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.     

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.     

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.     

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.     

自由基与重度颅脑外伤并发SIRS的原因及治疗研究探讨

就重型颅脑外伤由于过氧化反应后自由基产生的原因、自由基对神经细胞的继发损伤、自由基在重型颅脑外伤状态下诱发或并发全身炎性反应综合征以及两种因素所引起的神经细胞凋亡进行综述。同时就目前学者们在手术抢救、监测血液粘度、持续腰大池置管脑脊液外引流术、亚低温治疗、药物治疗、高压氧与活性氧液治疗、恒定磁场治疗等方面治疗自由基和全身炎性反应综合征对神经细胞的继发损伤进行了讨论。重型颅脑外伤后应重视自由基和全身炎性反应综合征的治疗。     

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.     

Reperfusion of Specific Brain Regions by Raising Blood Pressure Restores Selective Language Functions in Subacute Stroke

We report a series of six single subject studies examining the effects of pharmacological blood pressure elevation on regional brain perfusion and language function. Previous reports indicate that hypoperfusion of specific brain regions, as delineated by magnetic resonance perfusion weighted imaging (PWI), is associated with disruption of selective lexical functions. On this basis, we hypothesized that reperfusion of the same regions, in the absence of infarct in that region, would restore the associated lexical function. We present five patients with impaired lexical-semantics associated with poor perfusion, but not infarction, of Brodmann's area 22 (BA 22), and one patient with impaired lexical-semantics and a superimposed deficit in retrieving the phonological representations of words, associated with poor perfusion Brodmann's area 37 (BA 37) as well as BA 22. Each patient was treated with induced blood pressure elevation to increase perfusion of the ischemic and dysfunctional tissue. Daily testing of naming and comprehension, with stimulus sets matched for frequency, familiarity, and length, showed improved lexical-semantics in the patients who showed reperfusion of BA 22 and improved oral naming (but not lexical-semantics) in the patient who showed reperfusion of BA 37. These cases illustrate that loss of function with hypoperfusion of a circumscribed area of the brain, and recovery of the same function with improved perfusion of that brain region, can reveal brain/language relationships prior to reorganization after brain injury.     

中枢肥大细胞在脑功能和行为调节中的作用

已知肥大细胞作为免疫细胞在过敏反应和炎性疾病中发挥重要作用。肥大细胞在中枢亦有表达, 但对其作用了解不足。新近的研究发现中枢肥大细胞在脑功能和行为调节中发挥重要的内源性平衡作用。一方面, 中枢肥大细胞在维持相关脑区发育, 正常神经活动, 以及动机, 情绪和认知等多种行为中发挥保护性作用, 各种应激条件诱导的中枢肥大细胞表达和活动改变参与脑和行为的适应性反应过程。另一方面, 中枢肥大细胞过度激活或者过度抑制都可导致脑功能和行为异常, 并参与某些免疫相关心身疾病的病理过程。体外神经解剖学和功能学研究证据提示中枢肥大细胞与神经系统间存在结构性和功能性相互作用网络。肥大细胞和神经组织间通过形成类似突触的结构性联系直接影响相邻细胞的活动。肥大细胞还可以通过脱颗粒释放多种生物活性介质调节神经活动, 同时表达多种受体接受脑内免疫性和神经性分子调节。但是目前对于中枢肥大细胞-神经系统相互作用的认识主要基于体外研究, 其在脑内相互作用方式及其与特定脑区功能和行为表型的关系所知甚少, 开展相关研究可以为认识脑与行为的神经免疫调节机制提供新的视角。     

Mapping brain maturation and cognitive development during adolescence

Non-invasive mapping of brain structure and function with magnetic resonance imaging (MRI) has opened up unprecedented opportunities for studying the neural substrates underlying cognitive development. There is an emerging consensus of a continuous increase throughout adolescence in the volume of white matter, both global and local. There is less agreement on the meaning of asynchronous age-related decreases in the volume of grey matter in different cortical regions; these might equally represent loss ("pruning") or gain (intra-cortical myelination) of tissue. Functional MRI studies have so far focused mostly on executive functions, such as working memory and behavioural inhibition, with very few addressing questions regarding the maturation of social cognition. Future directions for research in this area are discussed in the context of processing biological motion and matching perceptions and actions.     

The Continuum of Deep/Surface Dyslexia

A right-handed male sustained traumatic brain injury which resulted in anomia, dyslexia, and agraphia. The most severe CT (computed tomography)-identified brain damage was located in the right parieto-temporal lobe. In the first months following the injury, the pattern of reading errors was similar to that associated with deep dyslexia. However, nonlexical derivation of phonology from print was not abolished. As the patient's ability to associate letter patterns with sounds improved, oral reading also improved. Although he no longer produced semantic errors in oral reading, he continued to produce oral reading errors that were visually and phonologically related to the targets. Four months after the injury, the error pattern observed in the patient's oral reading was consistent with very mild surface dyslexia. The significance of these observations to dual-deficit models of acquired dyslexia is discussed, as are their implications for rehabilitation.     

