Alterations in diffusion properties of white matter in Williams syndrome

Diffusion tensor imaging (DTI) was used to investigate the involvement of brain white matter in Williams syndrome (WS), a genetic neurodevelopmental disorder. Whole-brain DTIs were obtained from 16 young adults with WS and 16 normal controls. A voxel-based analysis was performed to compare fractional anisotropy (FA) values between the two groups. A tract-based analysis was also performed to compare FA values between the two groups along two major white matter tracts that pass through the external capsule: the uncinate and inferior fronto-occipital fasciculi. Several regions of both increased and decreased FA were found within major white matter tracts that connect functional regions that have previously been implicated in the cognitive and neurological symptoms of the syndrome. The tract-based analysis provided additional insight into the involvement of specific white matter tracts implicated in the voxel-based analysis within the external capsule. The results from this study support previously reported changes in white matter diffusion properties in WS and demonstrate the potential usefulness for tract-based analysis in future studies of the disorder.     

Intersubject variability in the analysis of diffusion tensor images at the group level: fractional anisotropy mapping and fiber tracking techniques

Introduction

Diffusion tensor imaging (DTI) provides comprehensive information about quantitative diffusion and connectivity in the human brain. Transformation into stereotactic standard space is a prerequisite for group studies and requires thorough data processing to preserve directional inter-dependencies. The objective of the present study was to optimize technical approaches for this preservation of quantitative and directional information during spatial normalization in data analyses at the group level.

Methods

Different averaging methods for mean diffusion-weighted images containing DTI information were compared, i.e., region of interest-based fractional anisotropy (FA) mapping, fiber tracking (FT) and corresponding tractwise FA statistics (TFAS). The novel technique of intersubject FT that takes into account directional information of single data sets during the FT process was compared to standard FT techniques. Application of the methods was shown in the comparison of normal subjects and subjects with defined white matter pathology (alterations of the corpus callosum).

Results

Fiber tracking was applied to averaged data sets and showed similar results compared with FT on single subject data. The application of TFAS to averaged data showed averaged FA values around 0.4 for normal controls. The values were in the range of the standard deviation for averaged FA values for TFAS applied to single subject data. These results were independent of the applied averaging technique. A significant reduction of the averaged FA values was found in comparison to TFAS applied to data from subjects with defined white matter pathology (FA around 0.2).

Conclusion

The applicability of FT techniques in the analysis of different subjects at the group level was demonstrated. Group comparisons as well as FT on group averaged data were shown to be feasible. The objective of this work was to identify the most appropriate method for intersubject averaging and group comparison which incorporates intersubject variability of the directional information.     

Analyzing diffusion tensor images with ghosting artifacts: the effects of direct and indirect normalization

The current study aims to assess the applicability of direct or indirect normalization for the analysis of fractional anisotropy (FA) maps in the context of diffusion-weighted images (DWIs) contaminated by ghosting artifacts. We found that FA maps acquired by direct normalization showed generally higher anisotropy than indirect normalization, and the disparities were aggravated by the presence of ghosting artifacts in DWIs. The voxel-wise statistical comparisons demonstrated that indirect normalization reduced the influence of artifacts and enhanced the sensitivity of detecting anisotropy differences between groups. This suggested that images contaminated with ghosting artifacts can be sensibly analyzed using indirect normalization.     

Evaluation of diffusion models of fiber tracts using diffusion tensor magnetic resonance imaging

