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Brain Injury in Premature Infants: A Complex Amalgam of Destructive and Developmental Disturbances
Abstract
Brain injury in premature infants is of enormous public health importance because of the large number of such infants who survive with serious neurodevelopmental disability, including major cognitive deficits and motor disability. This type of brain injury is generally thought to consist primarily of periventricular leukomalacia (PVL), a distinctive form of cerebral white matter injury. Important new work shows that PVL is frequently accompanied by neuronal/axonal disease, affecting the cerebral white matter, thalamus, basal ganglia, cerebral cortex, brain stem, and cerebellum. This constellation of PVL and neuronal/axonal disease is sufficiently distinctive to be termed "encephalopathy of prematurity". The thesis of this Review is that the encephalopathy of prematurity is a complex amalgam of primary destructive disease and secondary maturational and trophic disturbances. This Review integrates the fascinating confluence of new insights into both brain injury and brain development during the human premature period.
... Each year more than 15 million infants are born preterm worldwide [1]. Extremely premature infants born at less than 28 weeks of gestational age are at great risk of having a multi-organ injury that predominantly involves the lung and brain [2][3][4][5]. Born with immature lungs, these premature infants suffer respiratory failure soon after birth and often require oxygen (O 2 ) therapy and mechanical ventilation to survive. However, life-sustaining highconcentration O 2 therapy (hyperoxia) can cause lung inflammation that ultimately leads to bronchopulmonary dysplasia (BPD), characterized by disrupted alveolar and vascular development and reduced lung function [2,3]. ...
... However, life-sustaining highconcentration O 2 therapy (hyperoxia) can cause lung inflammation that ultimately leads to bronchopulmonary dysplasia (BPD), characterized by disrupted alveolar and vascular development and reduced lung function [2,3]. The immature brains in these premature infants are also affected by the hyperoxia that results in inflammation leading to short-term and long-term neurodevelopmental sequelae, such as intraventricular hemorrhage, encephalopathy of prematurity, cerebral palsy, intellectual disability, and cognitive deficits [4,5]. Therefore, survivors of BPD are known to suffer not only from longterm lung disease but also suffer from long-term sequelae involving the brain leading to long-term neurodevelopmental impairment (NDI). ...
... n = 5/group. **P < 0.01, WT-RA vs. WT-O 2. Discussion BPD, characterized by inflammatory lung injury, continues to be a major contributor to morbidity and mortality in extremely premature infants and is also a predictor of NDI [4,5,32]. Currently, no therapies are effective and safe for either condition. ...
Background
Neonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain’s inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury.
Methods
Newborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O 2 ) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes.
Results
Hyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O 2 exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO.
Conclusions
GSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.
... The immature brain passes through several essential sequences of CNS development during the last trimester of gestation: cell proliferation, differentiation, maturation (axonal outgrowth and dendritic arborization), migration, synapse formation, pruning, and an early phase of myelination that should provide for a well-orchestrated development of neural circuitry [14]. The speed and complexity of these processes account for their vulnerability to perturbations [9,[15][16][17][18]. ...
... The decreasing prevalence of previously observed necrosis and associated axonopathy (though still relevant in severe insults) [9,18] has increased interest in other mechanisms responsible for the only modest improvement in neurodevelopmental disabilities in extremely preterm infants [43]. In preterm neonates, especially those of extremely low gestational age, the underlying pathology is a combination of cerebral diffuse white matter injury (WMI) followed by a prolonged period of dysmaturation in both white and grey matter structures [15][16][17][18]44]. Apart from hypoxic-ischemic events that occur before, during, or shortly after birth, microglia activation and reactive astrogliosis play important pathophysiological roles in this context [17,[45][46][47][48]. ...
... Indeed, pre-OLs are thought to be the most important cellular targets in preterm brain damage. Their maturation-dependent sensitivity is supposed to arise from an abundance of excitatory receptors and an immature antioxidant system combined with mitochondrial dysfunction [9,15,16,18,49,50]. A disruption of oligodendrocyte-axonal integrity with poor trophic supply in the event of OL dysmaturation is of concern for axonal growth, function and survival, which may have a deleterious influence on the neuronal connection in different parts of the brain via decreased synaptogenesis [1,15,16,42]. ...
Despite significant improvements in survival following preterm birth in recent years, the neurodevelopmental burden of prematurity, with its long-term cognitive and behavioral consequences , remains a significant challenge in neonatology. Neuroprotective treatment options to improve neurodevelopmental outcomes in preterm infants are therefore urgently needed. Alleviating inflammatory and oxidative stress (OS), melatonin might modify important triggers of preterm brain injury, a complex combination of destructive and developmental abnormalities termed encephalopa-thy of prematurity (EoP). Preliminary data also suggests that melatonin has a direct neurotrophic impact, emphasizing its therapeutic potential with a favorable safety profile in the preterm setting. The current review outlines the most important pathomechanisms underlying preterm brain injury and correlates them with melatonin's neuroprotective potential, while underlining significant pharmacokinetic/pharmacodynamic uncertainties that need to be addressed in future studies.
... Neurological consequences include impaired cognition, attention, behaviour, and socialization, leading to a significant public health burden. Neonates are at high risk of developing WMI when born before 32 weeks of gestation [2,3]. ...
... The pathophysiology of WMI is complex. It involves inflammatory and hypoxic/ischemic (HI) insults triggering excitotoxicity and oxidative stress [3]. The free radicals generated by HI are particularly harmful to the precursor cells maturing into the myelin-forming oligodendrocytes [3]. ...
... It involves inflammatory and hypoxic/ischemic (HI) insults triggering excitotoxicity and oxidative stress [3]. The free radicals generated by HI are particularly harmful to the precursor cells maturing into the myelin-forming oligodendrocytes [3]. In addition, caspase-dependent cell death affects neuronal cells and oligodendrocyte precursors and participates in WMI pathogenesis [3]. ...