BDNF serum levels in subjects developing or not post-traumatic stress disorder after trauma exposure

Post-traumatic stress disorder (PTSD) is a syndrome resulting from exposure to a severe traumatic event that poses threatened death or injury and produces intense fear and helplessness. The neural structures implicated in PTSD development belong to the limbic system, an important region for emotional processing. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that serves as survival factor for selected populations of central nervous system (CNS) neurons and plays a role in the limbic system by regulating synaptic plasticity, memory processes and behavior. Impaired BDNF production in the brain can lead to a variety of CNS dysfunctions including symptoms associated with PTSD. However, so far fewer studies have investigated this neurotrophin in patients with PTSD. Furthermore, given the multiple role of BDNF in various CNS disorders, it cannot be excluded that traumatic events per se may influence neurotrophin levels, without a direct association to the PTSD syndrome.     

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.     

Neuroimaging Biomarkers in Mild Traumatic Brain Injury (mTBI)

Reviewed herein are contemporary neuroimaging methods that detect abnormalities associated with mild traumatic brain injury (mTBI). Despite advances in demonstrating underlying neuropathology in a subset of individuals who sustain mTBI, considerable disagreement persists in neuropsychology about mTBI outcome and metrics for evaluation. This review outlines a thesis for the select use of sensitive neuroimaging methods as potential biomarkers of brain injury recognizing that the majority of individuals who sustain an mTBI recover without neuroimaging signs or neuropsychological sequelae detected with methods currently applied. Magnetic resonance imaging (MRI) provides several measures that could serve as mTBI biomarkers including the detection of hemosiderin and white matter abnormalities, assessment of white matter integrity derived from diffusion tensor imaging (DTI), and quantitative measures that directly assess neuroanatomy. Improved prediction of neuropsychological outcomes in mTBI may be achieved with the use of targeted neuroimaging markers.     

Sensory sensitivity after acquired brain injury: A systematic review

Patients with acquired brain injury frequently report experiencing sensory stimuli as abnormally under- (sensory hyposensitivity) or overwhelming (sensory hypersensitivity). Although they can negatively impact daily functioning, these symptoms are poorly understood. To provide an overview of the current evidence on atypical sensory sensitivity after acquired brain injury, we conducted a systematic literature review. The primary aim of the review was to investigate the behavioural and neural mechanisms that are associated with self-reported sensory sensitivity. Studies were included when they studied sensory sensitivity in acquired brain injury populations, and excluded when they were not written in English, consisted of non-empirical research, did not study human subjects, studied pain, related sensory sensitivity to peripheral injury or studied patients with a neurodegenerative disorder, meningitis, encephalitis or a brain tumour. The Web of Science, PubMed and Scopus databases were searched for appropriate studies. A qualitative synthesis of the results of the 81 studies that were included suggests that abnormal sensory thresholds and a reduced information processing speed are candidate behavioural mechanisms of atypical subjective sensory sensitivity after acquired brain injury. Furthermore, there was evidence for an association between subjective sensory sensitivity and structural grey or white matter abnormalities, and to functional abnormalities in sensory cortices. However, further research is needed to explore the causation of atypical sensory sensitivity. In addition, there is a need for the development of adequate diagnostic tools. This can significantly advance the quantity and quality of research on the prevalence, aetiology, prognosis and treatment of these symptoms.     

MR Diffusion Tensor Imaging: A Window into White Matter Integrity of the Working Brain

As Norman Geschwind asserted in 1965, syndromes resulting from white matter lesions could produce deficits in higher-order functions and “disconnexion” or the interruption of connection between gray matter regions could be as disruptive as trauma to those regions per se. The advent of in vivo diffusion tensor imaging, which allows quantitative characterization of white matter fiber integrity in health and disease, has served to strengthen Geschwind’s proposal. Here we present an overview of the principles of diffusion tensor imaging (DTI) and its contribution to progress in our current understanding of normal and pathological brain function.     

A comparison of behavioral and emotional functioning in children and adolescents with Autistic Disorder and PDD-NOS.