Modeling of water diffusion in white matter is useful for revealing microstructure of the brain tissue and hence diagnosis and evaluation of white matter diseases. Researchers have modeled diffusion in white matter using mathematical and mechanical analysis at the cellular level. However, less work has been devoted to evaluate these models using macroscopic real data such as diffusion tensor magnetic resonance imaging (DTMRI) data. DTMRI is a noninvasive tool for evaluating white matter microstructure by measuring random motion of water molecules referred to as diffusion. It reflects directional information of microscopic structures such as fibers. Thus, it is applicable for evaluation and modification of mathematical models of white matter. Nevertheless, a realistic relation between a fiber model and imaging data does not exist. This work opens a promising avenue for relating DTMRI data to microstructural parameters of white matter. First, we propose a strategy for relating DTMRI and fiber model parameters to evaluate mathematical models in light of real data. The proposed strategy is then applied to evaluate and extend an existing model of white matter based on clinically available DTMRI data. Next, the proposed strategy is used to estimate microstructural characteristics of fiber tracts. We illustrate this approach through its application to approximation of myelin sheath thickness and fraction of volume occupied by fibers. Using sufficiently small imaging voxels, the proposed approach is capable of estimating model parameters with desirable precision.     

Aging effects on cerebral asymmetry: a voxel-based morphometry and diffusion tensor imaging study

The hemispheres of the human brain are functionally and structurally asymmetric. The purpose of this study was to evaluate the effects of aging on gray and white matter asymmetry. Two hundred twenty-six right-handed normal volunteers aged 21–71 years were included in this study. The effects of aging on gray matter volume asymmetry and white matter fractional anisotropy asymmetry were evaluated with use of voxel-based morphometry and voxel-based analysis of fractional anisotropy maps derived from diffusion tensor imaging (DTI), respectively. The voxel-based morphometry showed no significant correlation between age and gray matter volume asymmetry. The voxel-based analysis of DTI also showed no significant correlation between age and white matter fractional anisotropy asymmetry. Our results showed no significant effects of aging on either gray matter volume asymmetry or white matter fractional anisotropy asymmetry.     

Principal eigenvector field segmentation for reproducible diffusion tensor tractography of white matter structures

The study was aimed to test the feasibility of utilizing an algorithmically determinable stable fiber mass (SFM) map obtained by an unsupervised principal eigenvector field segmentation (PEVFS) for automatic delineation of 18 white matter (WM) tracts: (1) corpus callosum (CC), (2) tapetum (TP), (3) inferior longitudinal fasciculus (ILF), (4) uncinate fasciculus (UNC), (5) inferior fronto-occipital fasciculus (IFO), (6) optic pathways (OP), (7) superior longitudinal fasciculus (SLF), (8) arcuate fasciculus (AF), (9) fornix (FX), (10) cingulum (CG), (11) anterior thalamic radiation (ATR), (12) superior thalamic radiation (STR), (13) posterior thalamic radiation (PTR), (14) corticospinal/corticopontine tract (CST/CPT), (15) medial lemniscus (ML), (16) superior cerebellar peduncle (SCP), (17) middle cerebellar peduncle (MCP) and (18) inferior cerebellar peduncle (ICP). Diffusion tensor imaging (DTI)-derived fractional anisotropy (FA) and the principal eigenvector field have been used to create the SFM consisting of a collection of linear voxel structures which are grouped together by color-coding them into seven natural classes to provide PEVFS signature segments which greatly facilitate the selection of regions of interest (ROIs) for fiber tractography using just a single mouse click, as compared with a manual drawing of ROIs in the classical approach. All the 18 fiber bundles have been successfully reconstructed, in all the subjects, using the single ROIs provided by the SFM approach, with their reproducibility characterized by the fact that the ROI selection is user independent. The essentially automatic PEVFS method is robust, efficient and compares favorably with the classical ROI methods for diffusion tensor tractography (DTT).     

Validation of the anisotropy index ellipsoidal area ratio in diffusion tensor imaging

A new diffusion anisotropy index, ellipsoidal area ratio (EAR), was described recently and proved to be less noise-sensitive than fractional anisotropy (FA) by theory and simulation. Here we show that EAR has higher signal-to-noise ratios than FA in average diffusion tensor imaging data from 40 normal subjects. EAR was also more sensitive than FA in detecting white matter abnormalities in a patient with widespread diffuse axonal injury. Monte Carlo simulation showed that EAR's mean values are more biased by noise than FA when anisotropy is small, both for single fiber tracts and when fiber tracts cross. However, the improved signal-to-noise ratio of EAR relative to FA suggests that EAR may be a superior measure of anisotropy both in quantifying both deep white matter with relatively uniform fiber tracts and pericortical white matter structure with relatively low anisotropy and fiber crossings.     

