Exploratory voxel-based analysis of diffusion indices and hemispheric asymmetry in normal aging

Age-related microstructural changes in brain white matter can be studied by utilizing indices derived from diffusion tensor imaging (DTI): apparent diffusion coefficient (ADC) and fractional anisotropy (FA). The objective of this study is to examine alterations in FA and ADC by employing exploratory voxel-based analysis (VBA) and region(s) of interest (ROI)-based analysis. A highly nonlinear registration algorithm was used to align the ADC and FA image volumes of different subjects to perform accurate voxel-level statistics for two age groups, as well as for hemispheric asymmetry for both age groups. VBA shows significant age-related decline in FA with frontal predominance (frontal white matter, and genu and anterior body of the corpus callosum), superior portions of a splenium and highly oriented fibers of the posterior limb of the internal capsule and the anterior and posterior limbs of the external capsule. Hemispheric asymmetry of FA, as assessed by VBA, showed that for the young-age group, significant right-greater-than-left asymmetry exists in the genu, splenium and body of the corpus callosum and that left-greater-than-right asymmetry exists in the anterior limb of the external capsule and in the posterior limb of the internal capsule, thalamus, cerebral peduncle and temporal-parietal regions. VBA of the hemispheric asymmetry of the middle-age group revealed much less asymmetry. Regions showing age-related changes and hemispheric asymmetry from VBA were, for a majority of the findings, in conformance with ROI analysis and with the known pattern of development and age-related degradation of fiber tracks. The study shows the feasibility of the VBA of DTI indices for exploratory investigations of subtle differences in population cohorts, especially when findings are not localized and/or known a priori.     

An in vivo evaluation of the effects of local magnetic susceptibility-induced gradients on water diffusion measurements in human brain.

The effect of possible susceptibility-induced gradients on measurements of water diffusion along the transverse and longitudinal axes of white matter fibers in the brain was investigated in vivo at 1.5 T. Measurements obtained with sequences sensitive and insensitive, respectively, to susceptibility-induced gradients indicated that these gradients do not contribute significantly to diffusion anisotropy in brain white matter. Furthermore, diffusion measurements were unaffected by the presence of known susceptibility-induced gradients at the interface between the petrous bone and brain parenchyma. These results agree with those obtained on in vitro samples and appear to support the hypothesis that interactions between the diffusing water molecules and the cellular environment constitute the principal mechanism for diffusion anisotropy in brain white matter at 1.5 T. This, in turn, simplifies the interpretation of diffusion time-dependent measurements in terms of membrane separation and permeability.     

Comparison of multiple sclerosis clinical subgroups using navigated spin echo diffusion-weighted imaging.

The apparent diffusion coefficient (ADC) of tissue provides an indication of the size, shape, and orientation of the water spaces in tissue. Thus, pathologic differences between lesions in multiple sclerosis (MS) patients with different clinical courses may be reflected by changes in ADC measurements in lesions and white matter. Twelve healthy subjects and 35 MS patients with a relapsing-remitting (n = 10), benign (n = 8), secondary progressive (n = 8) and primary progressive (n = 9) clinical course were studied. T2-weighted and post-gadolinium T1-weighted images were obtained using a 1.5 T Signa Echospeed magnetic resonance imaging (MRI) system. Diffusion-weighted imaging was implemented using a pulsed gradient spin echo (PGSE) sequence with diffusion gradients applied in turn along three orthogonal directions in order to obtain the average apparent diffusion coefficient (ADCav). Navigator echo correction and cardiac gating were used to reduce motion artifact. ADC maps were derived using a two point calculation based on the Stejskal-Tanner formula. Diffusion anisotropy was estimated using the van Gelderen formula to calculate an anisotropy index. MS lesions had a higher ADC and reduced anisotropy compared with normal appearing white matter. Highest ADC values were found in gadolinium enhancing lesions and non-enhancing hypointense lesions on T1-weighted imaging. MS white matter had a slightly higher ADC and lower anisotropy than white matter of healthy subjects. Lesion and white matter ADC values did not differ between patients with different clinical courses of MS. There was no correlation between lesion ADC and disability. Diffusion-weighted imaging with measurement of ADC using the PGSE method provides quantitative information on acute edematous MS lesions and chronic lesions associated with demyelination and axonal loss but does not distinguish between clinical subtypes of MS.     

