Extra-axonal contribution to double diffusion encoding-based pore size estimates in the corticospinal tract.

OBJECTIVE: To study the origin of compartment size overestimation in double diffusion encoding MRI (DDE) in vivo experiments in the human corticospinal tract. Here, the extracellular space is hypothesized to be the origin of the DDE signal. By exploiting the DDE sensitivity to pore shape, it could be possible to identify the origin of the measured signal. The signal difference between parallel and perpendicular diffusion gradient orientation can indicate if a compartment is regular or eccentric in shape. As extracellular space can be considered an eccentric compartment, a positive difference would mean a high contribution to the compartment size estimates. MATERIALS AND METHODS: Computer simulations using MISST and in vivo experiments in eight healthy volunteers were performed. DDE experiments using a double spin-echo preparation with eight perpendicular directions were measured in vivo. The difference between parallel and perpendicular gradient orientations was analyzed using a Wilcoxon signed-rank test and a Mann-Whitney U test. RESULTS: Simulations and MR experiments showed a statistically significant difference between parallel and perpendicular diffusion gradient orientation signals ([Formula: see text]). CONCLUSION: The results suggest that the DDE-based size estimate may be considerably influenced by the extra-axonal compartment. However, the experimental results are also consistent with purely intra-axonal contributions in combination with a large fiber orientation dispersion.

Conventions and nomenclature for double diffusion encoding NMR and MRI.

Stejskal and Tanner's ingenious pulsed field gradient design from 1965 has made diffusion NMR and MRI the mainstay of most studies seeking to resolve microstructural information in porous systems in general and biological systems in particular. Methods extending beyond Stejskal and Tanner's design, such as double diffusion encoding (DDE) NMR and MRI, may provide novel quantifiable metrics that are less easily inferred from conventional diffusion acquisitions. Despite the growing interest on the topic, the terminology for the pulse sequences, their parameters, and the metrics that can be derived from them remains inconsistent and disparate among groups active in DDE. Here, we present a consensus of those groups on terminology for DDE sequences and associated concepts. Furthermore, the regimes in which DDE metrics appear to provide microstructural information that cannot be achieved using more conventional counterparts (in a model-free fashion) are elucidated. We highlight in particular DDE's potential for determining microscopic diffusion anisotropy and microscopic fractional anisotropy, which offer metrics of microscopic features independent of orientation dispersion and thus provide information complementary to the standard, macroscopic, fractional anisotropy conventionally obtained by diffusion MR. Finally, we discuss future vistas and perspectives for DDE.

Bimodal Interventional Instrument Markers for Magnetic Particle Imaging and Magnetic Resonance Imaging-A Proof-of-Concept Study.

The purpose of this work was to develop instrument markers that are visible in both magnetic particle imaging (MPI) and magnetic resonance imaging (MRI). The instrument markers were based on two different magnetic nanoparticle types (synthesized in-house KLB and commercial Bayoxide E8706). Coatings containing one of both particle types were fabricated and measured with a magnetic particle spectrometer (MPS) to estimate their MPI performance. Coatings based on both particle types were then applied on a segment of a nonmetallic guidewire. Imaging experiments were conducted using a commercial, preclinical MPI scanner and a preclinical 1 tesla MRI system. MPI image reconstruction was performed based on system matrices measured with dried KLB and Bayoxide E8706 coatings. The bimodal markers were clearly visible in both methods. They caused circular signal voids in MRI and areas of high signal intensity in MPI. Both the signal voids as well as the areas of high signal intensity were larger than the real marker size. Images that were reconstructed with a Bayoxide E8706 system matrix did not show sufficient MPI signal. Instrument markers with bimodal visibility are essential for the perspective of monitoring cardiovascular interventions with MPI/MRI hybrid systems.

Towards compartment size estimation in vivo based on double wave vector diffusion weighting.

It has been shown that double wave vector diffusion weighting, which employs two gradient pulse pairs of independent directions, can provide information about tissue structure that is not easily available otherwise, such as cell size or shape in a tissue sample. One approach to measure cell size is based on the signal difference between parallel and antiparallel gradient orientations at small mixing times between the two diffusion weightings. A major difficulty for in vivo application is the small size of the signal difference if clinical MR systems with limited gradient hardware are employed. In this study, the method is applied to human brain tissue in vivo, using whole-body gradients. Data are reported for the corticospinal tracts. The characteristics of the observed signal difference between parallel and antiparallel gradient orientations are consistent with both analytical and numerical predictions. As an estimate of pore size, the resulting mean squared radius of gyration of the pores amounts to approximately 4 µm(2) . An analysis that accounts for the finite values of gradient pulse duration and diffusion time yields a volume contribution-weighted mean pore diameter of 13 µm if a cylindrical pore shape is assumed. The results demonstrate that the technique can be applied in vivo.