Diffusion properties of cortical and pericortical tissue: regional variations, reliability and methodological issues

Characterizing the diffusion properties of cortical tissue is complicated by intersubject variability in the relative locations of gyri and sulci. Here we extend methods of measuring the average diffusion properties of gyral and sulcal structures after they have been aligned to a common template of cortical surface anatomy. Diffusion tensor image (DTI) data were gathered from 82 young subjects and co-registered with high-resolution T1 images that had been inflated and co-registered to a hemispherically unified spherical coordinate system based on FreeSurfer. We analyzed fractional anisotropy (FA), mean diffusivity (MD) and the novel quantity of cortical primary diffusion direction (cPDD) at five surfaces parallel to the white/gray junction, spanning approximately 5 mm from the pial surface into white matter. FA increased with increasing depth, whereas MD and cPDD were reduced. There were highly significant and reliable regional differences in FA, MD and cPDD as well as systematic differences between cortical lobes and between the two hemispheres. The influence of nearby cortical spinal fluid (CSF), local cortical curvature and thickness, and sulcal depth was also investigated. We found that FA correlated significantly with cortical curvature and sulcal depth, while MD was strongly influenced by nearby CSF. The measurement of FA, MD and cPDD near the cortical surface clarifies the organization of fiber projections to and from the cortex.     

Correlation of CSF neuroinflammatory molecules with leptomeningeal cortical subcortical white matter fractional anisotropy in neonatal meningitis

It has been previously hypothesized that the high fractional anisotropy (FA) values in leptomeningeal cortical subcortical white matter (LCSWM) regions of neonatal brain with bacterial meningitis is due to the presence of adhesion molecules in the subarachnoid space, which are responsible for adherence of inflammatory cells over the subarachnoid membrane. The aim of this study was to look for any relationship between FA values in LCSWM regions and various neuroinflammatory molecules (NMs) in cerebrospinal fluid (CSF) measured in neonates with bacterial meningitis. Diffusion tensor imaging was performed on 18 term neonates (median age, 10.5 days) having bacterial meningitis and 10 age-/sex-matched healthy controls. CSF enzyme-linked immunosorbent assay was performed to quantify NMs [soluble intracellular adhesion molecules (sICAM), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta)]. Significantly increased FA values were observed in LCSWM regions of the patients compared to controls. A significant positive correlation was observed between FA values in LCSWM regions and NMs [sICAM (r=0.67, P=.006), TNF-alpha (r=0.69, P=.005) and IL-1beta (r=0.82, P=.000)] in CSF of these patients. No difference in FA values (P=.99) in LCSWM regions was observed between patients with sterile (0.12+/-0.02) and culture-positive CSF study (0.12+/-0.02). FA may be used as noninvasive surrogate marker of NMs in neonatal meningitis in assessing therapeutic response in future.     

Moderating registration misalignment in voxelwise comparisons of DTI data: a performance evaluation of skeleton projection

An evaluative methodology and five accompanying performance measures were developed to quantitatively assess the performance of the skeleton projection algorithm constituting the heart of tract-based spatial statistics (TBSS). The performance measures were designed to quantify the accuracy of skeleton projection in its indented task of alleviating any residual misalignment that may remain after image registration. A ground truth fractional anisotropy (FA) image was slightly warped using a realistic warp field that served to model post-registration residual misalignment of varying magnitudes. Skeleton projection was then used to register the warped FA image to the ground truth. Performing skeleton projection was found to yield up to 50% better correspondence between the values of FA compared to smoothing, despite the fact that less than 10% of post-registration misalignment was corrected. The align-max-with-max strategy underlying TBSS was posited as a potential explanation for this high correspondence in the values of FA, at the expense of lesser alignment between anatomically concordant voxels.     

