Composite Hindered And Restricted Model Of Diffusion Research Articles

Applications of advanced diffusion MRI in early brain development: a comprehensive review.

Brain development follows a protracted developmental timeline with foundational processes of neurodevelopment occurring from the third trimester of gestation into the first decade of life. Defining structural maturational patterns of early brain development is a critical step in detecting divergent developmental trajectories associated with neurodevelopmental and psychiatric disorders that arise later in life. While considerable advancements have already been made in diffusion magnetic resonance imaging (dMRI) for pediatric research over the past three decades, the field of neurodevelopment is still in its infancy with remarkable scientific and clinical potential. This comprehensive review evaluates the application, findings, and limitations of advanced dMRI methods beyond diffusion tensor imaging, including diffusion kurtosis imaging (DKI), constrained spherical deconvolution (CSD), neurite orientation dispersion and density imaging (NODDI) and composite hindered and restricted model of diffusion (CHARMED) to quantify the rapid and dynamic changes supporting the underlying microstructural architectural foundations of the brain in early life.

Mutation-related magnetization-transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra-strong gradient MRI.

White matter (WM) alterations have been observed in Huntington disease (HD) but their role in the disease‐pathophysiology remains unknown. We assessed WM changes in premanifest HD by exploiting ultra‐strong‐gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion‐weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls. We used tractometry to investigate region‐specific alterations across callosal segments with well‐characterized early‐ and late‐myelinating axon populations, while brain‐wise differences were explored with tract‐based cluster analysis (TBCA). Behavioral measures were included to explore disease‐associated brain‐function relationships. We detected lower MTR in patients' callosal rostrum (tractometry: p = .03; TBCA: p = .03), but higher MTR in their splenium (tractometry: p = .02). Importantly, patients' mutation‐size and MTR were positively correlated (all p‐values < .01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls (p = .003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico‐spinal tract (p = .03), which correlated positively with MTR in the posterior callosum (p = .033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra‐strong gradient MRI study in HD provides novel evidence of mutation‐driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these.

A general role for ventral white matter pathways in morphological processing: Going beyond reading

The ability to recognize the structural components of words, known as morphological processing, was recently associated with the bilateral ventral white matter pathways, across different writing systems. However, it remains unclear whether these associations are specific to the context of reading. To shed light on this question, in the current study we investigated whether the ventral pathways are associated with morphological processing in an oral word production task that does not involve reading. Forty-five participants completed a morpheme-based fluency task in Hebrew, as well as diffusion MRI (dMRI) scans. We used probabilistic tractography to segment the major ventral and dorsal white matter pathways, and assessed the correlations between their microstructural properties and performance on the morpheme-based fluency task. We found significant correlations between morpheme-based fluency and properties of the bilateral ventral tracts, suggesting that the involvement of these tracts in morphological processing extends beyond the reading modality. In addition, significant correlations were found in the frontal aslant tract (FAT), a dorsal tract associated with oral fluency and speech production. Together, our findings emphasize that neurocognitive associations reflect both the cognitive construct under investigation as well as the task used for its assessment. Lastly, to elucidate the biological factors underlying these correlations, we incorporated the composite hindered and restricted model of diffusion (CHARMED) framework, measured in independent scans. We found that only some of our findings could be attributed to variation in a CHARMED-based estimate of fiber density. Further, we were able to uncover additional correlations that could not be detected using traditional dMRI indices. In sum, our results show that the involvement of the ventral tracts in morphological processing extends to the production domain, and demonstrate the added value of including sensitive structural measurements in neurocognitive investigations.

Drumming Motor Sequence Training Induces Apparent Myelin Remodelling in Huntington's Disease: A Longitudinal Diffusion MRI and Quantitative Magnetization Transfer Study.

Background:Impaired myelination may contribute to Huntington’s disease (HD) pathogenesis.Objective:This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function.Methods:Participants undertook two months of drumming exercises. Working memory and executive function were assessed before and post-training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking putamen and supplementary motor areas (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics.Results:MPF was reduced in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. Increased MPF suggests training-induced myelin changes in HD.Conclusion:Though only preliminary and based on a small sample size, these results suggest that tailored behavioural stimulation may lead to neural benefits in early HD, that could be exploited for delaying disease progression.

Evidence of early microstructural white matter abnormalities in multiple sclerosis from multi-shell diffusion MRI.

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.

The potential role of novel diffusion imaging techniques in the understanding and treatment of epilepsy.