Preterm birth is the leading cause of childhood morbidity and mortality and can result in white matter injury (WMI), leading to long-term neurological disabilities with global health burden. Mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEV) are a promising therapeutic agent for treating perinatal neurological injury. They carry microRNAs (miRNAs) predicted to be involved in the onset of premature WMI. We hypothesize that miRNAs have a key function in the beneficial effects of MSC-sEV. We isolated MSC from umbilical cord tissue, the Wharton’s jelly (WJ), and purified small extracellular vesicles (sEV) from WJ-MSC culture supernatant by ultracentrifugation and size exclusion chromatography. The miRNA content was quantified by real-time polymerase chain reaction. A luciferase gene assay validated silencing of TP53 and TAOK1, which we previously identified as predicted target genes of MSC-sEV miRNAs by Next Generation Sequencing and pathway enrichment analysis. The impact of sEV miRNAs on oligodendroglial maturation and neuronal apoptosis was evaluated using an in vitro oxygen-glucose deprivation model (OGD/R) by knocking-down DROSHA in WJ-MSC, which initiates miRNA processing. WJ-MSC-sEV contained miRNAs involved in WMI, namely hsa-miR-22-3p, hsa-miR-21-5p, hsa-miR-27b-3p, and the hsa-let-7 family. The luciferase assay strongly indicated an inhibitory effect of sEV miRNAs on the gene expression of TP53 and TAOK1. Small EV initiated oligodendrocyte maturation and reduced OGD/R-mediated neuronal apoptosis. Knocking-down DROSHA in WJ-MSC reduced the expression of sEV miRNAs and led to the loss of their beneficial effects. Our in vitro study strongly indicates the key function of miRNAs in the therapeutic potential of WJ-MSC-sEV in premature WMI.
... A major obstetric risk factor, preterm birth, is associated with reductions in whole brain volume, and regionally in the thalamus, hippocampus and basal ganglia [14,15,17,18,[22][23][24][25][26] as well as increases in the primary visual cortex [14,18,24]. The association between pre-and perinatal adversities and altered brain structure may be stronger in patients with schizophrenia, suggesting that genetic vulnerability and pre-and perinatal factors both affect neurodevelopment to increase the risk of schizophrenia. ...
... Striatal volume alterations associated with cumulative pre/perinatal risk varied according to PEs group. Typically, widespread reductions in cortical grey matter and subcortical volumes [14,15,17,18,[22][23][24][25][26] are associated with very preterm birth (often defined as <32 weeks gestational age). This pattern was seen in controls, whereas in those with psychotic disorder, striatal volume increased with pre/perinatal risk load. ...
Psychotic experiences (PEs) occur in 5-10% of the general population and are associated with exposure to childhood trauma and obstetric complications. However, the neurobiological mechanisms underlying these associations are unclear. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we studied 138 young people aged 20 with PEs (n = 49 suspected, n = 53 definite, n = 36 psychotic disorder) and 275 controls. Voxel-based morphometry assessed whether MRI measures of grey matter volume were associated with (i) PEs, (ii) cumulative childhood psychological trauma (weighted summary score of 6 trauma types), (iii) cumulative pre/peri-natal risk factors for psychosis (weighted summary score of 16 risk factors), and (iv) the interaction between PEs and cumulative trauma or pre/peri-natal risk. PEs were associated with smaller left posterior cingulate (pFWE < 0.001, Z = 4.19) and thalamus volumes (pFWE = 0.006, Z = 3.91). Cumulative pre/perinatal risk was associated with smaller left subgenual cingulate volume (pFWE < 0.001, Z = 4.54). A significant interaction between PEs and cumulative pre/perinatal risk found larger striatum (pFWE = 0.04, Z = 3.89) and smaller right insula volume extending into the supramarginal gyrus and superior temporal gyrus (pFWE = 0.002, Z = 4.79), specifically in those with definite PEs and psychotic disorder. Cumulative childhood trauma was associated with larger left dorsal striatum (pFWE = 0.002, Z = 3.65), right prefrontal cortex (pFWE < 0.001, Z = 4.63) and smaller left insula volume in all participants (pFWE = 0.03, Z = 3.60), and there was no interaction with PEs group. In summary, pre/peri-natal risk factors and childhood psychological trauma impact similar brain pathways, namely smaller insula and larger striatum volumes. The effect of pre/perinatal risk was greatest in those with more severe PEs, whereas effects of trauma were seen in all participants. In conclusion, environmental risk factors affect brain networks implicated in schizophrenia, which may increase an individual's propensity to develop later psychotic disorders. Molecular Psychiatry; https://doi.
... Furthermore, the brains of these infants are immature and vulnerable to harmful stimuli such as oxygen poisoning and inflammation. As a result, these infants remain at high risk of short-term and long-term neurological complications (Volpe, 2009). Hyperoxia is extremely damaging to the immature retina, and hyperoxia-induced brain injury can lead to neurodevelopmental abnormalities, including defective myelin formation (Obst et al., 2022). ...
... Extremely premature infants with gestational age of less than 28 weeks are highly likely to have multiple organ injuries and developmental abnormalities, mainly involving lung and brain (Jobe and Bancalari, 2001;Volpe, 2009). To explore the role of 1,25-(OH) 2 D 3 in hyperoxia-induced brain injury, we established this animal model which showed that treatment with 1,25-(OH) 2 D 3 in premature rat pups exposed to hyperoxia attenuates brain injury. ...
Studies have shown that vitamin D plays a crucial role in brain development, brain metabolism and neuroprotection. There is little evidence for the neuroprotective effect of 1, 25‑dihydroxyvitamin D3 (1,25‑(OH)2D3) on various brain injury models. The aim of this study was to investigate the neuroprotection effect of 1,25‑(OH)2D3 against hyperoxia‑induced brain injury in premature rats. Sprague‑Dawley rats were exposed to 95% oxygen or room air for 24 h and treated with 1,25‑(OH)2D3 or normal saline for 14 consecutive days. The histopathological changes of optic chiasma tissue were observed by hematoxylin‑eosin staining. Immunohistochemistry, qRT‑PCR, and western blot were performed to detect the expression of integrin‑β1 and yes‑associated protein (YAP) in the organization of the optic chiasm. Histopathological sections of optic chiasma showed visible optic nerve swelling, expanded nerve fiber space, uneven staining, obvious oligodendrocyte proliferation and disordered cell arrangement accompanied by inflammatory cell infiltration and exudation after 7 days and 14 days of hyperoxia exposure. The hyperoxia group treated with 1,25‑(OH)2D3 were showed improvement of brain injury with reduced inflammatory exudation, uniform nerve fiber staining and less obvious oligodendrocyte proliferation. Immunohistochemical staining, qRT‑PCR and western blot indicated that 1,25‑(OH)2D3 treatment upregulated the expression of integrin‑β1 and YAP in the hyperoxia group on day 7. However, the expression of YAP was significantly increased compared with control group and treatment with 1,25‑(OH)2D3 reduced the expression of YAP in the hyperoxic group on day 14. 1,25‑(OH)2D3 may regulate the expression of integrin‑β1 and YAP to alleviate hyperoxia‑induced brain injury in premature rats.