Removal of partial volume averaging with free water in MR diffusion tensor imaging using inversion recovery for b0 image

Purpose

To remove the partial volume averaging effect of free water in MR diffusion imaging of neural tissues by use of the fluid attenuated inversion recovery (FLAIR) without the penalty of an extended scan time.

Materials and methods

The magnetic resonance images were obtained from a normal volunteer in a coronal slice orientation at 3 T with the 20-channel rf coil. In diffusion imaging only the b0 images were obtained with the FLAIR contrast while the diffusion weighted images were obtained without the FLAIR contrast. A composition of FLAIR b0 and non-FLAIR diffusion weighted images was used in calculating the diffusion tensor and fractional anisotropy after compensating the reduced signal amplitude due to the inversion recovery in the FLAIR b0 images. The fractional anisotropy of the non-FLAIR, FLAIR, and the composite methods were analyzed for the mean and histogram in the corpus callosum, cervical spine, and the fornix tracts.

Results

The partial volume averaging effect was observed in the corpus callosum, the cervical spine, and the fornix tracts in the non-FLAIR b0 and diffusion images. The partial volume averaging effect was removed in the FLAIR diffusion images which took more than twice the scan time than the non-FLAIR diffusion imaging. The proposed composite FLAIR diffusion imaging removed the partial volume averaging effect as in the FLAIR diffusion imaging. The distribution of the FA histogram was very different between the non-FLAIR and FLAIR diffusion images, while it was very similar between the FLAIR and the composite FLAIR after correcting the white matter signal in the FLAIR b0 images.

Conclusions

The proposed composite FLAIR diffusion imaging method was equally effective in removing the partial volume averaging effect as the FLAIR diffusion imaging at a limited increase of the scan time since only a small number of b0 images needed to be obtained with the FLAIR contrast.     

The ellipsoidal area ratio: an alternative anisotropy index for diffusion tensor imaging

In the processing and analysis of diffusion tensor imaging (DTI) data, certain predefined morphological features of diffusion tensors are often represented as simplified scalar indices, termed diffusion anisotropy indices (DAIs). When comparing tensor morphologies across differing voxels of an image, or across corresponding voxels in different images, DAIs are mathematically and statistically more tractable than are the full tensors, which are probabilistic ellipsoids consisting of three orthogonal vectors that each has a direction and an associated scalar magnitude. We have developed a new DAI, the "ellipsoidal area ratio" (EAR), to represent the degree of anisotropy in the morphological features of a diffusion tensor. The EAR is a normalized geometrical measure of surface curvature in the 3D diffusion ellipsoid. Monte Carlo simulations and applications to the study of in vivo human data demonstrate that, at low noise levels, EAR provides a similar contrast-to-noise ratio (CNR) but a higher signal-to-noise ratio (SNR) than does fractional anisotropy (FA), which is currently the most popular anisotropy index in active use. Moreover, at the high noise levels encountered most commonly in real-world DTI datasets, EAR compared with FA is consistently much more robust to perturbations from noise and it provides a higher CNR, features useful for the analysis of DTI data that are inherently noise sensitive.     

Role of diffusion tensor imaging metrics and in vivo proton magnetic resonance spectroscopy in the differential diagnosis of cystic intracranial mass lesions

The purpose of this study was to determine whether proton magnetic resonance spectroscopy (PMRS) and diffusion tensor imaging (DTI) indices, fractional anisotropy (FA) and mean diffusivity (MD) can be used to distinguish brain abscess from cystic brain tumors, which are difficult to distinguish by conventional magnetic resonance imaging (MRI). Fifty-three patients with intracranial cystic mass lesions and 10 normal controls were studied. Conventional MRI, PMRS and DTI of all the patients were performed on a 1.5-T GE scanner. Forty patients were with brain abscess and 13 with cystic tumors. Cytosolic amino acids (AAs) were present in 32 of 40 brain abscess patients. Out of 13 patients with cystic tumors, lactate and choline were seen in 3 and only lactate was present in 10 patients on PMRS. All 40 cases of abscess had high FA, while all 13 cases of tumor cysts had high MD values. We conclude that FA measurements are more sensitive in predicting the abscess, while PMRS and MD are more specific in differentiating abscess from cystic tumors. We suggest that PMRS should be combined with DTI rather than with diffusion-weighted imaging as FA can be used as an additional parameter for separation of abscess from other cystic intracranial mass lesions.     

