Early microstructural white matter changes in patients with HIV: a diffusion tensor imaging study

ABSTRACT: Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV). We compared diffusion tensor imaging (DTI) derived WM fractional anisotropy (FA) between HIV-patients with and without mild macroscopic brain lesions determined using standard magnetic resonance imaging (MRI). We furthermore investigated whether WM alterations co-occurred with neurocognitive deficits and depression. We performed structural MRI and DTI for 19 patients and 19 age-matched healthy controls. Regionally-specific WM integrity was investigated using voxel-based statistics of whole-brain FA maps and region-of-interest analysis. Each patient underwent laboratory and neuropsychological tests. Structural MRI revealed no lesions in twelve (HIV-MRN) and unspecific mild macrostructural lesions in seven patients (HIV-MRL). Both analyses revealed widespread FA-alterations in all patients. Patients with HIV-MRL had FA-alterations primarily adjacent to the observed lesions and, whilst reduced in extent, patients with HIV-MRN also exhibited FA-alterations in similar regions. Patients with evidence of depression showed FA-increase in the ventral tegmental area, pallidum and nucleus accumbens in both hemispheres, and patients with evidence of HIV-associated neurocognitive disorder showed widespread FA-reduction. These results show that patients with HIV-MRN have evidence of FA-alterations in similar regions that are lesioned in HIV-MRL patients, suggesting common neuropathological processes. Furthermore, they suggest a biological rather a reactive origin of depression in HIV-patients.     

Bilateral fronto-parietal integrity in young chronic cigarette smokers: a diffusion tensor imaging study

Background

Cigarette smoking continues to be the leading cause of preventable morbidity and mortality in China and other countries. Previous studies have demonstrated gray matter loss in chronic smokers. However, only a few studies assessed the changes of white matter integrity in this group. Based on those previous reports of alterations in white matter integrity in smokers, the aim of this study was to examine the alteration of white matter integrity in a large, well-matched sample of chronic smokers and non-smokers.

Methodology/Principal Findings

Using in vivo diffusion tensor imaging (DTI) to measure the differences of whole-brain white matter integrity between 44 chronic smoking subjects (mean age, 28.0±5.6 years) and 44 healthy age- and sex-matched comparison non-smoking volunteers (mean age, 26.3±5.8 years). DTI was performed on a 3-Tesla Siemens scanner (Allegra; Siemens Medical System). The data revealed that smokers had higher fractional anisotropy (FA) than healthy non-smokers in almost symmetrically bilateral fronto-parietal tracts consisting of a major white matter pathway, the superior longitudinal fasciculus (SLF).

Conclusion/Significance

We found the almost symmetrically bilateral fronto-parietal whiter matter changes in a relatively large sample of chronic smokers. These findings support the hypothesis that chronic cigarette smoking involves alterations of bilateral fronto-parietal connectivity.     

Increased fractional anisotropy in white matter of the right frontal region in children with attention-deficit/hyperactivity disorder: a diffusion tensor imaging study

Abnormalities of frontal white matter (WM) have been found in some children with ADHD. The purpose of this study was to explore the changes in WM in child patients with ADHD by DTI, which detects changes in WM microstructure based on properties of diffusion. We also expect to investigate the relationship between the changes in WM and executive function in child patients with ADHD. DTI was performed on 24 patients with ADHD and 20 healthy controls. A series of neuropsychological tests and a structural interview were conducted to assess the cognitive functions and clinical data of the ADHD patients and controls. Firstly, child patients with ADHD have higher fractional anisotropy (FA) values in WM in the right frontal region. Secondly, FA in right frontal WM is positively correlated with scores in the Stroop test. CONCLUSIONS: Increased FA of right frontal WM implies a higher degree of myelination and lower degree of neural branching in WM, contributing to the neurological deficits of ADHD.     

Impaired structural connectivity of socio-emotional circuits in autism spectrum disorders: a diffusion tensor imaging study

Background

Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.

