Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms

Perinatal brain injury in survivors of premature birth has a unique and unexplained predilection for periventricular cerebral white matter. Periventricular white-matter injury (PWMI) is now the most common cause of brain injury in preterm infants and the leading cause of chronic neurological morbidity. The spectrum of chronic PWMI includes focal cystic necrotic lesions (periventricular leukomalacia; PVL) and diffuses myelination disturbances. Recent neuroimaging studies support that the incidence of PVL is declining, whereas focal or diffuse noncystic injury is emerging as the predominant lesion. Factors that predispose to PVL during prematurity include hypoxia, ischemia, and maternal-fetal infection. In a significant number of infants, PWMI appears to be initiated by perturbations in cerebral blood flow that reflect anatomic and physiological immaturity of the vasculature. Ischemic cerebral white matter is susceptible to pronounced free radical-mediated injury that particularly targets immature stages of the oligodendrocyte lineage. Emerging experimental data supports that pronounced ischemia in the periventricular white matter is necessary, but not sufficient to generate PWMI. The developmental predilection for PWMI to occur during prematurity appears to be related to both the timing of appearance and regional distribution of susceptible oligodendrocyte progenitors. Injury to oligodendrocyte progenitors may contribute to the pathogenesis of PWMI by disrupting the maturation of myelin-forming oligodendrocytes. Chemical mediators that may contribute to white-matter injury include reactive oxygen species glutamate, cytokines, and adenosine. As our understanding of the pathogenesis of PWMI improves, it is anticipated that new strategies for directly preventing brain injury in premature infants will develop.     

Inflammation in white matter: clinical and pathophysiological aspects

While the central nervous system (CNS) is generally thought of as an immunopriviledged site, immune-mediated CNS white matter damage can occur in both the perinatal period and in adults, and can result in severe and persistent neurological deficits. Periventricular leukomalacia (PVL) is an inflammatory white matter disease of premature infants that frequently results in cerebral palsy (CP). Clinical and experimental studies show that both hypoxic/ischemic and innate immune mechanisms contribute to the destruction of immature oligodendroglia and of axons in the deep cerebral white matter in PVL. No data are yet available as to whether there is any genetic predisposition to PVL or to its neurological sequelae. Multiple sclerosis (MS) is an inflammatory white matter disease that often begins in young adulthood, causes multifocal destruction of mature oligodendroglia and of axons, and eventually leads to substantial cumulative neurological disability. Certain genetic polymorphisms contribute to susceptibility to MS, and adaptive immune responses to myelin-associated self antigens, or to exogenous antigens that mimic these self antigens, play a central role in the pathophysiology of this disease.     

Transverse diffusivity of cerebral parenchyma predicts visual tracking performance in relapsing–remitting multiple sclerosis

This study investigated the relation between cerebral damage related to multiple sclerosis (MS) and cognitive decline as determined by two classical mental tracking tests. Cerebral damage in 15 relapsing–remitting MS patients was measured by diffusion tensor imaging (DTI). Fractional anisotropy, longitudinal and transverse diffusivity were defined in the cerebral parenchyma. Cognitive performance of the MS patients was assessed with the oral response format of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT). A significant correlation was found between performance on the SDMT and the fractional anisotropy in the brain. This correlation was predominantly induced by transverse diffusivity. Transverse diffusivity refers to the diffusion across fibers rather than along the fibers and is believed to be a specific marker for axonal loss and demyelination associated with MS. No significant association between DTI-measures and PASAT performance was found and this negative finding was mainly attributed to psychometric qualities. These results indicate that diffusivity along the non-principal diffusion direction, a possible signature of MS-related white matter pathology, contributes to information processing speed as measured with the SDMT, a task that requires close visual tracking and a widely used clinical marker for cognitive decline in MS.     

Metachromatic leukodystrophy and nonverbal learning disability: neuropsychological and neuroradiological findings in heterozygous carriers.

Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder due to deficiency of the enzyme arylsulfatase A that leads to progressive, diffuse demyelination. The syndrome of nonverbal learning disability has been attributed to white matter abnormality and has been reported in children with this disorder and in some healthy family member carriers of gene. We examined the neuropsychologic profiles and MRIs of eight members of the family of a 7-year-old girl with this disease, all of whom were heterozygous carriers of the mutation and five of whom were also carriers of the MLD pseudodeficiency gene. All had low normal levels of arylsulfatase A, and seven of the eight had average or better profiles across all assessed neuropsychological domains. The patient's younger sister had a profile with features of the syndrome of nonverbal learning disability despite a normal MRI, whereas two members with minor white matter findings did not. This family does not provide evidence for the syndrome of nonverbal learning disability in heterozygous carriers of the gene for MLD, even when associated with the MLD pseudodeficiency gene.     

Metachromatic Leukodystrophy and Nonverbal Learning Disability: Neuropsychological and Neuroradiological Findings in Heterozygous Carriers

Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder due to deficiency of the enzyme arylsulfatase A that leads to progressive, diffuse demyelination. The syndrome of nonverbal learning disability has been attributed to white matter abnormality and has been reported in children with this disorder and in some healthy family member carriers of gene. We examined the neuropsychologic profiles and MRIs of eight members of the family of a 7-year-old girl with this disease, all of whom were heterozygous carriers of the mutation and five of whom were also carriers of the MLD pseudodeficiency gene. All had low normal levels of arylsulfatase A, and seven of the eight had average or better profiles across all assessed neuropsychological domains. The patient's younger sister had a profile with features of the syndrome of nonverbal learning disability despite a normal MRI, whereas two members with minor white matter findings did not. This family does not provide evidence for the syndrome of nonverbal learning disability in heterozygous carriers of the gene for MLD, even when associated with the MLD pseudodeficiency gene.     

Information processing speed deficits may be better correlated with the extent of white matter sclerotic lesions in multiple sclerosis than previously suspected

Despite frequent use of the Paced Auditory Serial Addition Test (PASAT; Gronwall, 1977) for examining information processing speed (IPS) deficits in multiple sclerosis (MS), prior literature on the relationship between PASAT performance and severity of brain disease has been contradictory. In the present study, we found that PASAT performance is moderately well correlated with the total area of sclerotic brain lesions in MS patients only if a modified scoring method (mean "dyad" score; Snyder et al., 1993), but not the standard scoring method, is applied. We conclude that the PASAT remains a useful measure of IPS in MS, if a flaw in the typical scoring technique for this test is corrected. In our sample of 41 MS patients, for every one point decrease in mean dyad score, total lesion area increased by 364.08 mm2 on average, after controlling for age, sex, and education. IPS deficits are more severe for patients with greater brain disease, due to increased disruption of the white matter pathways that likely support the parallel distributed processing of complex information by geographically distant brain regions.     

White matter maturation supports the development of reasoning ability through its influence on processing speed

The structure of the human brain changes in several ways throughout childhood and adolescence. Perhaps the most salient of these changes is the strengthening of white matter tracts that enable distal brain regions to communicate with one another more quickly and efficiently. Here, we sought to understand whether and how white matter changes contribute to improved reasoning ability over development. In particular, we sought to understand whether previously reported relationships between white matter microstructure and reasoning are mediated by processing speed. To this end, we analyzed diffusion tensor imaging data as well as data from standard psychometric tests of cognitive abilities from 103 individuals between the ages of 6 and 18. We used structural equation modeling to investigate the network of relationships between brain and behavior variables. Our analyses provide support for the hypothesis that white matter maturation (as indexed either by microstructural organization or volume) supports improved processing speed, which, in turn, supports improved reasoning ability.     

Sex differences in the IQ-white matter microstructure relationship: A DTI study

Sex differences in the relationship between general intelligence and brain structure are a topic of increasing research interest. Early studies focused mainly on gray and white matter differences using voxel-based morphometry, while more recent studies investigated neural fiber tracts using diffusion tensor imaging (DTI) to analyze the white matter microstructure. In this study we used tract-based spatial statistics (TBSS) on DTI to test how intelligence is associated with brain diffusion indices and to see whether this relationship differs between men and women. 63 Men and women divided into groups of lower and higher intelligence were selected. Whole-brain DTI scans were analyzed using TBSS calculating maps of fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). The results reveal that the white matter microstructure differs between individuals as a function of intelligence and sex. In men, higher intelligence was related to higher FA and lower RD in the corpus callosum. In women, in contrast, intelligence was not related to the white matter microstructure. The higher values of FA and lower values of RD suggest that intelligence is associated with higher myelination and/or a higher number of axons particularly in men. This microstructural difference in the corpus callosum may increase cognitive functioning by reducing inter-hemispheric transfer time and thus account for more efficient brain functioning in men.     