... Brains of preterm newborns are particularly vulnerable to preterm birth-related adverse events such as hypoxia-ischemia, neuroinflammation, brain hemorrhage, and/or perinatal stress, which might cause aberrant brain development. Such persistent aberrant brain development is, for example, demonstrated by findings of altered brain structure and function throughout infancy, childhood, adolescence, and early adulthood (Back et al., 2002;Hasler et al., 2019;Hedderich et al., 2019;Hedderich et al., 2020;McClendon et al., 2017;Menegaux et al., 2020;Meng et al., 2016;Pascoe et al., 2019;Schmitz-Koep et al., 2020;Skranes et al., 2013;Volpe, 2009). ...
... In general, dopaminergic neurotransmission is critically involved in many aspects of cognitive functioning(Cools & Goldman-Rakic, 1991;Williams & Goldman-Rakic, 1995). While there is consistent evidence for cognitive performance with respect to D1R-availability following an inverted U-shaped model(Cools et al., 2008;Gjedde et al., 2010;Weber et al., 2022), the functioning of D2-like receptors is more complex and much less understood, with some authors reporting a link between D2R-availability with cognitive performance while others demonstrated no association(Kellendonk et al., 2006;Klein et al., 2019;Lee et al., 2021;Vyas et al., 2018).Indeed, very premature-born adults show on average lower general cognitive performance (on average about 12 points in IQ(Basten et al., 2015;Eves et al., 2021;Kroll et al., 2017;Volpe, 2009;Wolke et al., 2019)), aberrant dopaminergic neurotransmission might contribute to this deficit. However, beyond the definitive link between significant spatial-RC for D2/3R availability and cognitive performance, the current study can only indirectly support the relationship between aberrant D2/3R availability and IQ due to the indirect nature of spatial-RCs. ...
While animal models indicate altered brain dopaminergic neurotransmission after premature birth, corresponding evidence in humans is scarce due to missing molecular imaging studies. To overcome this limitation, we studied dopaminergic neurotransmission changes in human prematurity indirectly by evaluating the spatial co-localization of regional alterations in blood oxygenation fluctuations with the distribution of adult dopaminergic neurotransmission. The study cohort comprised 99 very premature-born (<32 weeks of gestation and/or birth weight below 1500 g) and 107 full-term born young adults, being assessed by resting-state functional MRI (rs-fMRI) and IQ testing. Normative molecular imaging dopamine neurotransmission maps were derived from independent healthy control groups. We computed the co-localization of local (rs-fMRI) activity alterations in premature-born adults with respect to term-born individuals to different measures of dopaminergic neurotransmission. We performed selectivity analyses regarding other neuromodulatory systems and MRI measures. In addition, we tested if the strength of the co-localization is related to perinatal measures and IQ. We found selectively altered co-localization of rs-fMRI activity in the premature-born cohort with dopamine-2/3-receptor availability in premature-born adults. Alterations were specific for the dopaminergic system but not for the used MRI measure. The strength of the co-localization was negatively correlated with IQ. In line with animal studies, our findings support the notion of altered dopaminergic neurotransmission in prematurity which is associated with cognitive performance.
... The emergence of these connections has been associated with the development of the white matter microstructural properties, including myelination (REFs). However, premature birth is known to alter the production of premyelinating oligodendrocytes during gestation, which consequently alters myelin production in later stages of development (Volpe, 2009). This interruption in myelin maturation may be associated with the lack of significant changes in the global efficiency of the network (Figure 12). ...
Premature infants, born before 37 weeks of gestation can have consequences on neurodevelopment and cognition, even when no anatomical lesions are evident. Resting-state functional neuroimaging of naturally sleeping babies has shown altered connectivity patterns, but there is limited evidence on the developmental trajectories of the functional organization in preterm neonates. By using a large dataset (n=597) from the developing Human Connectome Project, we explored the differences in graph theory properties between at-term and preterm neonates at term-equivalent age, considering the age subgroups proposed by the World Health Organization for premature birth. Leveraging the longitudinal follow-up for some preterm participants, we characterized the developmental trajectories for preterm and at-term neonates. We found significant differences between groups for connectivity strength, clustering coefficient, characteristic path length and global efficiency. Specifically, at term-equivalent ages, higher connectivity, clustering coefficient and efficiency are identified for neonates born at higher postmenstrual ages. Similarly, the characteristic path length showed the inverse pattern. These results were consistent for a variety of connectivity thresholds and both at the global (whole brain) and local level (brain regions). The brain regions with the greatest differences between groups include primary sensory and motor regions and the precuneus which may relate with the risk factors for sensorimotor and behavioral deficits associated with premature birth.Our results also show non-linear developmental trajectories for premature neonates, but decreased integration and segregation even at term-equivalent age. Overall, our results confirm altered functional connectivity, integration and segregation properties of the premature brain despite showing rapid maturation after birth. Keywords: Brain network; Connectome; Development; Preterm; Graph theory.
... 11 Brain damage is more common in preterm newborns than in term newborns for various reasons, such as developmental and genetic weaknesses and different exposure to adverse perinatal environments. 12,13 However, the mechanisms of neonatal brain injury have not been fully understood so far. 14 Studies have proven that glutamate excitotoxicity is one of the main mechanisms of preterm-related brain injury. ...
... 40 Such reduced perfusion can lead to oxidative stress and apoptotic cell death of immature WM cells. 41,42 Two additional factors predispose the developing WM to injury from hypoxia-ischemia: the presence of arterial end and border zones in the periventricular region, 43 and a propensity for the critically ill neonate to exhibit a pressure-passive circulation related to a disturbance of cerebral auto-regulation. These mechanisms may contribute to the typical finding of reduced and injured WM in CHD neonates. ...