Behavioral symptomatology was compared in 26 children and adolescents with Autistic Disorder ("autism") and 25 children and adolescents with Pervasive Developmental Disorder, Not Otherwise Specified ("PDD-NOS"). Relative to individuals with PDD-NOS, those with autism had more symptoms of depression, social withdrawal, atypical behavior, and immature social skills--and fewer family problems. These differences remained even when group differences in intellectual ability were statistically controlled. No group differences emerged in somatization, anxiety, or hyperactivity. Findings suggest that although both groups demonstrate considerable evidence of behavioral and emotional problems, those with autism are at particularly high risk for comorbid behavioral and emotional disabilities.     

Capuchin monkeys, inequity aversion, and the frustration effect

Each of 4 female capuchin monkeys ("model") was paired with another female capuchin ("witness") in an adjacent cage. In Phases 1 and 3, a model could remove a grape from the experimenter's hand while the witness watched. The witness was then offered a slice of cucumber, a less preferred food. Trials alternated between subjects 50 times, defining a session. In Phases 2 and 4, both were offered cucumber. Witness rejections of cucumber were infrequent and were not dependent on whether models received grape or cucumber. When models were offered cucumber, they rejected it at higher rates than did witnesses. These results fail to support findings of Brosnan and de Waal. An account based on the frustration effect accommodates these results and those of Brosnan and de Waal.     

Mechanisms for ovarian cycle disruption by immune/inflammatory stress

This review summarizes highlights of our experiments investigating mechanisms, mediators and sites by which endotoxin disrupts reproductive neuroendocrine activity and interferes with the estrous cycle of sheep. Endotoxin, or lipopolysaccharide (LPS), is a commonly used model for immune and inflammatory stress. When administered to ovary-intact ewes, endotoxin interrupts the follicular phase of the cycle by interfering with several steps in the preovulatory chain of endocrine events. One such step is the development of high frequency LH pulses, which provide an essential stimulus for the preovulatory increase in estradiol secretion from the ovarian follicle. Follow-up experiments in ovariectomized ewes demonstrate that endotoxin inhibits pulsatile LH secretion at both the hypothalamic and pituitary levels, suppressing pulsatile GnRH secretion and reducing pituitary responsiveness to GnRH. This disruption of GnRH and LH pulsatility is mediated by pathways that include the synthesis of prostaglandins and cortisol, both of which are increased by endotoxin. It is postulated that a prostaglandin-mediated pathway disrupts the cycle during immune and inflammatory stress, whereas a separate cortisol-mediated pathway reinforces this disruption and also participates more generally in suppressing cyclicity during other stressful situations that activate the hypothalamo-pituitary-adrenal axis.     

Negotiating reality after physical loss: hope, depression, and disability.

The utility of different reality negotiation strategies among 57 persons who had traumatically acquired severe physical disabilities was examined. It was predicted that a sense of goal-directed determination ("agency"; Snyder, 1989) would predict lower depression and psychosocial impairment scores soon after injury. To meet the demands of rehabilitation and social integration, however, it was hypothesized that a sense of ability to find ways to meet goals ("pathways") would predict lower depression and psychosocial impairment among persons who had been disabled for a longer period. The expected interaction was significant in the prediction of psychosocial impairment but not of depression. The sense of pathways was predictive of impairment and depression regardless of the time since injury. Results suggest that in the reality negotiation process the different components of hope as defined by Snyder have salient effects on perceptions of ability to function in social capacities.     

Neural substrates of word generation during stroke recovery: the influence of cortical hypoperfusion

Several studies have demonstrated reorganization of cognitive and motor function caused by stroke. This study examined the influence of hypoperfused brain regions, in addition to the area of the infarct itself, on reorganization of the cognitive processes underlying word generation in stroke patients. In addition, we also sought to determine the influence of hypoperfusion on the blood oxygen level dependent/(BOLD) effect. Subjects with left and right subacute or chronic subcortical strokes, along with normal controls, were imaged while performing a verbal fluency task (word generation). The study population included six normal subject and six stroke patients with subcortical infarcts and cortical hypoperfusion in the middle cerebral artery territory who had recovered or improved markedly in word fluency. While normal subjects displayed a left-lateralized fronto-temporo-parietal and bilateral cingulo-striatal-thalamic-cerebellar network, the activation pattern of stroke patients was determined both by the hypoperfused regions and infarcted areas of the brain. Specifically, patients showed diminished BOLD effect in the cortical regions that were hypoperfused, even though their infarcts were subcortical, and showed increased BOLD effect in the homologous regions of the normal hemisphere. This finding raises the possibility that cortical hypoperfusion in the absence of infarct can cause shift of language functions to the opposite, intact hemisphere. However, reduced BOLD effect in the task relative to rest was found in hypoperfused regions in two patients, raising the possibility that regional function persisted, even though vascular reactivity was impaired. Results illustrate the complexities of functional imaging studies of recovery in patients with vascular lesions.