Astrocytes and developmental white matter disorders

There is an increasing awareness that the astrocytes in the immature periventricular white matter are vulnerable to ischemia and respond to inflammation. Here we provide a synopsis of the articles that have evaluated the causes and consequences of developmental brain injuries to white matter astrocytes as well as the consequences of several genetic mutations that result in abnormal astrocyte development. Emerging data suggest that the astrocytes are not simply responding to the injury but are likely victims as well as culprits. Given the important roles that astrocytes play in maintaining ionic, neurotransmitter, and metabolic homeostasis in the brain, a more thorough understanding of the mechanisms that lead to their incapacitation, demise, or reactions as well as a better understanding of the stimuli that regulate their neuroprotective and regenerative properties will enable these cells to be manipulated to preserve the integrity of white matter and to potentially provide therapeutics to enhance neonatal regeneration and recovery from brain injury.     

Visuo-haptic transfer for object recognition in children with periventricular leukomalacia and bilateral cerebral palsy

Object recognition is a complex adaptive process that can be impaired in children with neurodevelopmental disabilities. Recently, we found a significant effect of time on the development of unimodal and crossmodal recognition skills for common objects in typical children and this was a starting point for the study of visuo-haptic object recognition skills in impaired populations. In this study, we investigated unimodal visual information, unimodal haptic information and visuo-haptic information transfer in 30 children, from 4.0 to 10.11 years of age, with bilateral Periventricular Leukomalacia (PVL) and bilateral cerebral palsy. Results were matched with those of 116 controls. Participants were tested using a clinical protocol, adopted in the previous study, involving visual exploration of black-and-white photographs of common objects, haptic exploration of real objects and visuo-haptic transfer of these two types of information. Results show that in the PVL group as in controls, there is an age-dependent development of object recognition abilities for visual, haptic and visuo-haptic modalities, even if PVL children perform worse in all the three conditions, in comparison with the typical group. Furthermore, PVL children have a specific deficit both in visual and haptic information processing, that improves with age, probably thanks to everyday experience, but the visual modality shows a better and more rapid maturation, remaining more salient compared to the haptic one. However, multisensory processes partially facilitate recognition of common objects also in PVL children and this finding could be useful for planning early intervention in children with brain lesion.     

Periventricular Leukomalacia (PVL): An Identical Twin Case Study Illustration of White Matter Dysfunction and Nonverbal Learning Disability (NLD)*

This paper discusses the implications of Periventricular Leukomalacia (PVL) lesions for the development of Nonverbal Learning Disabilities (NLD) as illustrated through an identical twin case study. PVL lesions were identified in an 8-year-old child, but were not detected in his identical twin brother who served as a matched comparison. While the nonclinical twin displayed a largely unremarkable neuropsychological profile, the clinical twin evidenced a distinct pattern of social, intellectual, academic, and neuropsychological test results often identified among children with PVL and those with the NLD syndrome. The clinical and theoretical implications for this case study are discussed.     

Periventricular leukomalacia (PVL): an identical twin case study illustration of white matter dysfunction and nonverbal learning disability (NLD).

This paper discusses the implications of Periventricular Leukomalacia (PVL) lesions for the development of Nonverbal Learning Disabilities (NLD) as illustrated through an identical twin case study. PVL lesions were identified in an 8-year-old child, but were not detected in his identical twin brother who served as a matched comparison. While the nonclinical twin displayed a largely unremarkable neuropsychological profile, the clinical twin evidenced a distinct pattern of social, intellectual, academic, and neuropsychological test results often identified among children with PVL and those with the NLD syndrome. The clinical and theoretical implications for this case study are discussed.     

