Normal and abnormal white matter maturation

The unique ability of MR to demonstrate both normal and abnormal white matter maturation with a high degree of sensitivity makes it an indispensable tool with which to evaluate children with clinical developmental delay or suspected dysmyelinating processes. Because the noninvasive nature of MRI allows sequential studies to be performed without additional risk to the patient, it offers an unprecedented opportunity to study the process of myelination in normal infants, developmentally delayed infants and to better understand the dysmyelinating disorders, a relatively rare, poorly understood group of diseases.     

Automatic segmentation of MR images of the developing newborn brain

This paper describes an automatic tissue segmentation method for newborn brains from magnetic resonance images (MRI). The analysis and study of newborn brain MRI is of great interest due to its potential for studying early growth patterns and morphological changes in neurodevelopmental disorders. Automatic segmentation of newborn MRI is a challenging task mainly due to the low intensity contrast and the growth process of the white matter tissue. Newborn white matter tissue undergoes a rapid myelination process, where the nerves are covered in myelin sheathes. It is necessary to identify the white matter tissue as myelinated or non-myelinated regions. The degree of myelination is a fractional voxel property that represents regional changes of white matter as a function of age. Our method makes use of a registered probabilistic brain atlas. The method first uses robust graph clustering and parameter estimation to find the initial intensity distributions. The distribution estimates are then used together with the spatial priors to perform bias correction. Finally, the method refines the segmentation using training sample pruning and non-parametric kernel density estimation. Our results demonstrate that the method is able to segment the brain tissue and identify myelinated and non-myelinated white matter regions.     

Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping

The elaboration of the myelinated white matter is essential for normal neurodevelopment, establishing and mediating rapid communication pathways throughout the brain. These pathways facilitate the synchronized communication required for higher order behavioral and cognitive functioning. Altered neural messaging (or 'disconnectivity') arising from abnormal white matter and myelin development may underlie a number of neurodevelopmental psychiatric disorders. Despite the vital role myelin plays, few imaging studies have specifically examined its maturation throughout early infancy and childhood. Thus, direct investigations of the relationship(s) between evolving behavioral and cognitive functions and the myelination of the supporting neural systems have been sparse. Further, without knowledge of the 'normative' developmental time-course, identification of early abnormalities associated with developmental disorders remains challenging. In this work, we examined the use of longitudinal (T(1)) and transverse (T(2)) relaxation time mapping, and myelin water fraction (MWF) imaging to investigate white matter and myelin development in 153 healthy male and female children, 3months through 60months in age. Optimized age-specific acquisition protocols were developed using the DESPOT and mcDESPOT imaging techniques; and mean T(1), T(2) and MWF trajectories were determined for frontal, temporal, occipital, parietal and cerebellar white matter, and genu, body and splenium of the corpus callosum. MWF results provided a spatio-temporal pattern in-line with prior histological studies of myelination. Comparison of T(1), T(2) and MWF measurements demonstrates dissimilar sensitivity to tissue changes associated with neurodevelopment, with each providing differential but complementary information.     

Microstructural maturation of the human brain from childhood to adulthood

Brain maturation is a complex process that continues well beyond infancy, and adolescence is thought to be a key period of brain rewiring. To assess structural brain maturation from childhood to adulthood, we charted brain development in subjects aged 5 to 30 years using diffusion tensor magnetic resonance imaging, a novel brain imaging technique that is sensitive to axonal packing and myelination and is particularly adept at virtually extracting white matter connections. Age-related changes were seen in major white matter tracts, deep gray matter, and subcortical white matter, in our large (n=202), age-distributed sample. These diffusion changes followed an exponential pattern of maturation with considerable regional variation. Differences observed in developmental timing suggest a pattern of maturation in which areas with fronto-temporal connections develop more slowly than other regions. These in vivo results expand upon previous postmortem and imaging studies and provide quantitative measures indicative of the progression and magnitude of regional human brain maturation.     

Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study

The underlying neurobiology of autism, a severe pervasive developmental disorder, remains unknown. Few neocortical brain MRI abnormalities have been reported. Using rest functional brain imaging, two independent studies have described localized bilateral temporal hypoperfusion in children with primary autism. In order to search for convergent evidence of anatomical abnormalities in autistic children, we performed an anatomical MRI study using optimized whole-brain voxel-based morphometry (VBM). High-resolution 3-D T1-weighted MRI data sets were acquired in 21 children with primary autism (mean age 9.3 +/- 2.2 years) and 12 healthy control children (mean age 10.8 +/- 2.7 years). By comparing autistic children to normal children, we found bilaterally significant decreases of grey matter concentration located in superior temporal sulcus (STS) (P < 0.05 corrected, after small volume correction; SVC). Children with autism were also found to have a decrease of white matter concentration located in the right temporal pole and in cerebellum (P < 0.05, corrected) compared to normal children. These results suggest that autism is associated with bilateral anatomical abnormalities localized in the STS and are remarkably consistent with functional hypoperfusion previously reported in children with autism. The multimodal STS areas are involved in highest level of cortical integration of both sensory and limbic information. Moreover, the STS is now recognized as a key cortical area of the "social brain" and is implicated in social perceptual skills that are characteristically impaired in autism. Therefore, the convergent anatomical and functional temporal abnormalities observed in autism may be important in the understanding of brain behavior relationships in this severe developmental disorder.     

Neuroanatomy in adolescents and young adults with 22q11 deletion syndrome: comparison to an IQ-matched group

22q11 deletion syndrome (22q11DS) is a common genetic condition associated with learning disability and high risk for psychiatric illness, in particular schizophrenia. Previous neuroimaging studies in children and adults with 22q11DS have uncovered a number of abnormalities, but have not differentiated between features relating to cognitive impairment and features relating to risk for schizophrenia. This structural MRI study compares adolescents with 22q11DS (n=14) to adolescents with idiopathic learning disability (n=13) and to typically-developing controls (n=14). Voxel-based morphometry and region-of-interest volumetric analyses were employed to test specific hypotheses based on prior studies of 22q11DS. Features that differentiated 22q11DS participants from both matched-IQ and higher-IQ controls were total white matter volume reduction, occipito-parietal and anterior temporal grey matter reduction, frontal and insula grey matter enlargement, and corpus callosum enlargement. On the other hand, hippocampal volume and cerebellar hemisphere reductions differed between 22q11DS and higher-IQ controls only. The neuroanatomical substrates for cognitive impairment and psychiatric illness in 22q11DS are at least partially separable. Correlations between regional volumetric abnormalities and age suggest that exaggerated processes of normal adolescent brain maturation contribute to psychosis-risk in 22q11DS, consistent with previous findings in childhood-onset schizophrenia.     

Diffusion tensor imaging of white matter tract evolution over the lifespan

Diffusion tensor imaging (DTI) has been used widely to show structural brain changes during both development and aging. Lifespan studies are valuable because they connect these two processes, yet few DTI studies have been conducted that include both children and elderly subjects. This study used DTI tractography to investigate 12 major white matter connections in 403 healthy subjects aged 5-83 years. Poisson fits were used to model changes of fractional anisotropy (FA) and mean diffusivity (MD) across the age span, and were highly significant for all tracts. FA increased during childhood and adolescence, reached a peak between 20 and 42 years of age, and then decreased. MD showed an opposite trend, decreasing first, reaching a minimum at 18-41 years, and then increasing later in life. These trajectories demonstrate rates and timing of development and degradation that vary regionally in the brain. The corpus callosum and fornix showed early reversals of development trends, while frontal-temporal connections (cingulum, uncinate, superior longitudinal) showed more prolonged maturation and delayed declines. FA changes were driven by perpendicular diffusivity, suggesting changes of myelination and/or axonal density. Tract volume changed significantly with age for most tracts, but did not greatly influence the FA and MD trajectories. This study demonstrates clear age-related microstructural changes throughout the brain white matter, and provides normative data that will be useful for studying white matter development in a variety of diseases and abnormal conditions.     

