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.     

The Yin and Yang of cell cycle progression and differentiation in the oligodendroglial lineage

In white matter disorders such as leukodystrophies (LD), periventricular leucomalacia (PVL), or multiple sclerosis (MS), the hypomyelination or the remyelination failure by oligodendrocyte progenitor cells involves errors in the sequence of events that normally occur during development when progenitors proliferate, migrate through the white matter, contact the axon, and differentiate into myelin-forming oligodendrocytes. Multiple mechanisms underlie the eventual progressive deterioration that typifies the natural history of developmental demyelination in LD and PVL and of adult-onset demyelination in MS. Over the past few years, pathophysiological studies have mostly focused on seeking abnormalities that impede oligodendroglial maturation at the level of migration, myelination, and survival. In contrast, there has been a strikingly lower interest for early proliferative and differentiation events that are likely to be equally critical for white matter development and myelin repair. This review highlights the Yin and Yang principles of interactions between intrinsic factors that coordinately regulate progenitor cell division and the onset of differentiation, i.e. the initial steps of oligodendrocyte lineage progression that are obviously crucial in health and diseases.     

Functional topography of early periventricular brain lesions in relation to cytoarchitectonic probabilistic maps

Early periventricular brain lesions can not only cause cerebral palsy, but can also induce a reorganization of language. Here, we asked whether these different functional consequences can be attributed to topographically distinct portions of the periventricular white matter damage. Eight patients with pre- and perinatally acquired left-sided periventricular brain lesions underwent focal transcranial magnetic stimulation to assess the integrity of cortico-spinal hand motor projections, and functional MRI to determine the hemispheric organization of language production. MRI lesion-symptom mapping revealed that two distinct portions of the periventricular lesions were critically involved in the disruption of cortico-spinal hand motor projections on the one hand and in the induction of language reorganization into the contra-lesional right hemisphere on the other hand. Both regions are located in a position compatible with the course of cortico-spinal/cortico-nuclear projections of the primary motor cortex in the periventricular white matter, as determined by the stereotaxic probabilistic cytoarchitectonic atlas developed by the Jülich group.     

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.     

Early gray-matter and white-matter concentration in infancy predict later language skills: A whole brain voxel-based morphometry study

Magnetic Resonance Imaging (MRI) brain scans were obtained from 19 infants at 7 months. Expressive and receptive language performance was assessed at 12 months. Voxel-based morphometry (VBM) identified brain regions where gray-matter and white-matter concentrations at 7 months correlated significantly with children’s language scores at 12 months. Early gray-matter concentration in the right cerebellum, early white-matter concentration in the right cerebellum, and early white-matter concentration in the left posterior limb of the internal capsule (PLIC)/cerebral peduncle were positively and strongly associated with infants’ receptive language ability at 12 months. Early gray-matter concentration in the right hippocampus was positively and strongly correlated with infants’ expressive language ability at 12 months. Our results suggest that the cerebellum, PLIC/cerebral peduncle, and the hippocampus may be associated with early language development. Potential links between these structural predictors and infants’ linguistic functions are discussed.     

丰富环境对脑缺血大鼠突触界面结构修饰和PSD-95基因表达的影响

探讨丰富环境干预对局部脑缺血大鼠突触界面结构修饰和突触后致密物-95 (postsynaptic density-95,PSD-95 ) mRNA表达的影响。栓塞健康雄性Sprague-Dawley大鼠的右侧大脑中动脉,建立脑中动脉栓塞(middle cerebral artery occlusion,MCAO)模型后,分为丰富环境缺血组(IE)、标准环境缺血组(IS),同时分别设丰富环境假手术组(SE)、标准环境假手术组(SS)。以Morris水迷宫检测大鼠的空间学习记忆能力,应用透射电镜、图像分析和细胞形态计量学技术,观察海马CA1区和额叶皮层突触界面结构变化,采用RT-PCR检测突触后脚手架蛋白PSD-95 mRNA的表达。结果表明：丰富环境干预能有效改善脑缺血导致的空间学习记忆能力下降,并对正常大鼠的空间学习记忆能力也有改善作用。同时,丰富环境干预能抑制局部脑缺血导致的突触数密度减少,该作用对额叶皮层特别明显;丰富环境干预不同程度地逆转脑缺血造成的突触界面参数变化,特别使突触间隙宽度显著减小、PSD厚度明显增加;并有效抑制因脑缺血诱导的PSD-95 mRNA表达下调。以上结果提示,丰富环境改善脑缺血大鼠的空间学习记忆能力可能与其促进缺血区边缘组织突触界面结构修饰,提高PSD-95 mRNA表达有关     

