Tract based spatial statistical analysis and voxel based morphometry of diffusion indices in temporal lobe epilepsy

White matter (WM) microstructure can be evaluated by diffusion tensor imaging (DTI). Tract-based spatial statistical (TBSS) analysis provides a means of assessing alterations in WM tracts. In this paper, both voxel-based morphometry (VBM) and TBSS are examined using DTI data of temporal lobe epilepsy (TLE) patients and nonepileptic subjects. In addition to fractional anisotropy (FA), ellipsoidal area ratio (EAR) is used in this study. Significant reductions of FA and EAR are identified by TBSS in the parahippocampal white matter. Because of methodological differences, TBSS detects more localized abnormalities than VBM, while the EAR is more sensitive to WM alteration than FA.     

Diffusion tensor imaging and Tract-Based Spatial Statistics in Alzheimer's disease and mild cognitive impairment

We aimed to explore the changes in fractional anisotropy (FA) in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by analyzing diffusion tensor imaging (DTI) data using the Tract-Based Spatial Statistics (TBSS). DTI data were collected from 17 AD patients, 27 MCI subjects and 19 healthy controls. Voxel-based analysis with TBSS was used to compare FA among the three groups. Additionally, guided by TBSS findings, a region of interest (ROI)-based analysis along the TBSS skeleton was performed on group-level and the accuracy of the method was assessed by the back-projection of ROIs to the native space FA. Neurofiber tracts with decreased FA included: the parahippocampal white matter, cingulum, uncinate fasciculus, inferior and superior longitudinal fasciculus, corpus callosum, fornix, tracts in brain stem, and cerebellar tracts. Quantitative ROI-analysis further demonstrated the significant decrease on FA values in AD patients relative to controls whereas FA values of MCI patients were found in between the controls and AD patients. We conclude that TBSS is a promising method in examining the degeneration of neurofiber tracts in MCI and AD patients.     

Major depressive disorder and white matter abnormalities: A diffusion tensor imaging study with tract-based spatial statistics

BackgroundA few diffusion tensor imaging (DTI) studies have shown abnormalities in areas of white matter tracts involved in mood regulation in geriatric depressive patients, using a region-of-interest technique. A voxel-based morphometry DTI study of young depressive patients reported similar results. In this study, we explored the structure of the white matter of the whole brain with DTI in middle-aged major depressive disorder (MDD) patients, using novel tract-based spatial statistics.MethodsSixteen MDD patients and 20 controls underwent DTI. An automated tract-based spatial method (TBSS) was used to analyze the scans.ResultsCompared with controls, the MDD patients showed a trend for lower values of fractional anisotropy (FA) in the left sagittal stratum, and suggestive decreased FA in the right cingulate cortex and posterior body of corpus callosum. Regressing out the duration and severity of disorder in the model did not change the finding in the sagittal stratum, but dissipated the decrease of FA in latter regions.LimitationsPossibly by reason of a relatively small study sample for a TBSS, the results are suggestive, and should be replicated in further studies.ConclusionsA novel observer-independent DTI method showed decreased FA in the middle-aged MDD patients in white matter regions that have previously connected to the emotional regulation. Lower FA might imply underlying structural abnormalities that contribute to the dysfunction detected in the limbic-cortical network of depressive patients.     

Diffusion tensor MRI with tract-based spatial statistics and histology reveals undiscovered lesioned areas in kainate model of epilepsy in rat