Methods/Principal Findings

DTI scans were acquired for 19 children and adolescents with ASD (∼8–18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8–18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.

Conclusions/Significance

Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder.     

Microstructure of temporo-parietal white matter as a basis for reading ability: evidence from diffusion tensor magnetic resonance imaging

Diffusion tensor magnetic resonance imaging (MRI) was used to study the microstructural integrity of white matter in adults with poor or normal reading ability. Subjects with reading difficulty exhibited decreased diffusion anisotropy bilaterally in temporoparietal white matter. Axons in these regions were predominantly anterior-posterior in direction. No differences in T1-weighted MRI signal were found between poor readers and control subjects, demonstrating specificity of the group difference to the microstructural characteristics measured by diffusion tensor imaging (DTI). White matter diffusion anisotropy in the temporo-parietal region of the left hemisphere was significantly correlated with reading scores within the reading-impaired adults and within the control group. The anisotropy reflects microstructure of white matter tracts, which may contribute to reading ability by determining the strength of communication between cortical areas involved in visual, auditory, and language processing.     

Functional diffusion tensor imaging: measuring task-related fractional anisotropy changes in the human brain along white matter tracts

Background

Functional neural networks in the human brain can be studied from correlations between activated gray matter regions measured with fMRI. However, while providing important information on gray matter activation, no information is gathered on the co-activity along white matter tracts in neural networks.

Methodology/Principal Findings

We report on a functional diffusion tensor imaging (fDTI) method that measures task-related changes in fractional anisotropy (FA) along white matter tracts. We hypothesize that these fractional anisotropy changes relate to morphological changes of glial cells induced by axonal activity although the exact physiological underpinnings of the measured FA changes remain to be elucidated. As expected, these changes are very small as compared to the physiological noise and a reliable detection of the signal change would require a large number of measurements. However, a substantial increase in signal-to-noise ratio was achieved by pooling the signal over the complete fiber tract. Adopting such a tract-based statistics enabled us to measure the signal within a practically feasible time period. Activation in the sensory thalamocortical tract and optic radiation in eight healthy human subjects was found during tactile and visual stimulation, respectively.

Conclusions/Significance

The results of our experiments indicate that these FA changes may serve as a functional contrast mechanism for white matter. This noninvasive fDTI method may provide a new approach to study functional neural networks in the human brain.     

Delay of gratification is associated with white matter connectivity in the dorsal prefrontal cortex: a diffusion tensor imaging study in chimpanzees (Pan troglodytes)

Individual variability in delay of gratification (DG) is associated with a number of important outcomes in both non-human and human primates. Using diffusion tensor imaging (DTI), this study describes the relationship between probabilistic estimates of white matter tracts projecting from the caudate to the prefrontal cortex (PFC) and DG abilities in a sample of 49 captive chimpanzees (Pan troglodytes). After accounting for time between collection of DTI scans and DG measurement, age and sex, higher white matter connectivity between the caudate and right dorsal PFC was found to be significantly associated with the acquisition (i.e. training phase) but not the maintenance of DG abilities. No other associations were found to be significant. The integrity of white matter connectivity between regions of the striatum and the PFC appear to be associated with inhibitory control in chimpanzees, with perturbations on this circuit potentially leading to a variety of maladaptive outcomes. Additionally, results have potential translational implications for understanding the pathophysiology of a number of psychiatric and clinical outcomes in humans.     

Changes in the brain microstructure of children with primary monosymptomatic nocturnal enuresis: a diffusion tensor imaging study

Background

Primary monosymptomatic nocturnal enuresis (PMNE) is a common disorder in school-aged children. Previous studies have suggested that a developmental delay might play a role in the pathology of children with PMNE. However, microstructural abnormalities in the brains of these children have not been thoroughly investigated.