... 20 La principal causa es la encefalopatía del prematuro, que genera secuelas y es la responsable que del 5 % al 25 % de los niños prematuros manifiesten déficits motores. 8,21 La encefalopatía del prematuro es provocada por lesiones en la sustancia blanca periventricular y frecuentemente está acompañada por lesiones en cerebelo, tálamo, ganglios basales y tronco encefálico, en una combinación de destrucción primaria y de impedimentos en los mecanismos tróficos. 22 Existe actualmente un amplio consenso sobre las ventajas que presenta el diagnóstico precoz en esta población, que permite brindar programas de intervención temprana dentro de su primer año de vida. ...
... 29 Finally, oxidative injury is found in other organs than the lung, including the brain and the eyes. 30,31 In our work, we had the opportunity to use human clinical grade MSC-EVs in a xenogenic model. Following the MISEV guideline, 32 there is no standard method of EVs separation and concentration, and several different techniques are equally acceptable, including (tangential flow filtration [TFF]). ...
Oxidative stress and fibrosis are important stress responses that characterize bronchopulmonary dysplasia (BPD), a disease for which only a therapy but not a cure has been developed. In this work, we investigated the effects of mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) on lung and brain compartment in an animal model of hyperoxia-induced BPD. Rat pups were intratracheally injected with MSC-EVs produced by human umbilical cord-derived MSC, following the Good Manufacturing Practice-grade (GMP-grade). After evaluating biodistribution of labelled MSC-EVs in rat pups left in normoxia and hyperoxia, oxidative stress and fibrosis investigation were performed. Oxidative stress protection by MSC-EVs treatment was proved both in lung and in brain. The lung epithelial compartment ameliorated glycosaminoglycan and surfactant protein expression in MSC-EVs-injected rat pups compared to untreated animals. Pups under hyperoxia exhibited a fibrotic phenotype in lungs shown by increased collagen deposition and also expression of profibrotic genes. Both parameters were reduced by treatment with MSC-EVs. We established an in vitro model of fibrosis and another of oxidative stress, and we proved that MSC-EVs suppressed the induction of αSMA, influencing collagen deposition and protecting from the oxidative stress. In conclusion, intratracheal administration of clinical-grade MSC-EVs protect from oxidative stress, improves pulmonary epithelial function, and counteracts the development of fibrosis. In the future, MSC-EVs could represent a new cure to prevent the development of BPD.
... Cerebral visual impairment (CVI) is the most common cause of pediatric visual impairment in developing countries 18 and has been de ned as a brainbased visual disorder associated with damage and/or maldevelopment of retrochiasmal visual processing structures and areas in the absence of major ocular disease 19,20 . The malfunction of key visual processing structures and pathways 21 is commonly associated with perinatal neurological injury and maldevelopment, including hypoxic-ischemic injury, trauma, and infection, as well as genetic and metabolic disorders 22,23 . While the pro le of visual impairments in CVI is broad and complex (including reduced visual acuity and contrast sensitivities, impaired visual eld function, and ocular motor abnormalities; 22,24 , higher-order visual perceptual de cits associated with visuospatial processing and attention are considered cardinal features, even in cases when visual acuity and visual eld functioning are at normal or near normal levels [25][26][27] . ...
Two main sources of information have been identified to explain what image features guide gaze behavior, namely, image salience (associated with bottom-up processing) and image semantics (influenced by top-down processing). In this study, we compared the relative influence of these two factors while subjects searched for a predetermined target in a naturalistic scene. We also compared visual search performance in individuals with neurotypical development and those with cerebral visual impairment (CVI); a neurodevelopmental condition associated with higher-order visual processing deficits. Participants searched for the prompted target (presented as either an image or text cue) in a series of indoor and outdoor naturalistic scenes. Gaze behavior was recorded with an eye tracker, and behavioral outcomes were success rate, reaction time, visual search area, and number of fixations. A receiver operating characteristic (ROC) analysis was performed to compare the distribution of individual eye gaze patterns based on predictions of image salience (using Graph-Based Visual Saliency) and image semantics (using Global Vectors for Word Representations combined with Linguistic Analysis of Semantic Salience) models. We found that overall, CVI participants were less likely and were slower to find the target than controls. Visual search behavior in CVI was also associated with a larger visual search area and a greater number of fixations. ROC-based analysis revealed that saliency scores were lower in CVI than controls for both the image salience and image semantics model predictions. Furthermore, search strategies in the CVI group were not affected by cue type, although search times and accuracy were correlated with Verbal IQ scores for text-cued searches. Collectively, these results suggest that individuals with CVI do not utilize image or semantic information as readily as controls, in line with their associated deficits related to higher-order processing.
... [21][22][23] For children born preterm, some or most of these developmental processes occur postnatally, where they could be disrupted by preterm birth and/or by postnatal brain injury caused by hypoxia, ischemia, hemorrhage, or in ammation. [24][25][26][27] Further, adverse experiences in the neonatal intensive care unit such as exposure to repeated painful procedures, sedatives and analgesics, noise, light and reduced parental stimulation can affect neurophysiological processes and exacerbate brain injury. 28-30 These adverse effects render the developing brains of children born preterm vulnerable to cognitive impairments, executive functions challenges, behavioral problems and learning disabilities, 31 all of which can have a negative impact on their educational performance. ...
Importance
Data on the middle school outcomes of preterm children are limited and have methodologic issues.
Objective
To study the association between preterm birth and grade 7 school performance.
Methods
A retrospective population-based cohort study of children born in Manitoba, Canada between 1994–2006 using their grade 7 school performance data. A secondary sibling cohort was created comprising children born preterm and their full-term siblings. Primary exposure was preterm birth categorized as < 28, 28–33 and 34–36 weeks gestation. The two co-primary grade 7 outcome measures were: not meeting the mathematics competencies, and not meeting the student engagement competencies. Multivariable logistic regression models tested the association between preterm birth and both co-primary outcomes; adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated.