In this study, we used tract-based spatial statistics (TBSS) to analyze diffusion tensor MR imaging (DTI) data acquired from the rat brain, ex vivo, for the first time. The aim was to highlight potential changes in the whole brain anatomy in the kainic acid model of epilepsy, and further characterize the changes with histology. Increased FA was observed in dorsal endopiriform nucleus, external capsule, corpus callosum, dentate gyrus, thalamus, and optic tract. A decrease in FA was seen in the horizontal limb of the diagonal band, stria medullaris, habenula, entorhinal cortex, and superior colliculus. Some of the areas have been described in kainic acid model before. However, we also found regions that to our knowledge have not been previously reported to undergo structural changes, in this model, including stria medullaris, nucleus of diagonal band, habenula, superior colliculus, external capsule, corpus callosum, and optic tract. Four of the areas highlighted in TBSS (dentate gyrus, entorhinal cortex, thalamus and stria medullaris) were analyzed in more detail with Nissl, Timm, and myelin-stained histological sections, and with polarized light microscopy. TBSS together with targeted histology confirmed that DTI changes were associated with altered myelination, neurodegeneration, and/or calcification of the tissue. Our data demonstrate that DTI in combination with TBSS has a great potential to facilitate the discovery of previously undetected anatomical changes in animal models of brain diseases.     

Myelination deficits in schizophrenia: evidence from diffusion tensor imaging

Background

Diffusion Tensor Imaging studies have repeatedly shown a decrease of the fractional anisotropy (FA) parameter in patients with schizophrenia. This has been interpreted as a disturbed microstructural integrity of white matter. However, FA is a relative parameter that is derived from eigenvalues of the diffusion tensor and FA reductions may be the result of decreases in parallel diffusivity (PD) or increases in radial diffusivity (RD). Despite the well-established FA reduction in schizophrenia, little is known what this reduction is based on.

Methods

Seventeen patients with schizophrenia were scanned with a DTI protocol and compared to a group of healthy control subjects. In addition to an FA comparison, a detailed analysis of PD and RD values was performed with two approaches to localize changes in diffusion values, i.e. a voxel-based analysis and an anatomically based tract specific analysis.

Results

We found significantly decreased FA values in the patient group when compared to healthy controls. FA decreases were based on an increase in RD, while we observed no significant changes of PD. These changes were predominantly localized in frontal and temporal areas.

Conclusion

RD increases as the underlying change in FA decreases is suggestive of desintegration of myelin, which is in line with histopathological studies suggesting a disturbed myelination in schizophrenia.     

Right lateralized white matter abnormalities in first-episode,drug-naive paranoid schizophrenia

Numerous studies in first-episode schizophrenia suggest the involvement of white matter (WM) abnormalities in multiple regions underlying the pathogenesis of this condition. However, there has never been a neuroimaging study in patients with first-episode, drug-naive paranoid schizophrenia by using tract-based spatial statistics (TBSS) method. Here, we used diffusion tensor imaging (DTI) with TBSS method to investigate the brain WM integrity in patients with first-episode, drug-naive paranoid schizophrenia. Twenty patients with first-episode, drug-naive paranoid schizophrenia and 26 healthy subjects matched with age, gender, and education level were scanned with DTI. An automated TBSS approach was employed to analyze the data. Voxel-wise statistics revealed that patients with paranoid schizophrenia had decreased fractional anisotropy (FA) values in the right superior longitudinal fasciculus (SLF) II, the right fornix, the right internal capsule, and the right external capsule compared to healthy subjects. Patients did not have increased FA values in any brain regions compared to healthy subjects. There was no correlation between the FA values in any brain regions and patient demographics and the severity of illness. Our findings suggest right-sided alterations of WM integrity in the WM tracts of cortical and subcortical regions may play an important role in the pathogenesis of paranoid schizophrenia.     

FSL在DTI大脑图像分析中的应用现状

随着弥散张量成像(diffusion tensor imaging,DTI)技术在大脑结构方面应用研究的增多,与之相关的数据分析软件也在增多,其中FMRIB Software Library(FSL)在示踪时使用的是基于概率性示踪的算法,在进行交叉纤维示踪和灰质连接上有很大优势。本文主要根据数据分析方式的不同对FSL包含的两个子工具(tract-based spatial statistics,TBSS和FMRIB’s diffusion toolbox,FDT)在DTI大脑图像分析方面的应用现状进行分类介绍,主要涉及老年抑郁症、精神分裂症以及认知功能等领域。本文首先简要介绍DTI原理,然后根据数据分析方式的不同,在TBSS部分分为全脑分析和感兴趣区域(region of interest,ROI)分析两方面,在FDT部分分为全脑示踪、ROI互连分析、基于连通度的分类三方面进行介绍,最后对FSL的局限性以及发展状况进行总结。     