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 tensor MRI in temporal lobe epilepsy

The purpose of this study was to investigate the diffusion characteristics of white matter in patients with focal temporal lobe epilepsy (TLE). Diffusion tensor imaging (DTI) was applied to patients and normal controls. Rotationally invariant mean diffusivity and diffusion anisotropy maps were calculated for all subjects. Comparisons between the two groups were performed for several white matter structures. Mean diffusivity and diffusion anisotropy of each selected structure were tested for correlations with age at onset and duration of epilepsy. Significantly lower diffusion anisotropy, and higher diffusivity in directions perpendicular to the axons, was detected in several white matter structures of the patients when compared to the controls. These structures were not located in the temporal lobes. No significant difference in mean diffusivity was detected between the selected structures from the two groups. Diffusion anisotropy was significantly correlated with age at onset of epilepsy in the posterior corpus callosum. Duration of epilepsy was not significantly correlated with the diffusion indices from any of the selected structures. The results of this study suggest that diffusion anisotropy may reveal abnormalities in patients with focal TLE. In addition, these abnormal changes are not necessarily restricted to the temporal lobes but might extend in other brain regions as well. Furthermore, the age at onset of epilepsy may be an important factor in determining the extent of the effect of epilepsy on white matter.     

Study of pediatric brain development using magnetic resonance imaging of anisotropic diffusion

The properties of water diffusion in human brain tissue can be characterized by diffusion tensors computed from diffusion weighted magnetic resonance images. Since these properties are strongly determined by the structural and geometrical characteristics of the tissue, the maturation process of white matter and gray matter tissue can be expected to be reflected in these images and derived tensor quantities. The purpose of this work was therefore to study the development of pediatric brain in terms of changes occurring in the observed diffusion behavior. Echo planar diffusion tensor imaging was performed on 22 (10 females and 12 males) full term newborn and infant patients, diagnosed in retrospect as neurologically healthy. The subjects were subdivided in three age categories. A number of quantities based on the diffusion images were calculated for each tissue type and age category, and the ability of these quantities to provide sensitive and consistent information about the tissue differences and evolution was evaluated. The results clearly illustrate that the rotationally invariant quantities (e.g., the highest diffusivity, anisotropy ratio and volume ratio) are superior to the rotationally variant ones (e.g., ADCs measured along the three axes of the magnet) often used in the clinic. On the basis of the anisotropy ratio and the volume ratio indices, a correlation between the white matter maturation and the evolution of the diffusion anisotropy could be established. The same quantities did not exhibit any age dependence for the gray matter tissues.     

High b-value q-space diffusion MRI in myelin-deficient rat spinal cords

In this study, we explore the effect of the lack of myelin on the diffusion characteristics and diffusion anisotropy obtained from high b-value q-space diffusion-weighted MRI (q-space DWI) in excised rat spinal cords. Twenty-one-day-old myelin-deficient (md) mutant (N=6) and control rats (N=6) were used in this study. The MRI protocol included multi-slice T(1), T(2), proton density (PD) MR images and high b-value q-space diffusion MRI measured perpendicular and parallel to the fibers of the spine. q-Space displacement and probability maps, in both directions, as well as displacement anisotropy maps, were computed from the diffusion data. At the end of the MRI protocol, representative spinal cords from both groups were subjected to electron microscopy (EM). The md spinal cords show different gray/white matter contrast in the T(1), T(2) and PD MR images as compared with controls. In addition, the mean displacement extracted from the high b-value q-space diffusion data was found to be dramatically higher in the white matter (WM) of the md spinal cords than the controls when diffusion was measured perpendicular and parallel to the fibers of the spine. However, interestingly, at the diffusion time used in the present study, the difference in the WM displacement anisotropies of the two groups was not found to be statistically significant. Myelin was found to have a pronounced effect on the diffusion characteristics of water in WM but less so on the diffusion anisotropy observed at the diffusion time used in the present study.     