Epilepsy is a common neurological disorder in which magnetic resonance imaging plays a key role. Diffusion imaging based on the molecular diffusion of water has been widely used clinically and in research for patients with epilepsy. Diffusion tensor imaging (DTI), the most common model, has been used for around two decades. Several parameters can be derived from DTI that are sensitive, but non-specific, to underlying structural changes. DTI assumes a single diffusion process following a Gaussian distribution within each voxel and is thus an overly simplistic representation of tissue microstructure. Several more advanced models of diffusion are now available that may have greater utility in the understanding of the effects of epilepsy on tissue microstructure. In this review, I summarise the principles, applications in epilepsy and future potential of three such techniques. Diffusion kurtosis imaging (DKI) characterises the degree to which diffusion deviates from Gaussian behaviour and gives an idea of the underlying tissue complexity. It has been used in both focal and generalised epilepsy and seems more sensitive than DTI. Multi-compartment models separate the signal from extra- and intra-axonal compartments in each voxel. The Composite Hindered and Restricted Model of Diffusion (CHARMED) can characterise axonal density but has not yet been applied in patients with epilepsy. The Neurite Orientation Dispersion and Density Imaging (NODDI) model can determine the intracellular volume fraction (ICVF) and degree of dispersion of neurite orientation. Preliminary data suggest it may more sensitive than conventional and diffusion imaging in localising focal epilepsy.

Using the biophysical CHARMED model to elucidate the underpinnings of contrast in diffusional kurtosis analysis of diffusion-weighted MRI

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). 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. 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. 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.

A general framework for experiment design in diffusion MRI and its application in measuring direct tissue‐microstructure features

This article introduces a new and general framework for optimizing the experiment design for diffusion MRI of samples with unknown orientation. An illustration then uses the framework to study the feasibility of measuring direct features of brain-tissue microstructure in vivo. The study investigates the accuracy and precision with which we can estimate potentially important new biomarkers such as axon density and radius in white matter. Simulation experiments use a simple model of white matter based on CHARMED (composite hindered and restricted model of diffusion). The optimization finds acquisition protocols achievable on modern human and animal systems that consist of 120 measurements with fixed maximum gradient strengths. Axon radii in brain tissue are typically in the range 0.25-10 microm. Simulations suggest that estimates of radii in the range 5-10 microm have highest precision and that a maximum gradient strength of 0.07 T m(-1) is sufficient to distinguish radii of 5, 10, and 20 microm. Smaller radii are more difficult to distinguish from one another but are identifiable as small. A maximum gradient strength of 0.2 T m(-1) distinguishes radii of 1 and 2 microm. The simulations also suggest that axon densities and diffusivity parameters in the normal range for white matter are recoverable. The experiment-design optimization has applications well beyond the current work to optimize the protocol for fitting any model of the diffusion process.

AxCaliber: an MRI method to measure the diameter distribution and density of axons in neuronal tissue

and Density of Axons in Neuronal Tissue P.J. Basser, T. Blumenfeld , G. Levin, Y. Yovel, Y. Assaf, STBB/LIMB/NICHD, NIH; Department of Neurobiochemistry, Tel Aviv University Discussion The experimental determination of the diameter distribution, p(d), of emulsions and droplets has long been studied using NMR methods (see (1,2)). In these experiments, p(d) is estimated from PFG data by assuming a model of restricted diffusion within spheres. We have adapted this approach to estimate the diameter distribution within cylindrical nerve fascicles—a pack or array of nerve axons—by assuming that axons contain a restricted pool of water within their intracellular spaces. A composite hindered and restricted model of diffusion (CHARMED) within axons was first elaborated and tested in (3), and then applied clinically in (4).

Composite hindered and restricted model of diffusion (CHARMED) MR imaging of the human brain

High b value diffusion-weighted images sampled at high angular resolution were analyzed using a composite hindered and restricted model of diffusion (CHARMED). Measurements and simulations of diffusion in white matter using CHARMED provide an unbiased estimate of fiber orientation with consistently smaller angular uncertainty than when calculated using a DTI model or with a dual tensor model for any given signal-to-noise level. Images based on the population fraction of the restricted compartment provide a new contrast mechanism that enhances white matter like DTI. Nevertheless, it is assumed that these images might be more sensitive than DTI to white matter disorders. We also provide here an experimental design and analysis framework to implement CHARMED MRI that is feasible on human clinical scanners.