Results
7653 preterm (gestational age median [IQR]: 35 weeks [34,36]) and 110,313 term (40 [39,40]) were included. 43% of < 28 weeks, 18% of 28–33 weeks and 17% of 34–36 weeks had the mathematics co-primary outcome compared to 13% of term children. The corresponding % for the student engagement outcome were 42%, 24%, 24% and 24% respectively. Preterm birth was associated with the mathematics (34–36 weeks: 1.26, 1.16–1.35; 28–33 weeks: 1.47, 1.27–1.70; <28 weeks: 5.48, 3.89–7.70) and student engagement outcomes (34–36 weeks: 1.09, 1.01–1.16; 28–33 weeks: 1.21, 1.06–1.39; <28 weeks: 2.49, 1.76–3.51). However, there was no difference in outcomes among the sibling cohort.
Conclusions and Relevance
Children born preterm had lower grade 7 performance compared to children born term in this population-based cohort. Screening and supports for them in their middle school years are warranted.
... It is associated with an increased risk of adverse clinical outcomes in the short or long term and is most common in intensive care unit (ICU) [4,5]. The underlying pathophysiology of delirium remains complex and speculative, involving various mechanisms contributing to nerve conduction disorders, neuroinflammation, inadequate brain metabolism, and neurotransmitter imbalances [6,7]. Delirium in elderly patients typically results from a complex interplay of factors, leading to exacerbated challenges in the ICU setting, such as prolonged hospitalization, increased mortality, and impaired quality of life [8][9][10]. ...
Background
The triglyceride-glucose index (TyG), an established indicator of insulin resistance, is closely correlated with the prognosis of several metabolic disorders. This study aims to investigate the association between the TyG index and the incidence of critical delirium in patients aged 65 years and older.
Methods
We focused on evaluating patients aged 65 years and older diagnosed with critical delirium. Data were obtained from the Medical Information Database for Intensive Care (MIMIC-IV) and the eICU Collaborative Research Database (eICU-CRD). Multivariate logistic regression and restricted cubic spline (RCS) regression were used to determine the relationship between the TyG index and the risk of delirium.
Results
Participants aged 65 years and older were identified from the MIMIC-IV (n = 4,649) and eICU-CRD (n = 1,844) databases. Based on optimal thresholds derived from RCS regression, participants were divided into two cohorts: Q1 (< 8.912), Q2 (≥ 8.912). The logistic regression analysis showed a direct correlation between the TyG index and an increased risk of critical delirium among ICU patients aged 65 and older. These findings were validated in the eICU-CRD dataset, and sensitivity analysis further strengthened our conclusions. In addition, the subgroup analysis revealed certain differences.
Conclusion
This study highlights a clear, independent relationship between the TyG index and the risk of critical delirium in individuals aged 65 years and older, suggesting the importance of the TyG index as a reliable cardio-cerebrovascular metabolic marker for risk assessment and intervention.
... Due to inter-slice motion and the thick slices, the cross-sectional views only poorly capture the 3D structure of the brain. Therefore, reconstruction of high-quality 3D fetal brain MR images from multiple motion-corrupted stacks with complementary information plays a crucial role in accurate visualization, quantification, characterization and understanding of the dynamic prenatal brain development in health and disease [3], [4]. ...
Fetal Magnetic Resonance Imaging (MRI) is challenged by fetal movements and maternal breathing. Although fast MRI sequences allow artifact free acquisition of individual 2D slices, motion frequently occurs in the acquisition of spatially adjacent slices. Motion correction for each slice is thus critical for the reconstruction of 3D fetal brain MRI. In this paper, we propose a novel multi-task learning framework that adopts a coarse-to-fine strategy to jointly learn the pose estimation parameters for motion correction and tissue segmentation map of each slice in fetal MRI. Particularly, we design a regression-based segmentation loss as a deep supervision to learn anatomically more meaningful features for pose estimation and segmentation. In the coarse stage, a U-Net-like network learns the features shared for both tasks. In the refinement stage, to fully utilize the anatomical information, signed distance maps constructed from the coarse segmentation are introduced to guide the feature learning for both tasks. Finally, iterative incorporation of the signed distance maps further improves the performance of both regression and segmentation progressively. Experimental results of cross-validation across two different fetal datasets acquired with different scanners and imaging protocols demonstrate the effectiveness of the proposed method in reducing the pose estimation error and obtaining superior tissue segmentation results simultaneously, compared with state-of-the-art methods.
... Multiple studies have reported significant changes in both cortical microstructure and morphology, including changes to mean diffusivity [2]- [4], cortical thickness and surface area [3], [5]- [7], and reduced white and grey matter volumes [7]- [9]. Atypical cortical neurodevelopment is known to be correlated to poorer cognitive outcomes including Attention-Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorders (ASD) and cerebral palsy [10]- [13]. ...
Cortical neurodevelopment is sensitive to disruption following preterm birth, with lasting impact on cognitive outcomes. The creation of generative models of neurodevelopment could aid clinicians in identifying atrisk subjects but is complicated by the degree of subject variability in cortical folding, and significant heterogeneity in the effect of preterm birth. In this work, we propose a graph convolutional generative adversarial network (GAN) and a training scheme to simulate neonatal cortical surface developmental trajectories. The proposed model is used to smoothly modify two cortical phenotypes: post-menstrual age at scan (PMA) and gestational age at birth (GA) on data from the developing Human Connectome Project (dHCP) [1]. The synthetic images were validated with an independently trained regression network, and compared against follow up scans, indicating that the model can realistically age individuals whilst preserving subject-specific cortical morphology. Deviation between simulated ‘healthy’ scans, and preterm follow up scans generated a metric of individual atypicality, which improved prediction of 18-month cognitive outcome over GA alone.
... ‡Severe haemorrhage with ventricular dilatation and with intraparenchymal haemorrhages (large unilateral parenchymal hyperdensity by ultrasound imaging, large unilateral porencephalic cyst, or both). 27,29 §Severe bronchopulmonary dysplasia defined as administration of oxygen for 28 days or longer and a need for more than 30% oxygen, with or without mechanical ventilation support or continuous positive airway pressure at 36 weeks postmenstrual age. Finally, in view of the positive effect of antenatal maternal treatment on neonatal presentation, we examined the neurological outcome of the eight children whose mothers had received amoxicillin before delivery. ...