Numerical simulation of double-wave vector experiments investigating diffusion in randomly oriented ellipsoidal pores.

Double-wave vector diffusion weighting is expected to represent a possibility to acquire information on cell size and shape. In numerical simulations, a theoretical description of the double wave vector-weighted signal is tested in a situation where the approximating assumptions (infinitely short gradient pulses, infinitely long diffusion time, infinitely long or zero delay between diffusion weightings, small gradient moment) are not strictly met. It is shown how the dependence of the signal on the angle between the diffusion gradient directions changes upon varying the delay between the second and the third gradient pulse, and how the measures of pore geometry derived from signal differences between two angles depend on the duration, temporal separation, and amplitude of the gradient pulses. The results indicate that a violation of the approximation conditions due to finite gradient pulse duration and separation generally leads to an underestimation of pore size and pore eccentricity. It is also concluded from the simulations that for pore sizes on the order of 10 microm the investigated effects are in a range that is observable even with whole-body gradient systems.

A tensor model and measures of microscopic anisotropy for double-wave-vector diffusion-weighting experiments with long mixing times.

Experiments with two diffusion-weighting periods applied successively in a single experiment, so-called double-wave-vector (DWV) diffusion-weighting experiments, are a promising tool for the investigation of material or tissue structure on a microscopic level, e.g. to determine cell or compartment sizes or to detect pore or cell anisotropy. However, the theoretical descriptions presented so far for experiments that aim to investigate the microscopic anisotropy with a long mixing time between the two diffusion weightings, are limited to certain wave vector orientations, specific pore shapes, and macroscopically isotropic samples. Here, the signal equations for fully restricted diffusion are re-investigated in more detail. A general description of the signal behavior for arbitrary wave vector directions, pore or cell shapes, and orientation distributions of the pores or cells is obtained that involves a fourth-order tensor approach. From these equations, a rotationally invariant measure of the microscopic anisotropy, termed MA, is derived that yields information complementary to that of the (macroscopic) anisotropy measures of standard diffusion-tensor acquisitions. Furthermore, the detailed angular modulation for arbitrary cell shapes with an isotropic orientation distribution is derived. Numerical simulations of the MR signal with a Monte-Carlo algorithms confirm the theoretical considerations. The extended theoretical description and the introduction of a reliable measure of the microscopic anisotropy may help to improve the applicability and reliability of corresponding experiments.

A tensor approach to double wave vector diffusion-weighting experiments on restricted diffusion.

Previously, it has been shown theoretically that in case of restricted diffusion, e.g. within isolated pores or cells, a measure of the pore size, the mean radius of gyration, can be estimated from double wave vector diffusion-weighting experiments. However, these results are based on the assumption of an isotropic orientation distribution of the pores or cells which hampers the applicability to samples with anisotropic or unknown orientation distributions, such as biological tissue. Here, the theoretical considerations are re-investigated and generalized in order to describe the signal dependency for arbitrary orientation distributions. The second-order Taylor expansion of the signal delivers a symmetric rank-2 tensor with six independent elements if the two wave vectors are concatenated to a single six-element vector. With this tensor approach the signal behavior for arbitrary wave vectors and orientation distributions can be described as is demonstrated by numerical simulations. The rotationally invariant trace of the tensor represents a pore size measure and can be determined from three orthogonal directions with parallel and antiparallel orientation of the two wave vectors. Thus, the presented tensor approach may help to improve the applicability of double wave vector diffusion-weighting experiments to determine pore or cell sizes, in particular in biological tissue.

Compartment size estimation with double wave vector diffusion-weighted imaging.

Double wave vector diffusion weighting uses gradients along two different directions between excitation and acquisition. It has been shown theoretically that for restricted diffusion the signal amplitude in such an experiment can depend on the angle between the two gradient vectors. The highest amplitude is obtained with antiparallel orientation, and the amplitude difference between parallel and antiparallel gradient orientations depends on the compartment size. The validity of this description is experimentally tested for water between polymer beads, for radish, and for porcine spinal cord, using a clinical MR system with limited gradient strength. The results indicate that the phenomenon is observable; however, the size of the signal difference is considerably diminished when compared with theory. This is attributed to violations of the approximating conditions underlying the theoretical description and to free diffusion contributions. It is concluded that the effect could successfully be used as a basis for developing a new noninvasive method for assessing cell size.

The cortical motor threshold reflects microstructural properties of cerebral white matter.