Methodology/Principal Findings

In this work, we evaluated structural changes in the brains of children with PMNE using diffusion tensor imaging (DTI). Two groups consisting of 26 children with PMNE and 26 healthy controls were scanned using magnetic resonance DTI. The diffusion parameters of fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain, voxel-wise group comparisons using statistical parametric mapping (SPM). When compared to healthy subjects, children with PMNE showed both a decrease in FA and an increase in MD in the thalamus. MD also increased in the frontal lobe, the anterior cingulate cortex and the insula; these areas are all involved in controlling micturition. The significant changes seen in the thalamus could affect both urine storage and arousal from sleep.

Conclusions/Significance

The microstructure abnormalities were observed in the thalamus, the medial frontal gyrus, the anterior cingulate cortex and the insula, which are involved in micturition control network. This indicates developmental delay in these areas may be the cause of PMNE.     

Clinical application of diffusion tensor imaging and tractography in a child with holoprosencephaly

Diffusion tensor imaging and fiber tracking can be methods used for the study of congenital brain malformations associated to white matter bundle abnormalities.Their use is illustrated in a child with semilobar holoprosencephaly in whom diffusion tensor imaging and tractography showed diencephalic ventral induction failure and abnormal white matter fascicles in brain and brainstem.     

Exploratory analysis of diffusion tensor imaging in children with attention deficit hyperactivity disorder: evidence of abnormal white matter structure

Abnormalities in the white matter microstructure of the attentional system have been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Diffusion tensor imaging (DTI) is a promising magnetic resonance imaging (MRI) technology that has increasingly been used in studies of white matter microstructure in the brain. The main objective of this work was to perform an exploratory analysis of white matter tracts in a sample of children with ADHD versus typically developing children (TDC). For this purpose, 13 drug-naive children with ADHD of both genders underwent MRI using DTI acquisition methodology and tract-based spatial statistics. The results were compared to those of a sample of 14 age- and gender-matched TDC. Lower fractional anisotropy was observed in the splenium of the corpus callosum, right superior longitudinal fasciculus, bilateral retrolenticular part of the internal capsule, bilateral inferior fronto-occipital fasciculus, left external capsule and posterior thalamic radiation (including right optic radiation). We conclude that white matter tracts in attentional and motor control systems exhibited signs of abnormal microstructure in this sample of drug-naive children with ADHD.     

Parameter comparison of white matter diffusion tensor imaging (DTI) in rhesus macaques (Macaca mulatta)

In this study, we analyzed diffusion tensor imaging(DTI) results of brain white matter in rhesus macaques(Macaca mulatta) with four different parameter settings and found that the sequence A(b=1 000 s/mm2, spatial resolution=1.25 mm×1.25 mm× 1.25 mm, numbers of direction=33, NSA=3) and B(b=800 s/mm2, spatial resolution=1.25 mm×1.25 mm×1.25 mm, numbers of direction=33, NSA=3) could accurately track coarse fibers. The fractional anisotropy(FA) derived from sequence C(b=1 000s/mm2, spatial resolution=0.55 mm×0.55 mm×2.5 mm, direction number=33, NSA=3) was too fuzzy to be used in tracking white matter fibers. By comparison, the high resolution and the FA with high contrast of gray matter and white matter derived from sequence D(b=800 s/mm2, spatial resolution=1.0 mm×1.0 mm ×1.0 mm, numbers of direction=33, NSA=3) qualified in its application in tracking both thick and thin fibers, making it an optimal DTI setting for rhesus macaques.     

Determining skeletal muscle architecture with Laplacian simulations: a comparison with diffusion tensor imaging