... Optimal parent-infant relationships can facilitate and promote healthy social-emotional development and improve infant self-regulation (Gunnar & Hostinar, 2015;Sanders & Hall, 2018). Biologically at-risk infants may be more sensitive to both negative and positive environmental effects, as shown by the enhanced effects of optimal or suboptimal parenting on preterm infant outcomes (McKenzie et al., 2022;Volpe, 2009). Given the fact that high quality parent-infant relationships are one of the most important environmental factors in mitigating early life stress and adversity, and the fact that the preterm parent-infant dyad faces increased biological and environment risks as well as increased challenges with bonding and communication, preterm parent-infant relationships warrant further investigation and understanding (Gunnar & Hostinar, 2015;Maroney, 2003). ...
Caregiving relationships in the postnatal period are critical to an infant's development. Preterm infants and their parents face unique challenges in this regard, with infants experiencing separation from parents, uncomfortable procedures, and increased biologic vulnerability, and parents facing difficulties assuming caregiver roles and increased risk for psychological distress. To better understand the NICU parent‐infant relationship, we conducted a review of the literature and identified 52 studies comparing observed maternal, infant, and dyadic interaction behavior in preterm dyads with full‐term dyads. Eighteen of 40 studies on maternal behavior found less favorable behavior, including decreased sensitivity and more intrusiveness in mothers of preterm infants, seven studies found the opposite, four studies found mixed results, and 11 studies found no differences. Seventeen of 25 studies on infant behavior found less responsiveness in preterm infants, two studies found the opposite, and the remainder found no difference. Eighteen out of 14 studies on dyad‐specific behavior reported less synchrony in preterm dyads and the remainder found no differences. We identify confounding factors that may explain variations in results, present an approach to interpret existing data by framing differences in maternal behavior as potentially adaptive in the context of prematurity, and suggest future areas for exploration.
... The physiological changes that occur in this period include the brain growth, realized through myelination and glial cell proliferation and differentiation, and the formation of functional neural networks, achieved through synaptogenesis and synaptic pruning (Back and Miller 2014;Kinney and Volpe 2012). Preterm birth disrupts this natural progression of brain development and puts the infant at risk of developing long-term neurodevelopmental impairments (Back 2017;Volpe 2009Volpe , 2019. ...
Preterm neonates are at risk of long-term neurodevelopmental impairments due to disruption of natural brain development. Electroencephalography (EEG) analysis can provide insights into brain development of preterm neonates. This study aims to explore the use of microstate (MS) analysis to evaluate global brain dynamics changes during maturation in preterm neonates with normal neurodevelopmental outcome.
The dataset included 135 EEGs obtained from 48 neonates at varying postmenstrual ages (26.4 to 47.7 weeks), divided into four age groups. For each recording we extracted a 5-minute epoch during quiet sleep (QS) and during non-quiet sleep (NQS), resulting in eight groups (4 age group x 2 sleep states). We compared MS maps and corresponding (map-specific) MS metrics across groups using group-level maps. Additionally, we investigated individual map metrics.
Four group-level MS maps accounted for approximately 70% of the global variance and showed non-random syntax. MS topographies and transitions changed significantly when neonates reached 37 weeks. For both sleep states and all MS maps, MS duration decreased and occurrence increased with age. The same relationships were found using individual maps, showing strong correlations (Pearson coefficients up to 0.74) between individual map metrics and post-menstrual age. Moreover, the Hurst exponent of the individual MS sequence decreased with age.
The observed changes in MS metrics with age might reflect the development of the preterm brain, which is characterized by formation of neural networks. Therefore, MS analysis is a promising tool for monitoring preterm neonatal brain maturation, while our study can serve as a valuable reference for investigating EEGs of neonates with abnormal neurodevelopmental outcomes.
... As many as 40% of surviving extremely preterm infants are diagnosed with neurodevelopmental disability such as cerebral palsy, cognitive and neurosensory deficits, attention-deficit disorder, and/or major psychiatric disorders before school age [6]. These early disabilities usually result in life-long consequences for the children and their families, such as reduced quality of life as well as increased health care and educational costs [7,8]. Evidence suggests that cerebral hypoxia is associated with the risk of brain injury as well as death in extremely preterm infants [9]. ...
Background
In the SafeBoosC-III trial, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth did not reduce the incidence of death or severe brain injury in extremely preterm infants at 36 weeks’ postmenstrual age, as compared with usual care. Despite an association between severe brain injury diagnosed in the neonatal period and later neurodevelopmental disability, this relationship is not always strong. The objective of the SafeBoosC-III follow-up study is to assess mortality, neurodevelopmental disability, or any harm in trial participants at 2 years of corrected age. One important challenge is the lack of funding for local costs for a trial-specific assessment.
Methods
Of the 1601 infants randomised in the SafeBoosC-III trial, 1276 infants were alive at 36 weeks’ postmenstrual age and will potentially be available for the 2-year follow-up. Inclusion criteria will be enrollment in a neonatal intensive care unit taking part in the follow-up study and parental consent if required by local regulations. We aim to collect data from routine follow-up programmes between the ages of 18 and 30 months of corrected age. If no routine follow-up has been conducted, we will collect informal assessments from other health care records from the age of at least 12 months. A local co-investigator blinded to group allocation will classify outcomes based on these records. We will supplement this with parental questionnaires including the Parent Report of Children’s Abilities—Revised. There will be two co-primary outcomes: the composite of death or moderate or severe neurodevelopmental disability and mean Bayley-III/IV cognitive score. We will use a 3-tier model for prioritisation, based on the quality of data. This approach has been chosen to minimise loss to follow-up assuming that little data is better than no data at all.
Discussion
Follow-up at the age of 2 years is important for intervention trials in the newborn period as only time can show real benefits and harms later in childhood. To decrease the risk of generalisation and data-driven biased conclusions, we present a detailed description of the methodology for the SafeBoosC-III follow-up study. As funding is limited, a pragmatic approach is necessary.
Trial registration
ClinicalTrials.gov NCT05134116. Registered on 24 November 2021.
... Hypoxia ischemia-related brain injury contributes to neonatal morbidities and is responsible for elevated mortality rates in both preterm and full-term neonates [13]. However, the types of brain injury differ in preterm and full-term infants [29]. HIE in full-term infants is associated with high mortality and morbidity rates [30,31]. ...