Abnormalities of brain neural circuits related to obesity: A Diffusion Tensor Imaging study

PurposeIncreased Body-Mass-Index (BMI) has been associated with brain atrophy in both gray and white matter structures. However, little is known concerning the integrity of white matter tracts in obesity. The purpose of the study was to evaluate the pattern of changes in white matter microstructure in human adiposity.Material and methodsThe study included 268 participants (52 obese, 96 overweight and 120 normal-weight) that were retrospectively evaluated by Diffusion Tensor Imaging. The fractional anisotropy, axial, radial and mean diffusivity values were compared between the above groups using Tract Based Spatial Statistics.ResultsThe analysis revealed that the increased BMI was related with decreased fractional anisotropy in several white matter regions including the anterior and posterior thalamic radiation, the inferior fronto-occipital fasciculus, the inferior and superior longitudinal fasciculus, the corpus callosum (callosal body and forceps minor), the uncinate fasciculus, the internal capsule, the corticospinal tract and the cingulum (cingulate gyrus and hippocampus).ConclusionsAnisotropic diffusion of anatomic regions governing important brain circuits such as reward seeking inhibition, motivation/drive and learning/conditioning decreases with increasing BMI.     

Mapping of neurokinin-like immunoreactivity in the human brainstem

Background

Using an indirect immunoperoxidase technique, we have studied the distribution of immunoreactive fibers and cell bodies containing neurokinin in the adult human brainstem with no prior history of neurological or psychiatric disease.

Results

Clusters of immunoreactive cell bodies and high densities of neurokinin-immunoreactive fibers were located in the periaqueductal gray, the dorsal motor nucleus of the vagus and in the reticular formation of the medulla, pons and mesencephalon. Moreover, immunoreactive cell bodies were found in the inferior colliculus, the raphe obscurus, the nucleus prepositus hypoglossi, and in the midline of the anterior medulla oblongata. In general, immunoreactive fibers containing neurokinin were observed throughout the whole brainstem. In addition to the nuclei mentioned above, the highest densities of such immunoreactive fibers were located in the spinal trigeminal nucleus, the lateral reticular nucleus, the nucleus of the solitary tract, the superior colliculus, the substantia nigra, the nucleus ambiguus, the gracile nucleus, the cuneate nucleus, the motor hypoglossal nucleus, the medial and superior vestibular nuclei, the nucleus prepositus hypoglossi and the interpeduncular nucleus.

Conclusion

The widespread distribution of immunoreactive structures containing neurokinin in the human brainstem indicates that neurokinin might be involved in several physiological mechanisms, acting as a neurotransmitter and/or neuromodulator.     

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.     

Inherent spatial structure in myelin water fraction maps

Myelin water fraction (MWF) images in brain tend to be spatially noisy with unknown or no apparent spatial patterns structure, so values are therefore typically averaged over large white matter (WM) volumes. We investigated the existence of an inherent spatial structure in MWF maps and explored the benefits of examining MWF values along diffusion tensor imaging (DTI)-derived white matter tracts. We compared spatial anisotropy between MWF and the more widely-used fractional anisotropy (FA) measure. Sixteen major white matter fibre bundles were extracted based on DTI data from 41 healthy subjects. MWF coefficients of variation (CoV) were computed in sub-segments along each fibre tract and compared to MWF CoVs from the surrounding “tubes” – i.e. voxels just exterior to the tract – of each segment. We further assessed the consistency of the MWF along fibre bundles across subjects and investigated the benefit of examining MWF values in sections along each fibre bundle rather than integrating over the whole tract. CoVs of MWF and FA were lower in fibre bundles compared to their enclosing tubes in all investigated tracts. Both measures possessed a spatial gradient of CoV that was smaller aligned along, compared to perpendicular to, the fibre bundles. All WM tracts showed MWF profiles along their trajectory that were consistent across subjects and were more accurate than the mean overall fibre MWF value in estimating ages of the subjects. We conclude that, although less obvious visually, the spatial MWF distribution in white matter consistently follows a distinct pattern along underlying fibre bundles across subjects. Assessing MWF in sections along white matter tracts may provide a sensitive and robust way to assess myelin across subjects.     