Age-related cognitive gains are mediated by the effects of white matter development on brain network integration

A fundamental, yet rarely tested premise of developmental cognitive neuroscience is that changes in brain activity and improvements in behavioral control across adolescent development are related to brain maturational factors that shape a more efficient, highly-interconnected brain in adulthood. We present the first multimodal neuroimaging study to empirically demonstrate that maturation of executive cognitive ability is directly associated with the relationship of white matter development and age-related changes in neural network functional integration. In this study, we identified specific white matter regions whose maturation across adolescence appears to reduce reliance on local processing in brain regions recruited for conscious, deliberate cognitive control in favor of a more widely distributed profile of functionally-integrated brain activity. Greater white matter coherence with age was associated with both increases and decreases in functional connectivity within task-engaged functional circuits. Importantly, these associations between white matter development and brain system functional integration were related to behavioral performance on tests of response inhibition, demonstrating their importance in the maturation of optimal cognitive control.     

Magnetization transfer ratio in mild cognitive impairment and dementia of Alzheimer's type

Almost half of the elderly subjects that are diagnosed with mild cognitive impairment (MCI) go on to develop dementia of Alzheimer's type (DAT) over a 5-year follow-up. MCI and DAT subjects show regional decreases in the volume of brain structures, which correlate with the cognitive decline among these groups. Volumetric changes are found more consistently in the DAT group than in the MCI group. Since not all MCI subjects demonstrate volumetric decline, we propose that the underlying changes in the structural integrity of the brain, measured using magnetization transfer ratio (MTR), may be used as an additional predictor for abnormal cognitive decline in the elderly. Magnetic resonance (MR) images were obtained in 15 DAT, MCI, and elderly control subjects. Using automatic tissue classification, the brain region of each MR volume was segmented into gray matter and white matter. Mean and standard error of the mean MTR measured within the gray matter was found to be significantly lower in the MCI (30.77 +/-0.29; P = 0.037) and the DAT (29.37 +/-0.41; P = 0.000) group compared to the control group (32.11 +/-0.20). The MTR of white matter was significantly lower only in the DAT group. The gray matter volume was significantly lower (P = 0.000) in the DAT (387.29 +/-26.04 cm(3)) group compared to controls (532.93 +/-20.53 cm(3)) and MCI (464.64 +/-16.93 cm(3)). No significant differences were found in the white matter volume between the three groups. We conclude that changes in MTR are measurable even in the absence of detectable volumetric changes in gray and white matter in the MCI group. Furthermore, MTR changes may present a novel MRI measure for the early diagnosis of dementia of Alzheimer's type.     

A longitudinal study of brain morphometrics using quantitative magnetic resonance imaging and difference image analysis

Serial quantitative magnetic resonance imaging (MRI) allows the detection of subtle volumetric changes in brain volume. We used serial volumetry and voxel-based difference image analysis to quantify and characterize longitudinal changes in the hippocampus, cerebellum, and neocortex in younger and middle-age individuals. Paired volumetric MRI brain scans 3.5 years apart were performed on 90 healthy subjects 14 to 77 years old. Quantitative assessment of registered images included hippocampal volumetry, cerebellar volumetry, and automatically determined regional brain volumes. Longitudinal volume changes in three age epochs (<35, 35-54, >54 years) were compared and neocortical changes beyond regions of interest were visualized using filtered difference images. Cross-sectional analysis revealed a significant association between age and reduction in all brain volumes except hippocampal volume. Changes in normalized hippocampal and white matter volume were significantly different among the three groups. Individual analysis revealed 5 subjects with significant longitudinal volume changes lying outside the normative range. Difference image analysis showed global involutional changes in the >54 age group. Our findings suggest that cross-sectional observations in intracranial volume, cerebellar volume, and gray matter volume are likely to reflect uniform rates of volume loss or secular changes. Accelerated brain atrophy was seen from the age of 35-54 and increased rates of hippocampal atrophy from the age of 54. Our findings emphasize the importance of controlling for age effects when studying pathological brain changes over a wide age range.     