Our current knowledge regarding the development of the human brain mostly derives from experimental studies on non-human primates, sheep, and rodents. However, these studies may not completely simulate all the features of human brain development as a result of species differences and variations in pre- and postnatal brain maturation. Therefore, it is important to supplement the in vivo animal models to increase the possibility that preclinical studies have appropriate relevance for potential future human trials. Three-dimensional brain organoid culture technology could complement in vivo animal studies to enhance the translatability of the preclinical animal studies and the understanding of brain-related disorders. In this review, we focus on the development of a model of hypoxic-ischemic (HI) brain injury using human brain organoids to complement the translation from animal experiments to human pathophysiology. We also discuss how the development of these tools provides potential opportunities to study fundamental aspects of the pathophysiology of HI-related brain injury including differences in the responses between males and females.
... In term infants, HI events result in a different neuropathology pattern from that observed in preterm infants due to the greater vulnerability of gray matter to excitotoxicity at this age (Jensen, 2002). Thus, ischemic injury in term newborns is more typically characterized by gray matter damage, particularly in the cortex, hip, str, and tha, with neuronal damage being a major factor (Fatemi et al., 2009;Volpe, 2009). DTI has been widely used to characterize white matter disease; however, imaging changes in the gray matter microstructure are limited due to gray matter isotropy. ...
Objective
Hypoxic-ischemic encephalopathy can lead to lifelong morbidity and premature death in full-term newborns. Here, we aimed to determine the efficacy of diffusion kurtosis (DK) [mean kurtosis (MK)] and diffusion tensor (DT) [fractional anisotropy (FA), mean diffusion (MD), axial diffusion (AD), and radial diffusion (RD)] parameters for the early diagnosis of early brain histopathological changes and the prediction of neurodegenerative events in a full-term neonatal hypoxic-ischemic brain injury (HIBD) rat model.
Methods
The HIBD model was generated in postnatal day 7 Sprague-Dawley rats to assess the changes in DK and DT parameters in 10 specific brain structural regions involving the gray matter, white matter, and limbic system during acute (12 h) and subacute (3 d and 5 d) phases after hypoxic ischemia (HI), which were validated against histology. Sensory and cognitive parameters were assessed by the open field, novel object recognition, elevated plus maze, and CatWalk tests.
Results
Repeated-measures ANOVA revealed that specific brain structures showed similar trends to the lesion, and the temporal pattern of MK was substantially more varied than DT parameters, particularly in the deep gray matter. The change rate of MK in the acute phase (12 h) was significantly higher than that of DT parameters. We noted a delayed pseudo-normalization for MK. Additionally, MD, AD, and RD showed more pronounced differences between males and females after HI compared to MK, which was confirmed in behavioral tests. HI females exhibited anxiolytic hyperactivity-like baseline behavior, while the memory ability of HI males was affected in the novel object recognition test. CatWalk assessments revealed chronic deficits in limb gait parameters, particularly the left front paw and right hind paw, as well as poorer performance in HI males than HI females.
Conclusions
Our results suggested that DK and DT parameters were complementary in the immature brain and provided great value in assessing early tissue microstructural changes and predicting long-term neurobehavioral deficits, highlighting their ability to detect both acute and long-term changes. Thus, the various diffusion coefficient parameters estimated by the DKI model are powerful tools for early HIBD diagnosis and prognosis assessment, thus providing an experimental and theoretical basis for clinical treatment.
... Globally, preterm birth, defined as birth before 37 weeks of gestation, affects around 10% of pregnancies 1 . People born preterm are at an increased risk for atypical brain development, termed encephalopathy of prematurity (EoP) 2 , which can lead to cerebral palsy, neurodevelopmental and cognitive impairments, autism, and psychiatric disorders 3 . There are no treatments for EoP, partly because the mechanisms linking preterm birth with altered cerebral development are incompletely understood. ...
Preterm birth is associated with atypical brain development and alterations in the gut microbiome. Variation in gut microbiome composition associates with neurobehavioural outcomes, but its relationship with brain development in preterm infants is unknown. First, we characterised the faecal microbiome in an observational cohort of 135 preterm (<32' weeks gestation) and 12 term neonates using 16S-based and shotgun metagenomic sequencing. Apart from sampling age, delivery mode had the strongest association with preterm microbiome shortly after birth; low birth gestational age, infant sex and antibiotics significantly associated with microbiome composition at NICU discharge. Second, we integrated these data with structural and diffusion MRI at term-equivalent age. Bacterial community composition associated with MRI features of encephalopathy of prematurity. Particularly, abundances of Escherichia coli and Klebsiella spp. correlated with microstructural parameters in deep and cortical grey matter. Metagenome functional capacity analyses using gut-brain modules suggested that these bacteria interact with brain microstructural development via tryptophan and propionate metabolism. This study indicates a role for microbiota-brain interactions in brain development following preterm birth.
... Several animal studies have investigated mechanisms of injury that lead to increased neurologic morbidity [8][9][10]. The effect from hypoxia/hypoxemia appears to be an important and dominant mechanism of injury [11]. Current continuous recordings of oxygen saturation reveal a much higher frequency of intermittent hypoxia (IH) events that were previously un-documented in medical charts and provide insight to high-risk patterns associated with both short-term and long-term morbidity [12,13]. ...
Preterm infants often experience frequent intermittent hypoxia (IH) episodes which is associated with neuroinflammation. We tested the hypotheses that early caffeine and/or non-steroidal in-flammatory drugs (NSAIDs) confer superior therapeutic benefits for protection against IH-induced neuroinflammation than late treatment. Newborn rats were exposed to IH or hy-peroxia (50% O2) from birth (P0) to P14. For early treatment, the pups were administered: 1) dai-ly caffeine citrate (Cafcit, 20 mg/kg IP loading on P0, followed by 5 mg/kg from P1-P14); 2) ke-torolac topical ocular solution in both eyes from P0 to P14; 3) ibuprofen (Neoprofen, 10 mg/kg loading dose on P0 followed by 5 mg/kg/day on P1 and P2); 4) caffeine+ketorolac co-treatment; 5) caffeine+ibuprofen co-treatment; or 6) equivalent volume saline. On P14, animals were placed in room air (RA) with no further treatment. For late treatment, pups received similar treatments from P15-P21 (caffeine and/or ketorolac), or P15-P17 (ibuprofen). RA control were similarly treated. At P21, whole brains were assessed for histopathology, apoptosis, mye-lination, and biomarkers of inflammation. IH caused significant inflammation, reduced mye-lination, and apoptosis in preterm rat brains, an effect that was improved predominantly with combined caffeine/NSAID early treatment. Early caffeine/NSAID co-treatment confers syner-gistic neuroprotection against IH-induced damage.