Determination of skeletal muscle architecture is important for accurately modeling muscle behavior. Current methods for 3D muscle architecture determination can be costly and time-consuming, making them prohibitive for clinical or modeling applications. Computational approaches such as Laplacian flow simulations can estimate muscle fascicle orientation based on muscle shape and aponeurosis location. The accuracy of this approach is unknown, however, since it has not been validated against other standards for muscle architecture determination. In this study, muscle architectures from the Laplacian approach were compared to those determined from diffusion tensor imaging in eight adult medial gastrocnemius muscles. The datasets were subdivided into training and validation sets, and computational fluid dynamics software was used to conduct Laplacian simulations. In training sets, inputs of muscle geometry, aponeurosis location, and geometric flow guides resulted in good agreement between methods. Application of the method to validation sets showed no significant differences in pennation angle (mean difference \(0.5{^{\circ }})\) or fascicle length (mean difference 0.9 mm). Laplacian simulation was thus effective at predicting gastrocnemius muscle architectures in healthy volunteers using imaging-derived muscle shape and aponeurosis locations. This method may serve as a tool for determining muscle architecture in silico and as a complement to other approaches.     

Changes of the corticospinal tract in the unaffected hemisphere in stroke patients: A diffusion tensor imaging study

We investigated changes of the corticospinal tract (CST) in the unaffected hemisphere according to severity of the CST injury, using diffusion tensor imaging (DTI). According to the severity of the CST injury in the affected hemisphere, the stroke patients showed different aspects of fiber volume increment of the CST in the unaffected hemisphere; the fiber volume was increased in the early phase in patients with mild injury of CST and later phase in patients with severe injury of CST.     

In ovo monitoring of smooth muscle fiber development in the chick embryo: diffusion tensor imaging with histologic correlation

Background

Magnetic resonance imaging is a noninvasive method of evaluating embryonic development. Magnetic resonance diffusion tensor imaging, which is based on the measuring the directional diffusivity of water molecules, is an established method of evaluating tissue structure. Prolonged imaging times have precluded the use of embryonic diffusion tensor imaging due to motion artifact. Using temperature-based motion suppression, we aimed to investigate whether diffusion tensor imaging can be used to monitor embryonic smooth muscle development in ovo, and to determine the correlation between histologically-derived muscle fiber fraction, day of incubation and diffusion tensor imaging fractional anisotropy values and length of tracked fibers.

Methodology/Principal Findings

From a set of 82 normally developing fertile chicken eggs, 5 eggs were randomly chosen each day from incubation days 5 to 18 and cooled using a dual-cooling technique prior to and during magnetic resonance imaging at 3.0 Tesla. Smooth muscle fibers of the gizzard were tracked using region of interests placed over the gizzard. Following imaging, the egg was cracked and the embryo was fixated and sectioned, and a micrograph most closely corresponding to the acquired magnetic resonance image was made. Smooth muscle fiber fraction was determined using an automated computer algorithm.

Conclusions/Significance

We show that diffusion tensor images of smooth muscle within the embryonic gizzard can be acquired in ovo from incubation day 11 through hatching. Length of tracked fibers and day of incubation were found to have statistical significance (p<0.05) by multiple linear regression correlation with histologic specimens of sacrificed embryos from day 11 of incubation through hatching. The morphologic pattern of development in our histologic specimens corresponds to the development of embryonic gizzard as reported in the literature. These results suggest that diffusion tensor imaging can provide a noninvasive method of evaluating in ovo development of smooth muscle tissue.     

White matter abnormalities in major depression: a tract-based spatial statistics and rumination study

Increasing evidence indicates that major depressive disorder (MDD) is usually accompanied by altered white matter in the prefrontal cortex, the parietal lobe and the limbic system. As a behavioral abnormity of MDD, rumination has been believed to be a substantial indicator of the mental state of the depressive state. So far, however, no report that we are aware of has evaluated the relationship between white matter alterations and the ruminative state. In this study, we first explored the altered white matter using a tract-based spatial statistics (TBSS) method based on diffusion tensor imaging of 19 healthy and 16 depressive subjects. We then investigated correlations between the altered white matter microstructure in the identified altered regions and the severity of ruminations measured by the ruminative response scale. Our results demonstrated altered white matter microstructure in circuits connecting the prefrontal lobe, the parietal lobe and the limbic system (p<0.005, uncorrected), findings which support previous research. More importantly, the result also indicated that a greater alteration in the white matter is associated with a more ruminative state (p<0.05, Bonferroni corrected). The detected abnormalities in the white matter should be interpreted cautiously because of the small sample size in this study. This finding supports the psychometric significance of white matter deficits in MDD.     