描述人体内水分子扩散各向异性特征的新方法

通过核磁共振扩散张量成像(DTI)得到的特定值域的扩散各向异性指数(DAI) 可用于揭示水分子扩散椭球的形态学特征, 定量反映被成像物体内部水分子扩散的优势方向和强度, 间接得到被成像物体内部的组织结构信息. DAI的可靠性直接影响对DTI数据的分析和理解. 本文基于扩散张量椭球的几何学信息, 提出利用扩散椭球几何比(EGR)定量描述水分子扩散的各向异性程度. 通过蒙特卡罗模拟实验和对人脑DTI数据进行分析, 并与当前广泛应用的水分子扩散各向异性分数(FA)和近期文献提出的扩散椭球面积比(EAR)进行对比. 实验发现EGR在不同级别噪声影响下的对比度效果和抗噪性都优于FA及EAR. 而且EGR 加入了体积修正, 增强了盘形扩散张量情况下的敏感性, 能够更好地鉴别神经纤维束交叉情况, 对于各向异性扩散程度较高的白质深层和相对均质的表层都有较好的量化区分结果. 关键词： 扩散系数 各向异性扩散 扩散张量成像 扩散椭球几何比     

Biexponential analysis of diffusion-related signal decay in normal human cortical and deep gray matter

Diffusion imaging with high-b factors, high spatial resolution and cerebrospinal fluid signal suppression was performed in order to characterize the biexponential nature of the diffusion-related signal decay with b-factor in normal cortical gray and deep gray matter (GM). Integration of inversion pulses with a line scan diffusion imaging sequence resulted in 91% cerebrospinal fluid signal suppression, permitting accurate measurement of the fast diffusion coefficient in cortical GM (1.142+/-0.106 microm2/ms) and revealing a marked similarity with that found in frontal white matter (WM) (1.155+/-0.046 microm2/ms). The reversal of contrast between GM and WM at low vs high b-factors is shown to be due to a significantly faster slow diffusion coefficient in cortical GM (0.338+/-0.027 microm2/ms) than in frontal WM (0.125+/-0.014 microm2/ms). The same characteristic diffusion differences between GM and WM are observed in other brain tissue structures. The relative component size showed nonsignificant differences among all tissues investigated. Cellular architecture in GM and WM are fundamentally different and may explain the two- to threefold higher slow diffusion coefficient in GM.     

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.     

Anisotropic diffusion of metabolites in peripheral nerve using diffusion weighted magnetic resonance spectroscopy at ultra-high field

Although the diffusivity and anisotropy of water has been investigated thoroughly in ordered axonal systems (i.e., nervous tissue), there have been very few studies on the directional dependence of diffusion of metabolites. In this study, the mean apparent diffusion coefficient (Trace/3 ADC) and fractional anisotropy (FA) values of the intracellular metabolites N-acetyl aspartate (NAA), creatine and phosphocreatine (tCr), choline (Cho), taurine (Tau), and glutamate and glutamine (Glx) were measured parallel and perpendicular to the length of excised frog sciatic nerve using a water suppressed, diffusion-weighted, spin-echo pulse sequence at 18.8T. The degree of anisotropy (FA) of NAA (0.41+/-0.09) was determined to be less than tCr (0.59+/-0.07) and Cho (0.61+/-0.11), which is consistent with previously reported human studies of white matter. In contrast, Glx diffusion was found to be almost isotropic with an FA value of 0.20+/-0.06. The differences of FA between the metabolites is most likely due to their differing micro-environments and could be beneficial as an indicator of compartment specific changes with disease, information not readily available with water diffusion.     

Detection of microscopic anisotropy in gray matter and in a novel tissue phantom using double Pulsed Gradient Spin Echo MR

A double Pulsed Gradient Spin Echo (d-PGSE) MR experiment was used to measure and assess the degree of local diffusion anisotropy in brain gray matter, and in a novel "gray matter" phantom that consists of randomly oriented tubes filled with water. In both samples, isotropic diffusion was observed at a macroscopic scale while anisotropic diffusion was observed at a microscopic scale, however, the nature of the resulting echo attenuation profiles were qualitatively different. Gray matter, which contains multiple cell types and fibers, exhibits a more complicated echo attenuation profile than the phantom. Since microscopic anisotropy was observed in both samples in the low q regime comparable to that achievable in clinical scanner, it may offer a new potential contrast mechanism for characterizing gray matter microstructure in medical and biological applications.     