The prematurity stereotype revisited: Impact on mothers' interactions with premature and full‐term infants

Research exploring the effects of labeling on maternal perceptions and behaviors was extended by simultaneously examining the cognitive and behavioral effects of prematurity stereotyping with both mothers of full‐term and premature infants, and by examining the effects of an information‐based intervention on the stereotyped responses of mothers of premature infants. An experimental design wherein mothers of both full‐term and premature infants were randomly assigned to interact with, and then rate, either a full‐term or premature infant who was described as either full‐term or premature was employed to test several hypotheses. Two hypotheses related to prematurity stereotyping received support: mothers showed more positive responses to infants labeled full‐term than to infants labeled premature, and mothers of full‐term infants exhibited more prematurity stereotyping than did mothers of premature infants. The hypothesis concerning gender effects also was supported, with mothers showing more positive responses to male infants than to female infants. In contrast to expectations, a brief cognitive intervention provided to some mothers of premature infants failed to reduce stereotyping, and, indeed, appeared to increase stereotyping. These results are compared with the results of previous studies, most of which did not include actual interactions between mothers and infants, and the implications of these results are considered. © 2000 Michigan Association for Infant Mental Health.     

The prematurity stereotype: Empirical evidence and implications for practice

The prematurity stereotype is defined as a set of biased beliefs about infants who are identified as having been born prematurely. This article reviews studies that have explored how this prematurity stereotype may negatively influence adults' perceptions of, expectations for, and behavior toward premature infants. The findings from these studies are considered in the context of more general knowledge about how expectations can influence behavior and result in self-fulfilling prophecies. Recent research designed to investigate how prematurity stereotyping can be reduced also is described and evaluated. Finally, the implications of this program of research for intervention with parents of premature infants and suggestions for future research directions are discussed.     

Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults

White matter damage (WMD) in preterm neonates is strongly associated with adverse outcome. The etiology of white matter injury is not known but clinical data suggest that ischemia-reperfusion and/or infection-inflammation are important factors. Furthermore, antenatal infection seems to be an important risk factor for brain injury in term infants. In order to explore the pathophysiological mechanisms of WMD and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, numerous novel animal models have been developed over the past decade. WMD can be induced by antenatal or postnatal administration of microbes (E. coli or Gardnerella vaginalis), virus (border disease virus) or bacterial products (lipopolysaccharide, LPS). Alternatively, various hypoperfusion paradigms or administration of excitatory amino acid receptor agonists (excitotoxicity models) can be used. Irrespective of which insult is utilized, the maturational age of the CNS and choice of species seem critical. Generally, lesions with similarity to human WMD, with respect to distribution and morphological characteristics, are easier to induce in gyrencephalic species (rabbits, dogs, cats and sheep) than in rodents. Recently, however, models have been developed in rats (PND 1-7), using either bilateral carotid occlusion or combined hypoxia-ischemia, that produce predominantly white matter lesions. LPS is the infectious agent most often used to produce WMD in immature dogs, cats, or fetal sheep. The mechanism whereby LPS induces brain injury is not completely understood but involves activation of toll-like receptor 4 on immune cells with initiation of a generalized inflammatory response resulting in systemic hypoglycemia, perturbation of coagulation, cerebral hypoperfusion, and activation of inflammatory cells in the CNS. LPS and umbilical cord occlusion both produce WMD with quite similar distribution in 65% gestational sheep. The morphological appearance is different, however, with a more pronounced infiltration of inflammatory cells into the brain and focal microglia/macrophage ("inflammatory WMD") in response to LPS compared to hypoperfusion evoking a more diffuse microglial response usually devoid of cellular infiltrates ("ischemic WMD"). Furthermore, low doses of LPS that by themselves have no adverse effects in 7-day-old rats (maturation corresponding to the near term human fetus), dramatically increase brain injury to a subsequent hypoxic-ischemic challenge, implicating that bacterial products can sensitize the immature CNS. Contrary to this finding, other bacterial agents like lipoteichoic acid were recently shown to induce tolerance of the immature brain suggesting that the innate immune system may respond differently to various ligands, which needs to be further explored.     