Transcranial magnetic stimulation (TMS) can be used to probe distinct aspects of excitability of the primary motor hand area (M1(Hand)). The motor threshold (MT) reflects the trans-synaptic excitability of corticospinal output neurons. The MT corresponds to the minimal intensity at which TMS evokes a contralateral motor response. Here, we employed diffusion-weighted imaging (DWI) to examine whether inter-individual differences in MT of the left and right M1(Hand), an index of cortical excitability, are associated with variations in fractional anisotropy (FA), an index of white matter microstructure. Resting and active MT showed an inverse linear relationship with regional FA values in large bihemispheric clusters, including the white matter underlying primary motor, premotor and posterior prefrontal cortices, as well as the genu of the internal capsule, cerebral peduncles and corpus callosum. The linear increase in FA with cortical excitability as indexed by the MT remained significant after controlling for differences in handedness or coil-cortex distance. The posterior limb of the internal capsule, where fast-conducting corticospinal fibres from M1(Hand) pass through, showed only a weak linear relationship between FA and MT. The FA measurements show that a high level of corticospinal excitability is associated with a higher fibre coherence in large parts of cerebral white matter. The higher FA values in the white matter beneath premotor and motor cortices may reflect a structural property of cortico-cortical connections that renders M1(Hand) more susceptible to TMS-induced trans-synaptic excitation of the corticospinal fibres and may account for the inverse linear relationship between MT and FA.

A PLA/calcium phosphate degradable composite material for bone tissue engineering: an in vitro study.

Biodegradable polymers reinforced with an inorganic phase such as calcium phosphate glasses may be a promising approach to fulfil the challenging requirements presented by 3D porous scaffolds for tissue engineering. Scaffolds' success depends mainly on their biological behaviour. This work is aimed to the in vitro study of polylactic acid (PLA)/CaP glass 3D porous constructs for bone regeneration. The scaffolds were elaborated using two different techniques, namely solvent-casting and phase-separation. The effect of scaffolds' micro and macrostructure on the biological response of these scaffolds was assayed. Cell proliferation, differentiation and morphology within the scaffolds were studied. Furthermore, polymer/glass scaffolds were seeded under dynamic conditions in a custom-made perfusion bioreactor. Results indicate that the final architecture of the solvent-cast or phase separated scaffolds have a significant effect on cells' behaviour. Solvent-cast scaffolds seem to be the best candidates for bone tissue engineering. Besides, dynamic seeding yielded a higher seeding efficiency in comparison with the static method.

Gradient and stimulated echo (GRASTE) imaging.

As a modification of single-shot stimulated echo acquisition mode (STEAM) MRI, a gradient and stimulated echo (GRASTE) sequence is presented that acquires multiple gradient echoes in addition to each stimulated echo. While "contiguous" GRASTE exploits all stimulated echoes for the central part of k-space and the gradient echoes for outer lines, "interleaved" GRASTE assigns all echoes of a particular readout interval to directly neighboring lines. Phase distortions may be corrected by the reference signals of a single readout interval without phase encoding. Experimental results obtained for the human brain demonstrate that contiguous GRASTE yields up to 30% better SNR per acquisition time than conventional single-shot STEAM due to a better efficiency and maintains most of its robustness. Interleaved GRASTE can improve the SNR by a factor of 2 because of the possibility of using larger flip angles in the readout interval. However, its more pronounced sensitivity to off-resonance effects requires short echo trains.

An investigation of functional and anatomical connectivity using magnetic resonance imaging.

This article examines functional and anatomical connectivity in healthy human subjects measured with magnetic resonance imaging methods. Anatomical connectivity in white matter is obtained from measurements of the diffusion tensor. A Monte-Carlo simulation determines the probability that a particle diffuses between two points, with the probability of a jump in a particular direction from a given voxel being based on the local value of the diffusion tensor components. Functional connectivity between grey matter pixels is assessed without recourse to a specific activation paradigm, by calculating the correlation coefficient between random fluctuations in the blood oxygenation level-dependent signal time course in different pixels. The methods are used to examine the anatomical and functional connectivities between crowns of adjacent gyri. A high functional connectivity was found between grey matter pixels, with white matter displaying only very low correlation. A comparison of the measurements of anatomical and functional connectivity found that there is no simple correlation between these measures, except that low values of functional connectivity were not found together with high values of anatomical connectivity. Furthermore pairs of regions situated around the central sulcus indicated a dependence of the two connectivity measures on each other. These results are in accordance with an interpretation that regions which are clearly directly linked by white matter fiber tracts should show high functional connectivity, but that the inverse need not be true as functional connectivity may also be indirectly mediated via more distant grey matter regions.

Functional magnetic resonance imaging: a review of methodological aspects and clinical applications.