Spatiotemporal microstructural white matter changes in diffusion tensor imaging after transient focal ischemic stroke in rats

Structural reorganization in white matter (WM) after stroke is a potential contributor to substitute or to newly establish the functional field on the injured brain in nature. Diffusion tensor imaging (DTI) is an imaging modality that can be used to evaluate damage and recovery within the brain. This method of imaging allows for in vivo assessment of the restricted movements of water molecules in WM and provides a detailed look at structural connectivity in the brain. For longitudinal DTI studies after a stroke, the conventional region of interest method and voxel‐based analysis are highly dependent on the user‐hypothesis and parameter settings for implementation. In contrast, tract‐based spatial statistics (TBSS) allows for reliable voxel‐wise analysis via the projection of diffusion‐derived parameters onto an alignment‐invariant WM skeleton. In this study, spatiotemporal WM changes were examined with DTI‐derived parameters (fractional anisotropy, FA; mean diffusivity, MD; axial diffusivity, DA; radial diffusivity, RD) using TBSS 2 h to 6 weeks after experimental focal ischemic stroke in rats (N = 6). FA values remained unchanged 2–4 h after the stroke, followed by a continuous decrease in the ipsilesional hemisphere from 24 h to 2 weeks post‐stroke and gradual recovery from the ipsilesional corpus callosum to the external capsule until 6 weeks post‐stroke. In particular, the fibers in these areas were extended toward the striatum of the ischemic boundary region at 6 weeks on tractography. The alterations of the other parameters in the ipsilesional hemisphere showed patterns of a decrease at the early stage, a subsequent pseudo‐normalization of MD and DA, a rapid reduction of RD, and a progressive increase in MD, DA and RD with a decreased extent in the injured area at later stages. The findings of this study may reflect the ongoing processes on tissue damage and spontaneous recovery after stroke.     

首发重症抑郁症的弥散张量成像研究:基于纤维束示踪的空间统计学分析结果

目的:应用基于纤维束示踪的空间统计分析(Tract-Based Spatial Statistics,TBSS)方法,探讨重症抑郁症病患者全脑白质纤维的完整性是否受到损害。方法:对20(8男,12女)例重症抑郁症病患者组和20(8男,12女)例与抑郁症组按性别、年龄、教育程度匹配的正常人进行全脑弥散张量成像扫描。应用TBSS方法来比较两组的各向异性分数。结果:抑郁症组的左侧内囊前肢、右侧海马旁回、左侧后扣带回的各向异性分数显著低于正常组(P<0.05,t>3,校正),患者组内囊前肢的各向异性分数和抑郁症严重程度呈现负相关。结论:白质病变在抑郁症发病早期即已存在,这些病变区域主要涉及前额叶和边缘系统等与认知和情感调节关系较密切的神经环路的纤维束,这些改变可能导致皮层和皮层下连接受损,从而有利于深入了解抑郁症疾病的发病机理。     

User‐independent diffusion tensor imaging analysis pipelines in a rat model presenting ventriculomegalia: A comparison study

Automated analysis of diffusion tensor imaging (DTI) data is an appealing way to process large datasets in an unbiased manner. However, automation can sometimes be linked to a lack of interpretability. Two whole‐brain, automated and voxelwise methods exist: voxel‐based analysis (VBA) and tract‐based spatial statistics (TBSS). In VBA, the amount of smoothing has been shown to influence the results. TBSS is free of this step, but a projection procedure is introduced to correct for residual misalignments. This projection assigns the local highest fractional anisotropy (FA) value to the mean FA skeleton, which represents white matter tract centers. For both methods, the normalization procedure has a major impact. These issues are well documented in humans but, to our knowledge, not in rodents. In this study, we assessed the quality of three different registration algorithms (ANTs SyN, DTI‐TK and FNIRT) using study‐specific templates and their impact on automated analysis methods (VBA and TBSS) in a rat pup model of diffuse white matter injury presenting large unilateral deformations. VBA and TBSS results were stable and anatomically coherent across the three pipelines. For VBA, in regions around the large deformations, interpretability was limited because of the increased partial volume effect. With TBSS, two of the three pipelines found a significant decrease in axial diffusivity (AD) at the known injury site. These results demonstrate that automated voxelwise analyses can be used in an animal model with large deformations.     