Diffusion tensor imaging and tractwise fractional anisotropy statistics: quantitative analysis in white matter pathology

Background  

Information on anatomical connectivity in the brain by measurements of the diffusion of water in white matter tracts lead to quantification of local tract directionality and integrity.     

Transmural heterogeneity of diffusion anisotropy in the sheep myocardium characterized by MR diffusion tensor imaging

The orientation of MRI-measured diffusion tensor in the myocardium has been directly correlated to the tissue fiber direction and widely characterized. However, the scalar anisotropy indexes have mostly been assumed to be uniform throughout the myocardial wall. The present study examines the fractional anisotropy (FA) as a function of transmural depth and circumferential and longitudinal locations in the normal sheep cardiac left ventricle. Results indicate that FA remains relatively constant from the epicardium to the midwall and then decreases (25.7%) steadily toward the endocardium. The decrease of FA corresponds to 7.9% and 12.9% increases in the secondary and tertiary diffusion tensor diffusivities, respectively. The transmural location of the FA transition coincides with the location where myocardial fibers run exactly circumferentially. There is also a significant difference in the midwall-endocardium FA slope between the septum and the posterior or lateral left ventricular free wall. These findings are consistent with the cellular microstructure from histological studies of the myocardium and suggest a role for MR diffusion tensor imaging in characterization of not only fiber orientation but, also, other tissue parameters, such as the extracellular volume fraction.     

Mapping traumatic axonal injury using diffusion tensor imaging: correlations with functional outcome

Background

Traumatic brain injury is a major cause of morbidity and mortality worldwide. Ameliorating the neurocognitive and physical deficits that accompany traumatic brain injury would be of substantial benefit, but the mechanisms that underlie them are poorly characterized. This study aimed to use diffusion tensor imaging to relate clinical outcome to the burden of white matter injury.

Methodology/Principal Findings

Sixty-eight patients, categorized by the Glasgow Outcome Score, underwent magnetic resonance imaging at a median of 11.8 months (range 6.6 months to 3.7 years) years post injury. Control data were obtained from 36 age-matched healthy volunteers. Mean fractional anisotropy, apparent diffusion coefficient (ADC), and eigenvalues were obtained for regions of interest commonly affected in traumatic brain injury. In a subset of patients where conventional magnetic resonance imaging was completely normal, diffusion tensor imaging was able to detect clear abnormalities. Significant trends of increasing ADC with worse outcome were noted in all regions of interest. In the white matter regions of interest worse clinical outcome corresponded with significant trends of decreasing fractional anisotropy.

Conclusions/Significance

This study found that clinical outcome was related to the burden of white matter injury, quantified by diffusivity parameters late after traumatic brain injury. These differences were seen even in patients with the best outcomes and patients in whom conventional magnetic resonance imaging was normal, suggesting that diffusion tensor imaging can detect subtle injury missed by other techniques. An improved in vivo understanding of the pathology of traumatic brain injury, including its distribution and extent, may enhance outcome evaluation and help to provide a mechanistic basis for deficits that remain unexplained by other approaches.     

Principles of diffusion tensor imaging and its applications to basic neuroscience research

The brain contains more than 100 billion neurons that communicate with each other via axons for the formation of complex neural networks. The structural mapping of such networks during health and disease states is essential for understanding brain function. However, our understanding of brain structural connectivity is surprisingly limited, due in part to the lack of noninvasive methodologies to study axonal anatomy. Diffusion tensor imaging (DTI) is a recently developed MRI technique that can measure macroscopic axonal organization in nervous system tissues. In this article, the principles of DTI methodologies are explained, and several applications introduced, including visualization of axonal tracts in myelin and axonal injuries as well as human brain and mouse embryonic development. The strengths and limitations of DTI and key areas for future research and development are also discussed.