Assessment of the early organization and maturation of infants' cerebral white matter fiber bundles: a feasibility study using quantitative diffusion tensor imaging and tractography

The human infant is particularly immature at birth and brain maturation, with the myelination of white matter fibers, is protracted until adulthood. Diffusion tensor imaging offers the possibility to describe non invasively the fascicles spatial organization at an early stage and to follow the cerebral maturation with quantitative parameters that might be correlated with behavioral development. Here, we assessed the feasibility to study the organization and maturation of major white matter bundles in eighteen 1- to 4-month-old healthy infants, using a specific acquisition protocol customized to the immature brain (with 15 orientations of the diffusion gradients and a 700 s mm(-2)b factor). We were able to track most of the main fascicles described at later ages despite the low anisotropy of the infant white matter, using the FACT algorithm. This mapping allows us to propose a new method of quantification based on reconstructed tracts, split between specific regions, which should be more sensitive to specific changes in a bundle than the conventional approach, based on regions-of-interest. We observed variations in fractional anisotropy and mean diffusivity over the considered developmental period in most bundles (corpus callosum, cerebellar peduncles, cortico-spinal tract, spino-thalamic tract, capsules, radiations, longitudinal and uncinate fascicles, cingulum). The results are in good agreement with the known stages of white matter maturation and myelination, and the proposed approach might provide important insights on brain development.     

婴儿神经学检查联合头颅MRI检测对脑瘫高危儿不良神经发育的预测价值

目的 探讨Hammersmith婴儿神经学检查（HINE）联合头颅MRI检测对脑瘫高危儿12月龄诊断脑瘫和运动发育迟缓的预测价值。 方法 选取矫正2～6月龄行HINE和头颅MRI检查的脑瘫高危儿45例,随访至矫正12月龄,最终完成随访共36例,采用Peabody运动发育量表(PDMS)对其运动发育程度进行评估,分为正常组（21例）、迟缓组（8例）和脑瘫组（7例）。根据头颅MRI检测Woodward白质评分法评价患儿的脑白质异常程度,计算2～6月龄HINE得分、12月龄HINE得分与头颅MRI脑白质异常程度之间的Spearman系数,计算2～6月龄HINE得分与脑瘫严重程度和迟缓严重程度之间的Spearman系数,计算单独使用HINE、头颅MRI及其联合使用与婴儿发育结局之间的Spearman系数。采用受试者工作特征曲线(ROC)描绘单独使用HINE、头颅MRI、HINE或头颅MRI异常、HINE且头颅MRI异常四个指标预测矫正12月龄时诊断脑瘫和迟缓的曲线下面积(AUC),并评价其预测价值。 结果 ①36例高危儿中,12例HINE得分预测为脑瘫;头颅MRI脑白质评分,中重度异常9例,轻度异常9例,无异常18例;随访至矫正12月龄,发育正常21例,运动发育迟缓8例（7例差,1例非常差）,脑瘫7例,其中脑瘫粗大运动功能分级系统（GMFCS）分级Ⅲ级2例,Ⅳ级4例,Ⅴ级1例。②2～6月HINE得分与脑瘫严重程度分级（r=-0.867,P＝0.012）、迟缓严重程度（r=-0.598,P＝0.000）之间均具有相关性,HINE得分越低其预后越差。③矫正2～6月龄HINE得分和12月龄HINE得分与头颅MRI的脑白质异常程度之间均具有相关性（r值分别为-0.790和-0.683,P值均为0.000）。④HINE、头颅MRI、HINE或头颅MRI异常、HINE且头颅MRI异常与脑瘫和迟缓结局均具有相关性（r值分别为0.644、0.772、0.572、0.839和0.781、0.783、0.714、0.944,P值均为0.000）;预测脑瘫和迟缓结局诊断的敏感性分别为100.0%、100.0%、100.0%、100.0%和93.3%、93.3%、100.0%、93.3%,特异性分别为82.8%、93.1%、79.3%、96.6%和85.7%、81.0%、71.4%、100.0%,AUC值分别为0.914、0.966、0.897、0.983和0.895、0.871、0.857、0.967（P值均为0.000）。 结论 HINE联合头颅MRI检测对脑瘫高危儿12月龄发育结局预测价值更高。     

Myelin mapping in the living mouse brain using manganese-enhanced magnetization transfer MRI