Different early rearing experiences have long‐term effects on cortical organization in captive chimpanzees (Pan troglodytes)

Consequences of rearing history in chimpanzees (Pan troglodytes) have been explored in relation to behavioral abnormalities and cognition; however, little is known about the effects of rearing conditions on anatomical brain development. Human studies have revealed that experiences of maltreatment and neglect during infancy and childhood can have detrimental effects on brain development and cognition. In this study, we evaluated the effects of early rearing experience on brain morphology in 92 captive chimpanzees (ages 11–43) who were either reared by their mothers (n = 46) or in a nursery (n = 46) with age‐group peers. Magnetic resonance brain images were analyzed with a processing program (BrainVISA) that extracts cortical sulci. We obtained various measurements from 11 sulci located throughout the brain, as well as whole brain gyrification and white and grey matter volumes. We found that mother‐reared chimpanzees have greater global white‐to‐grey matter volume, more cortical folding and thinner grey matter within the cortical folds than nursery‐reared animals. The findings reported here are the first to demonstrate that differences in early rearing conditions have significant consequences on brain morphology in chimpanzees and suggests potential differences in the development of white matter expansion and myelination.     

Mapping the development of white matter tracts with diffusion tensor imaging

In this study, the development of white matter was studied using an optimized diffusion tensor imaging (DTI) protocol in 20 normal subjects (10–40 years old). The normal development of white matter tracts was addressed by comparing the diffusion anisotropy results between two sub‐groups: eight adults (26–38 years old) and eight adolescents (13–15 years old). The difference in myelination extent between these two groups as indexed by the fractional anisotropy was identified by conducting a student t‐test of the measured diffusion anisotropy maps. Significant differences (p < 0.01) were detected in the gyrus frontalis medialis (GFM), gyrus temporalis medialis (GTM) and gyrus cinguli (GC), in addition to the developmental changes in corpus callosum. A brief overview of previous published DTI studies in developmental science and current progress in DTI techniques is also given at the end of this paper. It may be useful for readers interested in using DTI to study developmental problems but who are not familiar with the various technical aspects.     

Canavan disease: a white matter disorder

Breakdown of oligodendrocyte-neuron interactions in white matter (WM), such as the loss of myelin, results in axonal dysfunction and hence a disruption of information processing between brain regions. The major feature of leukodystrophies is the lack of proper myelin formation during early development or the onset of myelin loss late in life. These early childhood WM diseases are described as hypomyelination or dysmyelination arising from a primary block in normal myelin synthesis because of a genetic mutation expressed in oligodendrocytes, or failure in myelination secondary to neuronal or astroglial dysfunctions (van der Knaap 2001 Dev. Med. Child Neurol. 43:705-712). Here, we describe the pathophysiological parameters of Canavan disease (CD), caused by genetic mutations of the aspartoacylase (ASPA) gene, a metabolic enzyme restricted in the central nervous system (CNS) to oligodendrocytes. CD presents pathophysiological dysfunctions similar to diseases caused by myelin gene mutations, such as Pelizaeus-Merzbacher disease (PMD) and several animal models, such as myelin deficient rat (md), jimpy (jp), shiverer (sh), and quaking (qk viable) mutant mice. These single gene mutations have pleiotropic effects, whereby the alteration of one myelin gene expression disrupts functional expression of other oligodendrocyte genes with an outcome of hypomyelination/dysmyelination. Among all of the known leukodystrophies, CD is the first disorder, which was approved and tested for the adeno-associated virus vector (AAV)-ASPA gene therapy (Leone et al. 2000 Ann. Neurol. 48:27-38; Janson et al. 2001 Trends Neurosci. 24:706-712) without much success following the first two attempts. ASPA gene delivery attempts in animal models have shown a lowering of N-acetyl L-aspartate and a change in motor functions, while sponginess of the WM, a characteristic of CD remained unchanged (Matalon et al. 2003 Mol. Ther. 7 (5, Part 1):580-587; McPhee et al. 2005 Brain Res. Mol. Brain Res. 135:112-121) even with better viral serotype and delivery of the gene during early phase of development (Klugmann et al. 2005 Mol. Ther. 11:745-753). While different approaches are being sought for the success of gene therapy, there are pivotal developmental questions to address regarding the specific regions of the CNS and cell lineages that become the target for the onset and progression of CD symptoms from early to late stages of development.     