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.     

Manifestation and post hoc correction of gradient cross-term artifacts in DTI

Cross-terms between imaging and diffusion gradients, unaccounted for during tensor calculations, can lead to erroneous estimation of diffusivity and fractional anisotropy (FA) in regions of isotropic and anisotropic diffusion. Cross-term of magnitude 136.8±1.6 s/mm(2), artificially introduced in the slice-encode direction, caused an increase in FA in isotropic phantom from 0.0546±0.0001 to 0.0996±0.0001, while the change in chimpanzee brain depended on the orientation of the white matter (WM). Mean diffusivity (MD) remained unchanged in isotropic phantom, but increased by ～20% in the WM due to cross-terms. A bias was observed in the principal eigenvectors in both phantom and chimpanzee brain, resulting in significant increase in midline crossing fibers along the bias than perpendicular to it in tractography in chimpanzee brain. Post hoc correction of these artifacts was achieved by estimating the cross-term factors using calibration scans on an isotropic phantom and modifying the b-matrix before tensor calculation. Upon correction, the FA and MD values closely resembled the values obtained from sequence without cross-terms, and the bias in principal eigenvectors was eliminated. Customized sequences involving large b-values, high-resolution imaging, or long diffusion or echo times should therefore be evaluated and any residual cross-terms corrected before implementation.     

Novel multisection design of anisotropic diffusion phantoms

Diffusion-weighted magnetic resonance imaging provides access to fiber pathways and structural integrity in fibrous tissues such as white matter in the brain. In order to enable better access to the sensitivity of the diffusion indices to the underlying microstructure, it is important to develop artificial model systems that exhibit a well-known structure, on the one hand, but benefit from a reduced complexity on the other hand. In this work, we developed a novel multisection diffusion phantom made of polyethylene fibers tightly wound on an acrylic support. The phantom exhibits three regions with different geometrical configuration of fibers: a region with fibers crossing at right angles, a region with parallel fibers and homogeneous density, and, finally, a region with parallel fibers but with a gradient of fiber density along the axis of symmetry. This gives rise to a gradual change of the degree of anisotropy within the same phantom. In this way, the need to construct several phantoms with different fiber densities is avoided, and one can access different fractional anisotropies in the same experiment under the same physical conditions. The properties of the developed phantom are demonstrated by means of diffusion tensor imaging and diffusion kurtosis imaging. The measurements were performed using a diffusion-weighted spin-echo and a diffusion-weighted stimulated-echo pulse sequence programmed in-house. The influence of the fiber density packing on the diffusion parameters was analyzed. We also demonstrate how the novel phantom can be used for the validation of high angular resolution diffusion imaging data analysis.     

Enhancing the effect of repetitive I-wave paired-pulse TMS (iTMS) by adjusting for the individual I-wave periodicity

Background

The aberrant pyramidal tract (APT) refers to the collateral pathway of the pyramidal tract (PT) through the medial lemniscus in the midbrain and pons. Using diffusion tensor tractography (DTT), we investigated the characteristics of the APT in comparison with the PT in the normal human brain.

Results

In thirty-four (18.3%, right hemisphere: 20, left hemisphere: 14) of the 186 hemispheres, the APTs separated from the PT at the upper midbrain level, descended through the medial lemniscus from the midbrain to the pons, and then rejoined with the PT at the upper medulla. Nine (26.5%) of the 34 APTs were found to originate from the primary somatosensory cortex without a primary motor cortex origin. Values of fractional anisotropy (FA) and tract volume of the APT were lower than those of the PT (P < 0.05); however, no difference in mean diffusivity (MD) value was observed (P > 0.05).

Conclusion

We found that the APT has different characteristics, including less directionality, fewer neural fibers, and less origin from the primary motor cortex than the PT.