This work demonstrates manganese-enhanced magnetization transfer (MT) MRI to improve the contrast of myelinated structures in mouse brain in vivo. Systemic administration of manganese chloride led to a reduction of the MT ratio by 23% in white matter and 35% in gray matter. The effect increased their contrast-to-noise ratio by 48% and facilitated a mapping of myelin-rich white matter tissues. Relaxation time measurements revealed the manganese-induced shortening of T1 to be smaller in the corpus callosum (?42%) than in the cortex (?52%) or hippocampus (?60%). These findings are in line with the assumption that a high myelin and correspondingly low water content hinder the free diffusion and uptake of manganese ions. The resulting preferential accumulation of manganese in gray matter structures causes a stronger reduction of the MT saturation in gray matter than in white matter. Extending MRI assessments with conventional MT contrast, manganese-enhanced MT MRI at 76 × 80 × 160 μm³ resolution and 2.35 T field strength allowed for a delineation of small myelinated structures such as the fornix, mammillothalamic tract, and fasciculus retroflexus in the living mouse brain.     

The lateral asymmetry of the human brain studied by volumetric magnetic resonance imaging

Improvements in in vivo imaging methods have boosted research on brain asymmetry aimed at further establishing putative anatomical substrates for brain functional lateralization and particularly to explain left-hemisphere specialization for language. We analyzed volume asymmetries for major anatomical divisions of the lateral (perisylvian) brain region and their relative white matter content. A total of 100 healthy right-handed subjects were examined with 3D magnetic resonance imaging (MRI). The insular plane was used to limit the lateral brain, and the sylvian fissure and central sulcus to define frontal, parietal, temporal, and temporo-parieto-occipital regions. Results revealed a frontal region showing similar volumes in both hemispheres, a parietal region and a temporal region both larger in the left hemisphere, and a temporo-parieto-occipital region with predominantly right-sided asymmetry. Volume measurements of the parietal, temporal, and temporo-parieto-occipital regions complemented each other and accounted for 58% of planum temporale area variations. All study regions showed significant asymmetry for relative white matter content (percentage of white matter relative to region volume). White matter asymmetry, however, was particularly relevant for the frontal and temporal regions showing a highly frequent left-sided pattern (frontal region, 90%; temporal region, 91% of subjects). Leftward asymmetry in these two regions occurred in both genders, although hemisphere differences were significantly larger in men. Results from this MRI volume analysis of structural asymmetries in the lateral brain region complement data obtained by other methods and suggest a high occurrence of leftward asymmetry for relative white matter content in language-related regions.     

Accelerated maturation of white matter in young children with autism: a high b value DWI study

The goal of this work was to study white matter maturation in young children with autism following previous reports of increased cerebral volume during early development, as well as arguments for abnormal neural growth patterns and regulation at this critical developmental period. We applied diffusion tensor imaging (DTI) and high b value diffusion-weighted imaging (DWI) to young children diagnosed with autism and to a typically developing (TD) control group. Fractional anisotropy (FA), probability and displacement were measured in overall analysis as well as in regions of interest (ROI). Individual data points of children with autism were compared to the developmental curves obtained from typically developing children. Increased restriction, reflected in significantly increased FA and probability along with reduced displacement values, was detected in overall analysis as well as in several brain regions. Increased restriction, suggesting an early and accelerated abnormal maturation of white matter, was more dominant in the left hemisphere and was mainly detected in the frontal lobe. No changes were detected in the occipital lobes. These results support previous claims of abnormal brain overgrowth in young children with autism and are in contrast to the decreased restricted diffusion reported in previous studies in adolescent with autism.     

正常足月新生儿脑的MRI信号特点

目的:研究正常足月新生儿脑的MRI信号特点。材料与方法:用0.15T磁共振成像设备SE序列对20例正常足月新生儿进行颅脑T_1和T_2加权成像。以孕期胎龄与出生后日龄之和做为新生儿的实际胎龄。结果与结论:①T_1加权成像脑白质表现低信号,髓鞘化区城为高信号,灰质为稍高信号。髓鞘化的范围和灰白质对比度与新生儿的实际胎龄成正相关;②T_2加权成像,脑白质为较高信号,灰质和髓鞘化区域呈明显的低信号,全组新生儿的灰白质对比均清晰明显;③全组新生儿的侧脑室前角和后角周围的小片白质均呈长T_1和T_2信号特点,与邻近的白质和灰质对比清楚。此属生理现象。     