道德概念的黑白隐喻表征及其对道德认知的影响

采用不同的研究方法在不同水平上考察道德概念的黑白隐喻表征, 探讨了黑白视知觉对道德认知的影响。实验1a发现, 在词汇选择任务中被试倾向于判断白色希腊文词汇具有道德意义, 判断黑色希腊文词汇具有不道德意义。实验1b通过词性判断任务表明, 当道德词以白色呈现、不道德词以黑色呈现时被试的判断反应更快。实验2显示, 当将道德两难故事呈现在黑色背景上时, 相比于呈现在白色背景上, 被试会在道德评判任务中将故事中人物的行为判断为更加不道德。实验3通过情境实验发现, 相比明亮环境, 在黑暗环境中完成实验的被试会更倾向于认为他人会不公正地对待自己。研究证明, 黑白颜色概念与道德概念的隐喻联结存在心理现实性, 黑白颜色刺激知觉会对道德判断产生影响作用, 且环境的亮度也会影响到人们对道德相关问题的认知判断。     

White matter development during adolescence as shown by diffusion MRI

Previous volumetric developmental MRI studies of the brain have shown white matter development continuing through adolescence and into adulthood. This review presents current findings regarding white matter development and organization from diffusion MRI studies. The general trend during adolescence (age 12–18 years) is towards increasing fractional anisotropy (FA) with age and decreasing mean diffusivity (MD) with age, findings primarily due to decreasing radial diffusivity with age. However, results of studies vary as to the regional specificity of such age-related changes, likely due in part to methodological issues. Another general trend is for FA to positively correlate and MD to negatively correlate with cognitive function. This trend is however region-specific, task-specific, and population-specific; some studies have in fact found negative correlations of FA and positive correlations of MD in specific regions with specific measures of cognitive performance. There are also published reports of sexual dimorphism in white matter development, indicating differing developmental trajectories between males and females as well as differing relationships developmentally between white matter architecture and cognitive function. There is a need for more research to further elucidate the development of white matter and its relation to cognitive function during this critical developmental period.     

Laterality of the frontal aslant tract (FAT) explains externalizing behaviors through its association with executive function

We investigated the development of a recently identified white matter pathway, the frontal aslant tract (FAT) and its association with executive function and externalizing behaviors in a sample of 129 neurotypical male and female human children ranging in age from 7 months to 19 years. We found that the FAT could be tracked in 92% of those children, and that the pathway showed age‐related differences into adulthood. The change in white matter microstructure was very rapid until about 6 years, and then plateaued, only to show age‐related increases again after the age of 11 years. In a subset of those children (5–18 years; n = 70), left laterality of the microstructural properties of the FAT was associated with greater attention problems as measured by the Child Behavior Checklist (CBCL). However, this relationship was fully mediated by higher executive dysfunction as measured by the Behavior Rating Inventory of Executive Function (BRIEF). This relationship was specific to the FAT—we found no relationship between laterality of a control pathway, or of the white matter of the brain in general, and attention and executive function. These findings suggest that the degree to which the developing brain favors a right lateralized structural dominance of the FAT is directly associated with executive function and attention. This novel finding provides a new potential structural biomarker to assess attention deficit hyperactivity disorder (ADHD) and associated executive dysfunction during development.     

Conceptual development in learning-disabled and normal boys

In two related studies, a pictorial sorting task served as the means of measuring conceptual development in LD and normal boys. The studies found no differences in the bases on which groups were formed (perceptible attributes, function, or nominal class membership) or in the manner in which groups were structured (thematically, in complexive groups or superordinate groups). Furthermore, parallel developmental trends were found in both LD and normal subjects groups. These findings are not consistent with early studies of concept formation in brain-damaged subjects, most of whom were retarded. Subjects in the present studies were selected on the basis of clinical diagnosis of LD and average IQ. The findings of the present studies suggest that generalizations about conceptual abilities of LD children of normal intelligence should not be based on early studies of the effects of brain damage.