Elevations of diffusion anisotropy are associated with hyper-acute stroke: a serial imaging study

Diffusion tensor imaging (DTI) studies of human ischemic stroke within 24 h of symptom onset have reported variable findings of changes in diffusion anisotropy. Serial DTI within 24 h may clarify these heterogeneous results. We characterized longitudinal changes of diffusion anisotropy by analyzing discrete ischemic white matter (WM) and gray matter (GM) regions during the hyperacute (2.5-7 h) and acute (21.5-29 h) scanning phases of ischemic stroke onset in 13 patients. Mean diffusivity (MD), fractional anisotropy (FA) and T2-weighted signal intensity were measured for deep and subcortical WM and deep and cortical GM areas in lesions outlined by a > or =30% decrease in MD. Average reductions of approximately 40% in relative (r) MD were observed in all four brain regions during both the hyperacute and acute phases post stroke. Overall, 9 of 13 patients within 7 h post symptom onset showed elevated FA in at least one of the four tissues, and within the same cohort, 11 of 13 patients showed reduced FA in at least one of the ischemic WM and GM regions at 21.5-29 h after stroke. The fractional anisotropy in the lesion relative to the contralateral side (rFA, mean+/-S.D.) was significantly elevated in some patients in the deep WM (1.10+/-0.11, n=4), subcortical WM (1.13+/-0.14, n=4), deep GM (1.07+/-0.06, n=1) and cortical GM (1.22+/-0.13, n=5) hyperacutely (< or =7 h); however, reductions of rFA at approximately 24 h post stroke were more consistent (rFA= 0.85+/-0.12).     

Influence of steady background gradients on the accuracy of molecular diffusion anisotropy measurements

Spatial susceptibility variations of body components lead to local gradients of the static magnetic field. Effects of such background gradients on fractional diffusion anisotropy (FA) measurements on whole-body magnetic resonance units operating at 1.5, 3.0 and 7.0 T were analyzed theoretically and experimentally. Analytical expressions were derived for the cases of diffusion occurring in isotropic media and in tissues with cylindrical symmetry (e.g., white matter tracts or skeletal musculature). Typical magnitudes of background gradient strengths were estimated from in vivo and in vitro measurements with B0 field mapping sequences. Additionally, numerical simulations of magnetic field distributions and resulting field gradients were performed considering tissue-air interfaces in simplified geometrical arrangements. For media with isotropic diffusion, both measurements and analytical calculations showed increasing FA inaccuracy with stronger coupling between diffusion-encoding and background gradients. For cylindrical symmetry, FA values were estimated for a standard diffusion tensor imaging protocol in a realistic scenario. At 1 mm distance from a water-air interface, susceptibility-related background gradients amount to approximately 9 mT/m at 7 T and lead to a relative error of the measured FA of up to 48%. The error in the anisotropy assessment rises considerably with increasing field strength and must be taken into account especially for experimental and clinical studies on modern high-field systems.     