Walking and periventricular leukomalacia: locomotor characteristics and brain imaging (MRI)

The aim of the present study was to compare the walking abilities in infants with and without periventricular leukomalacia and to see whether the severity of the brain damage was related to locomotor outcome of the infants at 12 and 18 months. 47 newborns were included in the study based on white matter abnormalities on ultrasound. Magnetic resonance imaging (MRI) recordings during the neonatal period were used to identify and quantify the location and severity of the brain lesions. Locomotor outcome was assessed in terms of disability at 12 and 18 months. The quality of walking, including global and segmental gait parameters, was measured for the infants who could walk independently at 18 months and compared to a group of healthy control infants. The number of children who could walk was related to the extent of white matter abnormalities seen on the neonatal MRI, but the quality of walking was not.     

Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm

Only sparse information is available about a possible association between antenatal infection outside the brain and subsequent cognitive limitations among preterm infants. Based on published studies, we provide a theoretical schema that links them via the fetal inflammatory response and neonatal white matter damage. We conclude that the relationship between antenatal infection and cognitive limitations deserves much further attention by researchers interested in the prevention of this undesirable outcome of prematurity.     

Cerebral palsy in very preterm infants: new epidemiological insights

The focus of this review is on new insights from recent epidemiological research on cerebral palsy in preterm infants. These include: 1) a better understanding of issues related to diagnosis and classification; 2) new information about the brain abnormalities underlying cerebral palsy in preterm infants; and 3) a better understanding of biological mechanisms that may underlie previously described epidemiological associations. Ongoing efforts to improve the diagnosis and classification of cerebral palsy have been enhanced by findings from serial examinations of cohorts of very preterm infants. Cranial ultrasonography through the anterior fontanelle of very preterm infants has provided information about grossly evident brain damage, found in about one-half of preterm infants who develop cerebral palsy. Insights into the pathophysiologic basis for certain epidemiologic associations have come from studies of experimental brain damage in animals and clinical studies of neurologic disorders in adults. Much of the current epidemiological research into the causes of cerebral palsy in preterm infants has focused on two potential mechanisms of brain damage. One mechanism involves insufficient cerebral perfusion; the other, cytokine-mediated damage, potentially triggered by events such as maternal infection (e.g., intrauterine or periodontal infection), neonatal infection (e.g., sepsis and necrotizing enterocolitis), and neonatal oxygen- or ventilator-induced lung injury. In addition to the preterm infant's increased exposure to such damaging factors, the high frequency of cerebral palsy in these infants might be due, in part, to insufficient levels of developmentally regulated protective substances, such as thyroid hormone and glucocorticoids. Models of causation currently are being investigated using recently developed methods for quantifying, with small quantities of blood, biomolecules that are suspected to either promote or protect against brain damage in the neonate. Clinical investigations now under way can be expected to identify strategies to be tested in clinical trials that could lower the risk of cerebral palsy in very preterm infants.     

Kicking coordination captures differences between full-term and premature infants with white matter disorder

This study explores the relation of white matter disorder (WMD) to intralimb coordination patterns in premature infants with very low birth weight (VLBW). We specifically measured the temporal-spatial characteristics of intralimb coordination patterns of the legs. Three groups of infants were compared at one month corrected age (CA): 10 premature infants born VLBW and WMD (PTWMD), 10 premature infants born VLBW without WMD (PT) and 10 full term infants (FT). Using kinematic variables, we discriminate among VLBW infants with WMD from the two comparison groups. Infants born with WMD maintain patterns of tight coupling among leg joints (all flexion or all extension) while PT and FT term infants have begun to decouple leg joints by this age (combinations of flexion with extension). The coupling pattern is captured through joint correlations, discrete relative phase, and phase plane portraits. The PTWMD infants also demonstrate aberrant patterns of coordination evident through both temporal and spatial characteristics of the kicks. This is the first evidence that movement disorder associated with brain lesions can be identified and quantified with kinematic variables as early as one month of age.     