In vivo analysis of the post-natal development of normal mouse brain by DTI

The water diffusion characteristics of wild-type mouse brains have been studied in vivo by DTI to follow developmental changes. Here, axial (lambda(//)) and radial (lambda(perpendicular)) diffusivities and fractional anisotropy were measured from the fifth day of life (P5) and at three other post-natal ages (P12, P19 and P54). Magnetic resonance images were collected from a single sagittal slice in the middle of the two hemispheres; ROI were chosen in nine different structures of both grey and white matter. Fractional anisotropy (FA) from P5 onwards distinguished structures of both white and grey matter, even though myelination had yet to occur. Between P5 and P54, a significant increase in FA was observed in the genu of the corpus callosum due to a significant decrease in lambda(perpendicular) whereas lambda(//) remained stable. Many other significant variations of lambda(//) and lambda(perpendicular) were measured in different structures. They were substantially correlated with axon and myelin maturation which are responsible for the main evolutions of the brain during its post-natal development. These quantitative data show that in vivo characterization of the anatomy and microstructure of the normal mouse brain during development is possible. The normative data will greatly improve the characterization of abnormal development in the transgenic mouse brain.     

Altered diffusion tensor imaging measurements in aged transgenic Huntington disease rats

Rodent models of Huntington disease (HD) are valuable tools for investigating HD pathophysiology and evaluating new therapeutic approaches. Non-invasive characterization of HD-related phenotype changes is important for monitoring progression of pathological processes and possible effects of interventions. The first transgenic rat model for HD exhibits progressive late-onset affective, cognitive, and motor impairments, as well as neuropathological features reflecting observations from HD patients. In this report, we contribute to the anatomical phenotyping of this model by comparing high-resolution ex vivo DTI measurements obtained in aged transgenic HD rats and wild-type controls. By region of interest analysis supplemented by voxel-based statistics, we find little evidence of atrophy in basal ganglia regions, but demonstrate altered DTI measurements in the dorsal and ventral striatum, globus pallidus, entopeduncular nucleus, substantia nigra, and hippocampus. These changes are largely compatible with DTI findings in preclinical and clinical HD patients. We confirm earlier reports that HD rats express a moderate neuropathological phenotype, and provide evidence of altered DTI measures in specific HD-related brain regions, in the absence of pronounced morphometric changes.     

Microstructural white matter damage at orbitofrontal areas in borderline personality disorder

ObjectivesPrefrontal cortex plays a major role in the modulation of behaviors and emotions through regulation of both information processing and impulse control. Low prefrontal function in borderline personality disorder (BPD) has been consistently reported by a number of studies using neuropsychological assessments and functional neuroimaging techniques. To further explore this findings, this study aimed to investigate microstructural damage of prefrontal white matter tracts in subjects with BPD by using the novel, voxel-based approach, tract-based spatial statistics (TBSS).MethodsA Diffusion Tensor Image (DTI) study was performed in 28 patients with DSM-IV BPD (13 males and 15 females) and in 26 healthy control subjects. Voxel wise analysis was performed using TBSS (diffusion toolbox of FSL — functional MRI Software Library) to localize regions of white matter showing significant changes of fractional anisotropy (FA).ResultsTBSS analysis revealed a statistically significant decrease of FA in the genu and rostral areas of the corpus callosum (p < 0.005), as well as in left and right prefrontal white matter fasciculi (p < 0.002) in BPD participants compared with controls. White matter abnormalities were not correlated with age, neurological symptoms or comorbid ADHD.ConclusionsDespite the reduced sample size, the results are in line with previous findings on reduced orbitofrontal functions in BPD with prominent affective-depressive feature and suggest that emotional and behavioral symptoms of BPD patients might be associated to damage at the connectivity tracts in these brain areas.     

