influenze reciproche all’interno della loro produzione dantesca.
Diffusion-based MR imaging is the only non-invasive method for characterising the microstructural organization of brain tissue
in vivo
. Diffusion tensor MRI (DT-MRI) is currently routinely used in ...both research and clinical practice. However, other diffusion approaches are gaining more and more popularity and an increasing number of researchers express interest in using them concomitantly with DT-MRI. While non tensor-based methods hold great promises for increasing the specificity of diffusion MR imaging, including them in the experimental routine inevitably leads to longer experimental times. In most cases, this may preclude the translation of the full protocol to clinical practice, especially when these methods are to be used with subjects that are not compatible with long scanning sessions (e.g., with elderly and pediatric subjects who have difficulties in maintaining a fixed head position during a long imaging session).
The aim of this review is to guide the end-users on obtaining the maximum from the experimental time allocated to collecting diffusion MRI data. This is done by: (i) briefly reviewing non tensor-based approaches; (ii) reviewing the optimal protocols for both tensor and non tensor-based imaging; and (iii) drawing the conclusions for different experimental times.
In multiple sclerosis (MS), it would be of clinical value to be able to track the progression of axonal pathology, especially before the manifestation of clinical disability. However, non-invasive ...evaluation of short-term longitudinal progression of white matter integrity is challenging. This study aims at assessing longitudinal changes in the restricted (i.e. intracellular) diffusion signal fraction (FR) in early-stage MS by using ultra-high gradient strength multi-shell diffusion magnetic resonance imaging. In 11 early MS subjects (disease duration ≤5 years), FR was obtained at two timepoints (one year apart) through the Composite Hindered and Restricted Model of Diffusion, along with conventional Diffusion Tensor Imaging metrics. At follow-up, no statistically significant change was detected in clinical variables, while all imaging metrics showed statistically significant longitudinal changes (p < 0.01, corrected for multiple comparisons) in widespread regions in normal-appearing white matter (NAWM). The most extensive longitudinal changes were observed in FR, including areas known to include a large fraction of crossing fibers. Furthermore, FR was also the only metric showing significant longitudinal changes in lesions that were present at both time points (p = 0.007), with no significant differences found for conventional diffusion metrics. Finally, FR was the only diffusion metric (as compared to Diffusion Tensor Imaging) that revealed pre-lesional changes already present at baseline. Taken together, our data provide evidence for progressive microstructural damage in the NAWM of early MS cases detectable already at 1-year follow-up. Our study highlights the value of multi-shell diffusion imaging for sensitive tracking of disease evolution in MS before any clinical changes are observed.
This article is part of a Special Issue entitled: SI: MRI and Neuroinflammation.
•We use the CHARMED diffusion model to assess restricted signal fraction (FR) in 11 multiple sclerosis patients at 1 year follow-up.•The most extensive longitudinal changes were observed in FR, including areas known to include a large fraction of crossing fibers.•FR was the only metric showing significant longitudinal changes in lesions that were present at both time points.•FR was the only metric that revealed pre-lesional changes already present at baseline.•We evidence for progressive microstructural damage in the NAWM of early MS cases detectable already at 1-year follow-up.
Irreversible white matter (WM) damage, including severe demyelination and axonal loss, is a main determinant of long-term disability in multiple sclerosis (MS). Non-invasive detection of changes in ...microstructural WM integrity in the disease is challenging since commonly used imaging metrics lack the necessary sensitivity, especially in the early phase of the disease. This study aims at assessing microstructural WM abnormalities in early-stage MS by using ultra-high gradient strength multi-shell diffusion MRI and the restricted signal fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED), a metric sensitive to the volume fraction of axons. In 22 early MS subjects (disease duration ≤5 years) and 15 age-matched healthy controls, restricted fraction estimates were obtained through the CHARMED model along with conventional Diffusion Tensor Imaging (DTI) metrics. All imaging parameters were compared cross-sectionally between the MS subjects and controls both in WM lesions and normal-appearing white matter (NAWM). We found a significant reduction in FR focally in WM lesions and widespread in the NAWM in MS patients relative to controls (corrected p < .05). Signal fraction changes in NAWM were not driven by perilesional tissue, nor were they influenced by proximity to the ventricles, challenging the hypothesis of an outside-in pathological process driven by CSF-mediated immune cytotoxic factors. No significant differences were found in conventional DTI parameters. In a cross-validated classification task, FR showed the largest effect size and outperformed all other diffusion imaging metrics in discerning lesions from contralateral NAWM. Taken together, our data provide evidence for the presence of widespread microstructural changes in the NAWM in early MS stages that are, at least in part, unrelated to focal demyelinating lesions. Interestingly, these pathological changes were not yet detectable by conventional diffusion imaging at this early disease stage, highlighting the sensitivity and value of multi-shell diffusion imaging for better characterizing axonal microstructure in MS.
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