“Prematurity stereotype” in a sample of Dutch mothers: Do researchers suffer from a “prejudiced parent stereotype”?

This paper reports a Dutch replication of North American research on the “prematurity stereotype” among mothers. In a rating task, infants labeled as “premature” were given less favorable scores on a number of dimensions. A questionnaire study also showed negative expectations concerning premature infants. Associations with the mothers' number of children and level of education were found. Methodological problems of this type of research are discussed. To a large extent, the effects found can be ascribed to the “demand characteristics” of the experiment and the normal effects of expectations on perception. It is argued that researchers should not automatically label such behavior as “stereotyping”: There must also be evidence of a failure to adapt expectations in the face of conflicting evidence. Recommendations are made concerning future research in this area, and the importance of providing clear and complete information for the public on the effects of prematurity is stressed.     

MRA和无创FAIR灌注成像在早期脑缺血中的诊断价值

为了探讨3D—TOFMRA脑血管成像及流动敏感交互式反转恢复（FAIR）MR灌注成像在早期（发病2h-7d）脑缺血中的诊断价值,对27例早期脑缺血患者行3D—TOFMRA和FAIR检查。结果显示,MRA异常27例,表现为血管闭塞、狭窄、硬化;FAIR异常27例,表现为缺血区血流灌注的减低,患侧和对侧灰、白质信号强度的差异均有统计学意义（P〈0．005）,患者患侧与志愿者灰、白质信号强度的差异亦均有统计学意义（P〈0．005）。FAIR灌注技术无需注射造影剂,能够提供早期脑缺血患者血流动力学受损情况,FAIR与3D—TOF法MRA联合运用,对早期脑缺血的诊断、血流灌注评价会更全面、更准确。     

Infection markers and early signs of neonatal encephalopathy in the term infant

Recent evidence points to an association between intrauterine infection and cerebral palsy (CP) in the preterm as well as the term infant. The mechanisms that link these two conditions are unclear. Chorioamnionitis is a common clinical problem complicating 5-10% of pregnancies, whereas the incidence of CP attributed to intrapartum asphyxia is rare. Chorioamnionitis may result in brain injury as a result of interruption of placental blood flow (asphyxia), or via fever and/ or the cytokine release associated with infection. This review will attempt to establish the link between perinatal infection and brain damage in term infants. The characteristics of the perinatal inflammatory response, the potential mechanisms of brain injury associated with infection, and the clinical characteristics of neonatal encephalopathy will be discussed.     

早产高胆红素血症患儿脑干听觉诱发电位测听的临床意义

检测分析早产高胆红素血症（HB）患儿脑干听觉诱发电位测听（BAEP）指标。连续选择近期在我院住院的早产HB患儿176例,入选对象治疗前接受了BAEP检测。胎龄较短、分娩体重较轻、日龄较小和血清高浓度早产儿BAEP检测通过耳数、通过率均明显少于胎龄较长、出生体重较重、日龄较大和胆红素较低浓度旱产儿组（P均〈0．05）。不...     

Auditory temporal processing deficits in children with periventricular brain injury

The present study investigated whether auditory temporal processing deficits are related to the presence and/or the severity of periventricular brain injury and the reading difficulties experienced by extremely low birthweight (ELBW: birthweight <1000 g) children. Results indicate that ELBW children with mild or severe brain lesions obtained significantly lower scores on a test requiring auditory temporal order judgments than ELBW children without periventricular brain injury or children who were full-term. Structural equation modeling indicated that a model in which auditory temporal processing deficits predicted speech sound discrimination and phonological processing ability provided a better fit for the data than did a second model, which hypothesized that auditory temporal processing deficits are associated with poor reading abilities through a working memory deficit. These findings suggest that an impairment in auditory temporal processing may contribute to the reading difficulties experienced by ELBW children.     

Ophthalmological problems of the premature infant

Preterm infants are more likely than term infants to have significant abnormalities of all parts of the visual system leading to reduced vision. The most common problem is retinopathy of prematurity (ROP). The frequency and severity of this disorder is inversely related to gestational age. Damage ranges from minor to catastrophic. Preterm infants also have higher rates of amblyopia, strabismus, refractive error, and cortical visual impairment. The later problem is largely associated with neonatal brain injury. Years later, these children may develop glaucoma and retinal detachments.