This paper gives an overview of the recent literature on methodological developments of functional magnetic resonance imaging (fMRI) and recent trends in clinical applications. With the recent introduction of high-field systems and methodological developments leading to more robust signal behavior, fMRI is in a transition state from a research modality for use by experts to a standard procedure with useful applications in patient management. Compared to the use in neuroscientific research, which is often based on BOLD techniques alone, the application in patients is distinguished by a multiparametric characterization of the brain using a combination of several techniques. Neuronal fiber tracking based on diffusion anisotropy measurements, in particular, has already turned out to provide relevant supplementary information to the BOLD-based cortical activation maps.

Diffusion tensor imaging detects early Wallerian degeneration of the pyramidal tract after ischemic stroke.

We used diffusion tensor imaging (DTI) to assess Wallerian degeneration of the pyramidal tract within the first 2 weeks after ischemic stroke, and correlated the extent of Wallerian degeneration with the motor deficit. Nine patients with middle cerebral artery stroke were examined 2-16 days after stroke by DTI and T2-weighted MRI. We measured fractional anisotropy (FA), averaged diffusivity (Dav), eigenvalues of the diffusion tensor and T2-weighted signal in the cerebral peduncle and compared these values between the affected and the unaffected side and between patients and six controls. FA was significantly reduced on the affected side compared to the unaffected side and compared to the control group. The largest eigenvalue was reduced, whereas the smallest eigenvalue was elevated on the affected side. There was no significant difference in T2-weighted signal and Dav. The decrease of anisotropy correlated positively with the motor deficit at the time of DTI study and 90 days after stroke. The reduction of anisotropy mirrors the disintegration of axonal structures, as it occurs in the early phase of Wallerian degeneration. DTI detects changes of water diffusion related to beginning pyramidal tract degeneration within the first 2 weeks after stroke that are not yet visible in conventional T2-weighted or orientationally averaged diffusion weighted MRI. We demonstrated for the first time a correlation of early DTI findings of pyramidal tract damage with the motor deficit. DTI can help prognosing recovery of motor function after stroke within the early subacute phase.

Disconnection of speech-relevant brain areas in persistent developmental stuttering.

BACKGROUND: The neuronal basis of persistent developmental stuttering is unknown. The disorder could be related to a reduced left hemisphere dominance, which functional neuroimaging data suggest might lead to right hemispheric motor and premotor overactivation. Alternatively, the core deficit underlying stuttering might be located in the speech-dominant left hemisphere. Furthermore, magnetoencephalography study results show profound timing disturbances between areas involved in language preparation and execution in the left hemisphere, suggesting that persistent developmental stuttering might be related to impaired neuronal communication, possibly caused by a disruption of white matter fibre tracts. We aimed to establish whether disconnection between speech-related cortical areas was the structural basis of persistent developmental stuttering. METHODS: We analysed the speech of 15 people with persistent developmental stuttering and 15 closely matched controls for the percentage of syllables stuttered. We used diffusion tensor imaging to assess participants' brain tissue structure, and used and two-sample t test to compare diffusion characteristics between groups. FINDINGS: Diffusion characteristics of the group with persistent developmental stuttering and controls differed significantly immediately below the laryngeal and tongue representation in the left sensorimotor cortex (mean difference in fractional anisotropy 0.04 [95% CI 0.03-0.05]). INTERPRETATION: Our findings show that persistent developmental stuttering results from disturbed timing of activation in speech-relevant brain areas, and suggest that right hemisphere overactivation merely reflects a compensatory mechanism, analogous to right hemisphere activation in aphasia.

Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative system disorder affecting both upper and lower motor neurons. Despite supportive electrophysiological investigations, the involvement of the upper motor neuron is often difficult to assess at an early stage of disease. Diffusion tensor MRI provides an estimate of the orientation of fibre bundles in white matter on the basis of the diffusion characteristics of water. Diffusivity is generally higher in directions along fibre tracts than perpendicular to them. This degree of directionality of diffusion can be measured as fractional anisotropy. Changes in tissue structure due to degeneration of the corticospinal fibres can lead to a modification of the degree of directionality which can be detected by diffusion tensor MRI. We investigated 15 patients with ALS, six of whom had no clinical signs of upper motor neuron involvement at the time of MRI investigation, but developed pyramidal tract symptoms later in the course of their disease. These patients met the El Escorial criteria as their disease progressed. We found a decrease in fractional anisotropy in the corticospinal tract, corpus callosum and thalamus in all 15 ALS patients, including the patients without clinical signs of upper motor neuron lesion, compared with healthy controls. Regression analysis showed a negative correlation between fractional anisotropy and central motor conduction time obtained by transcranial magnetic stimulation, allowing spatial differentiation between the degenerated corticospinal tract fibres that supply the upper and lower extremities. Thus, diffusion tensor MRI can be used to assess upper motor neuron involvement in ALS patients before clinical symptoms of corticospinal tract lesion become apparent, and it may therefore contribute to earlier diagnosis of motor neuron disease.