Understanding changes in DTI metrics in patients with different stages of neurocysticercosis

Diffusion tensor imaging (DTI) was performed on 25 patients with neurocysticercosis (NCC). The aim of this study was to investigate the changes in DTI measures during the evolutionary course of NCC lesions from vesicular to calcified stage in the brain. DTI measures were quantified from the NCC lesions of all patients. On the basis of conventional imaging findings, NCC lesions were classified into vesicular, vesicular colloidal, granular nodular and calcified stages. Significant inverse correlation was observed between the evolutionary stage of NCC lesion and mean diffusivity (MD; r=−0.748, P<0.001) and spherical anisotropy (CS; r=−0.585, P<.001) values. Significant direct correlations were observed between evolutionary stages of NCC lesion and mean fractional anisotropy (FA; r=0.575, P<0.001), linear anisotropy (CL; r=0.478, p<0.001) and planar anisotropy (CP; r=0.561, p<0.001) values. Successive decrease in MD values calculated from NCC lesions was observed, moving from vesicular to granular nodular stage. On FA, CL and CP maps, a significant increase in signal intensity value was observed in calcified as compared to other stages. We conclude that DTI measures may indicate the evolutionary changes in NCC from vesicular to calcified stage.     

Reproducibility and biases in high field brain diffusion MRI: An evaluation of acquisition and analysis variables

Diffusion tensor imaging (DTI) of in-vivo human brain provides insights into white matter anatomical connectivity, but little is known about measurement difference biases and reliability of data obtained with last generation high field scanners (> 3 T) as function of MRI acquisition and analyses variables. Here we assess the impact of acquisition (voxel size: 1.8 × 1.8 × 1.8, 2 × 2 × 2 and 2.5 × 2.5 × 2.5 mm³, b-value: 700, 1000 and 1300 s/mm²) and analysis variables (within-session averaging and co-registration methods) on biases and test-retest reproducibility of some common tensor derived quantities like fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivity in a group of healthy subjects at 4 T in three regions: arcuate fasciculus, corpus callosum and cingulum. Averaging effects are also evaluated on a full-brain voxel based approach. The main results are: i) group FA and MD reproducibility errors across scan sessions are on average double of those found in within-session repetitions (≈ 1.3 %), regardless of acquisition protocol and region; ii) within-session averaging of two DTI acquisitions does not improve reproducibility of any of the quantities across sessions at the group level, regardless of acquisition protocol; iii) increasing voxel size biased MD, axial and radial diffusivities to higher values and FA to lower values; iv) increasing b-value biased all quantities to lower values, axial diffusivity showing the strongest effects; v) the two co-registration methods evaluated gave similar bias and reproducibility results. Altogether these results show that reproducibility of FA and MD is comparable to that found at lower fields, not significantly dependent on pre-processing and acquisition protocol manipulations, but that the specific choice of acquisition parameters can significantly bias the group measures of FA, MD, axial and radial diffusivities.     

Quantitative assessment of motion correction for high angular resolution diffusion imaging

Several methods have been proposed for motion correction of high angular resolution diffusion imaging (HARDI) data. There have been few comparisons of these methods, partly due to a lack of quantitative metrics of performance. We compare two motion correction strategies using two figures of merit: displacement introduced by the motion correction and the 95% confidence interval of the cone of uncertainty of voxels with prolate tensors. What follows is a general approach for assessing motion correction of HARDI data that may have broad application for quality assurance and optimization of postprocessing protocols. Our analysis demonstrates two important issues related to motion correction of HARDI data: (1) although neither method we tested was dramatically superior in performance, both were dramatically better than performing no motion correction, and (2) iteration of motion correction can improve the final results. Based on the results demonstrated here, iterative motion correction is strongly recommended for HARDI acquisitions.     

Dependence of the fractional anisotropy in cervical spine from the number of diffusion gradients,repeated acquisition and voxel size

The aim of this study is to investigate the consequences of using different gradient schemes, number of repeated measurements and voxel size on the fractional anisotropy (FA) value in a diffusion tensor imaging (DTI) sequence on the cervical tract of the spinal cord. Twenty healthy volunteers underwent a total of 86 DTI axial acquisitions performed by using different voxel size and number of diffusion gradient directions (NDGDs). Three different diffusion gradient schemes were applied, named 6, 15 and 32 according to the NDGD. Furthermore, some acquisitions were repeated to investigate the effects of image averaging on FA value.