A comparative study of bone marrow mesenchymal stem cell functionality in C57BL and mdx mice

Abnormalities of the white matter (WM) tracts integrity in brain areas involved in emotional regulation have been postulated in major depressive disorder (MDD). However, there is no diffusion tensor imaging (DTI) study in patients with treatment-responsive MDD at present. DTI scans were performed on 22 patients with treatment-responsive MDD and 19 well-matched healthy subjects. Tract-based spatial statistics (TBSS) approach was employed to analyze the scans. Voxel-wise statistics revealed four brain WM tracts with lower fractional anisotropy (FA) in patients compared to healthy subjects: the bilateral internal capsule, the genu of corpus callosum, the bilateral anterior corona radiata, and the right external capsule. FA values were nowhere higher in patients compared to healthy subjects. Our findings demonstrate that the abnormalities of the WM tracts, major in the projection fibers and corpus callosum, may contribute to the pathogenesis of treatment-responsive MDD.     

基于不同FA模板的全脑体素分析方法可靠性的研究

比较基于两种不同FA模板的全脑体素分析(VBA)方法的结果,了解该方法的可靠性,以期为脑白质的功能研究和相关疾病的诊治提供基础信息。选择27例健康成年志愿者,分为青年组(14例)和老年组(13例),行磁共振弥散张量成像扫描。首先使用DTIStudio软件对图像进行自动配准和张量计算,获取部分各向异性(FA)图,然后利用统计参数图(SPM8)软件对FA图进行配准、归一化、平滑等预处理,最后分别基于SPM8软件下产生的专用FA模板和本实验室自主开发的正常中国人FA模板,对两组间的脑白质FA值进行全脑体素分析比较。以纤维束示踪的空间统计学(TBSS)方法和相关文献结果为标准,对以上比较结果进行验证。在基于SPM8产生的专用FA模板下,与青年组对比,老年组的双侧内囊前、后肢,左外囊,左额上回,左枕叶,右放射冠,右大脑脚底,右额中、下回,右小脑中脚的FA值显著下降(P<0.05,簇错误率校正);在基于正常中国人FA模板下,老年组的左内囊后肢,左外囊,左额上回,左颞中回,左枕叶,右放射冠,右内囊前、后肢,右大脑脚底,右额中、下回和胼胝体膝部的FA值相对于青年组显著下降(P<0.05,簇错误率校正);两种模板结果的不一致区域共有4个,即:左内囊前肢、右小脑中脚和左颞中回、胼胝体膝部,前两个区域出现在第一个模板中,后两个区域出现在第二个模板中,根据TBSS方法的激活区结果可得出左内囊前肢、右小脑中脚是假阳性,TBSS方法和相关文献结果支持第二个模板的结论。在采用VBA方法对脑白质进行分析时,基于正常中国人FA模板有助于提高结果的客观性和可靠性。     

A meta-analysis of diffusion tensor imaging studies in amyotrophic lateral sclerosis

Studies involving diffusion tensor imaging (DTI) of amyotrophic lateral sclerosis (ALS) with whole-brain voxel-based analysis yielded variable findings. A systematic review was conducted on whole-brain voxel-based diffusion tensor imaging fractional anisotropy (FA) studies of ALS patients and healthy controls (HC) in PubMed, ISI Web of Science, Embase, and MEDLINE databases from 1990 to December 25, 2010. Coordinates were extracted from clusters with significant difference in FA between ALS patients and HC. Meta-analysis was performed using signed differential mapping. Eight studies were enrolled, comprising 143 ALS patients and 145 HC. The included studies reported FA reduction at 67 coordinates in ALS and no FA increased. Significant reductions were present in the bilateral frontal white matter/cingulate gyrus and the posterior limb of bilateral internal capsule. The findings remain largely unchanged in quartile and jackknife sensitivity analyses. Our finding suggests that ALS is a multisystem disease beyond motor dysfunction and provides evidence that FA reduction in the frontal white matter and cingulate gyrus may be a special biomarker of ALS.     