Automated morphometric study of brain variation in XXY males

This paper studies brain morphometry variation associated with XXY males (Klinefelter's syndrome) by using an automated whole-brain volumetric analysis method. The application to 34 XXY males and 62 normal male controls reveals pronounced volume reduction in the brains of XXY males, relative to the brains of normal controls, localized at the insula, temporal gyri, amygdala, hippocampus, cingulate, and occipital gyri. Most of these statistically significant regions are in the gray matter structures, with the exception of one cluster of atrophy involved in white matter structure, i.e., right parietal lobe white matter. Compared to previous findings documented in the literature, our findings provide a better spatial localization of the affected regions. In addition to the reduction of local volume, overall enlargement of ventricles and overall volume reduction of both white matter and gray matter are also found in XXY males.     

Longitudinal analysis of gray and white matter loss in patients with systemic lupus erythematosus

Cerebral atrophy has been described to occur in systemic lupus erythematosus (SLE) with variable frequency. The aim of this study was to determine white and gray matter abnormalities in brain magnetic resonance imaging (MRI) of patients with SLE and to determine if these abnormalities progress over a one-year period. Seventy-five patients with SLE and 44 healthy age and sex-matched controls were enrolled in this study. T1-weighted volumetric images were used for voxel based morphometry (VBM) analyses. SLE patients exhibited a significant reduction in white matter and gray matter volume compared to controls (p=0.001). Follow-up images, after an average interval of 19 months, revealed a progressive white matter and gray matter atrophy (p=0.001). Reduced white and gray matter volume was associated with disease duration and the presence of antiphospholipid antibodies. Patients with severe cognitive impairment had a more pronounced white and gray matter reduction than patients with moderate cognitive impairment. Total corticosteroid dose was associated with gray matter reduction and not with white matter loss in SLE patients. We concluded that brain tissue loss associated with SLE is significant and progresses over a relatively short period of time. Disease duration, the presence of antiphospholipid antibodies and cognitive impairment were associated with white and gray matter loss. Corticosteroid was associated only with gray matter atrophy.     

注意缺陷多动障碍患儿脑结构和功能磁共振成像研究

目的使用三维高分辨结构磁共振和静息态功能磁共振成像技术研究注意缺陷多动障碍(attention deficit/hyperactivity disorder,ADHD)儿童的脑部改变,探讨其脑功能改变是否具有结构基础。材料与方法对10例ADHD患儿及10例正常对照组儿童进行全脑扫描,获取高分辨T1加权图像,得到每个被试的灰质及白质体积参数图;获取静息态功能图像,得到低频振幅(amplitude of low frequency fluctuation,ALFF)参数图。采用基于体素的分析方法比较两组被试参数图之间的差别。结果与正常对照组相比,ADHD患儿双侧额中回、中央前回、前扣带皮质、壳核,左侧眶额皮质、尾状核及右侧小脑的灰质体积减小;双侧前额叶白质、胼胝体前部和后部及左侧眶额白质体积减小。在前扣带回、前额叶、尾状核等区域,ADHD患儿存在显著的ALFF的升高,提示自发功能活动更加活跃。结论 ADHD儿童在脑部功能和结构两方面均有异常,且存在相互关联,揭示该疾病的病理机制。     

Magnetic resonance and diffusion tensor imaging in pediatric white matter diseases

The central nervous system undergoes profound and predictable developmental changes during the first few years of life that provide the structural and functional elements necessary for normal neurological development. The establishment and maturation of white matter pathways is a critical component of the developing nervous system. Diffusion tensor imaging (DTI) offers a noninvasive and quantitative means for the evaluation of white matter changes. DTI has contributed to the evaluation of a number of childhood leukoencephalopathies; it has also been used to follow brain maturation in abnormal states, such as premature birth or early brain injury. Furthermore, it has helped characterize the relation between white matter integrity and cognitive abilities. In the future, DTI is expected to play an increasingly large role in defining developmental abnormalities at an early age and in assessing therapies for pediatric disorders such as leukodystrophies.