Low responsiveness of hepatitis B virus-transgenic mice in antibody response to T-cell-dependent antigen: defect in antigen-presenting activity of dendritic cells.

The experiments presented here were performed to evaluate immune responsiveness of hepatitis B virus (HBV)-transgenic mice (transgenic mice), as a model of HBV-carrier state to a T-cell-dependent antigen, keyhole limpet haemocyanin (KLH). The transgenic mice which were completely unresponsive to hepatitis B surface antigen (HBsAg), responded poorly to KLH. The levels of anti-KLH antibodies (Ab) produced in vivo were significantly lower in transgenic mice compared with the normal control mice at respective immunizing doses of KLH. In addition, a little or no anti-KLH Ab production was detected in culture supernatants of KLH-primed transgenic mice spleen cells. KLH-primed T cells from normal and transgenic mice induced anti-KLH Ab production from transgenic B cells in the presence of antigen-presenting spleen adherent cells (SAC) from normal mice, but not those from transgenic mice. Depletion of dendritic cells from normal mice-derived SAC completely abrogated the anti-KLH Ab response in transgenic spleen cell culture and their addition to the culture restored the response. Low efficiency of transgenic dendritic cells was demonstrated in sodium periodate (NaIO4)-induced non-specific and allogenic antigen-induced T-cell proliferation. Finally, cytofluorometric analyses showed a reduced Ia antigen expression on transgenic dendritic cells. These results indicate that low responsiveness of transgenic mice in specific-antibody response is not due to functional defects in T cells or B cells but rather to a defect of antigen-presenting activity of dendritic cells.     

Circulating gp120 alters the blood-brain barrier permeability in HIV-1 gp120 transgenic mice

The mechanism underlying invasion of the central nervous system by HIV-1 is unclear. We recently demonstrated blood–brain barrier changes in a model of HIV-1 gp120 transgenic mice. To test whether this alteration was intrinsic to the brain endothelium of transgenic mice or depended on circulating gp120, we used brain endothelial cultures from gp120 transgenic and non-transgenic mice and exposed them to serum from gp120 transgenic or non-transgenic mice. We measured permeability to albumin as a marker of functional endothelial integrity. A significant increase in permeability (up to 47%) was observed in transgenic and non-transgenic cultures exposed to serum samples from transgenic but not to those from non-transgenic mice. This permeability was neutralized after immunoabsorption of sera with anti-gp120 monoclonal antibody. These findings demonstrate that the blood–brain barrier alteration in HIV-1 gp120 transgenic mice is due to circulating gp120.     

BAG1 over-expression in brain protects against stroke

The co-chaperone BAG1 binds and regulates 70 kDa heat shock proteins (Hsp70/Hsc70) and exhibits cytoprotective activity in cell culture models. Recently, we observed that BAG1 expression is induced during neuronal differentiation in the developing brain. However, the in vivo effects of BAG1 during development and after maturation of the central nervous system have never been examined. We generated transgenic mice over-expressing BAG1 in neurons. While brain development was essentially normal, cultured cortical neurons from transgenic animals exhibited resistance to glutamate-induced, apoptotic neuronal death. Moreover, in an in vivo stroke model involving transient middle cerebral artery occlusion, BAG1 transgenic mice demonstrated decreased mortality and substantially reduced infarct volumes compared to wild-type littermates. Interestingly, brain tissue from BAG1 transgenic mice contained higher levels of neuroprotective Hsp70/Hsc70 protein but not mRNA, suggesting a potential mechanism whereby BAG1 exerts its anti-apoptotic effects. In summary, BAG1 displays potent neuroprotective activity in vivo against stroke, and therefore represents an interesting target for developing new therapeutic strategies including gene therapy and small-molecule drugs for reducing brain injury during cerebral ischemia and neurodegenerative diseases.