... Structural MRI (T1-and T2-weighted) and diffusion MRI (dMRI) have revealed a phenotype of preterm birth that includes changes in global and regional tissue volumes and cortical complexity, and altered microstructural integrity of the WM Pecheva et al., 2018). These imaging features capture the encephalopathy of prematurity (EoP), which is thought to underlie long term impairments (Volpe, 2009). Diffusion metrics are influenced by microstructural properties of the underlying tissue including axonal density and diameter, and water content; although myelination may alter/contribute to water diffusivity, myelin does not directly contribute to the diffusion signal due to short T2 (Mancini et al., 2020;van der Weijden et al., 2020). ...
A cardinal feature of the encephalopathy of prematurity is dysmaturation of developing white matter and subsequent hypomyelination. Magnetisation transfer imaging (MTI) offers surrogate markers for myelination including magnetisation transfer ratio (MTR) and magnetisation transfer saturation (MTsat). Using data from 105 neonates, we characterise MTR and MTsat in the developing brain and investigate how these markers are affected by gestational age at scan and preterm birth. We explore correlations of the two measures with fractional anisotropy (FA), radial diffusivity (RD) and T1w/T2w ratio which are commonly used markers of white matter integrity in early life. We used two complementary analysis methods: voxel-wise analysis across the white matter skeleton, and tract-of-interest analysis across 16 major white matter tracts. We found that MTR and MTsat positively correlate with gestational age at scan. Preterm infants at term-equivalent age had lower values of MTsat in the genu and splenium of the corpus callosum, while MTR was higher in central white matter regions, the corticospinal tract and the uncinate fasciculus. Correlations of MTI metrics with other MRI parameters revealed that there were moderate positive correlations between T1w/T2w and MTsat and MTR at voxel-level, but at tract-level FA had stronger positive correlations with these metrics. RD had the strongest correlations with MTI metrics, particularly with MTsat in major white matter tracts. The observed changes in MTI metrics are consistent with an increase in myelin density during early postnatal life, and lower myelination and cellular/axonal density in preterm infants at term-equivalent age compared to term controls. Furthermore, correlations between MTI-derived features and conventional measures from dMRI provide new understanding about the contribution of myelination to non-specific imaging metrics that are often used to characterise early brain development.
... Another form of brain damage in preterm infants is white matter damage, with periventricular leukomalacia (PVL) being the main and best known finding. PVL is a focal periventricular necrosis associated with diffuse reactive gliosis and microglial activation in the surrounding white matter [18]. Banker and Larroche were the first to describe cerebral injury in detail and associated it with cardiorespiratory changes and cerebral ischemia [19]. ...
Premature newborns are patients who need detailed monitoring of vital processes such as respiration, blood circulation, central and peripheral perfusion, and brain activity. From this point of view, the use of modern methods of visualization of respiratory activity, which can be implemented in the NAVA mode, is a very promising solution to this problem. Our study shows that adequate respiratory support not only contributes to the prevention of ventilator-induced diseases but also reduces the duration of ventilation and the length of stay of patients in the intensive care unit. In addition, this study presents a comparative description of some indicators of ventilation parameters such as peak pressure and tidal volume. We also analyzed the values of gas composition of the venous blood during the first three days. The incidence of bronchopulmonary dysplasia, intraventricular hemorrhages and retinopathy depending on the mode, parameters and duration of ventilation in premature newborns with extremely low birth weight was estimated.
... Quantitative analysis is a more objective and suitable method for assessing the brain volume loss. The comprehensive volumetric assessment may be an important tool for detecting structural changes severity due to intracerebellar and cerebellar-cortical injuries [43][44][45], although other techniques such as functional MRI, may have an auxiliary role in assessing supra-and infratentorial regions connectivity [46,47]. ...
This study aims to evaluate in extremely premature infants the severity of brain structural injury causing total absence or near-total absence of cerebellar hemispheres by using MRI visual and volumetric scoring systems. It also aims to assess the role of the score systems in predicting motor outcome. We developed qualitative and quantitative MRI scoring systems to grade the overall brain damage severity in 16 infants with total absence or near-total absence of cerebellar hemispheres. The qualitative scoring system assessed the severity of macrostructural abnormalities of cerebellum, brainstem, supratentorial gray and white matters, ventricles while the quantitative scoring system weighted the loss of brain tissue volumes, and gross motor function classification system (GMFCS) was used to assess motor function at 1- and 5-year follow-ups.
Positive correlations between both MRI scores and GMFCS scales were detected at follow-ups (p > 0.05), but only the volumetric score could identify those infants developing higher levels of motor impairment.
Brain volumetric MRI offers an unbiassed assessment of prenatal brain damage. The quantitative scoring system, performed at term equivalent age, can be a helpful tool for predicting the long-term motor outcome in extremely preterm infants with a near-total absence of cerebellum.
... Periventricular white matter damage (WMD) is a common type of brain injury in preterm infants and is the leading cause of cerebral palsy and cognitive impairment. The neuropathological features of WMD primarily include cerebral white matter ischemia, coagulative necrosis, myelination impairment, microglia activation, astrocyte proliferation, and neuronal death [4], which eventually lead to cerebral palsy and disorders of cognition, language, and behavior, among others [5,6]. The clinical manifestations of WMD in preterm infants are often atypical, and diagnosis is often delayed. ...
White matter damage (WMD) is a primary cause of cerebral palsy and cognitive impairment in preterm infants, and no effective treatments are available. Microglia are a major component of the innate immune system. When activated, they form typical pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes and regulate myelin development and synapse formation. Therefore, they may play a pivotal role in hypoxic–ischemic (HI) WMD. Herein, we investigated neural inflammation and long-term microglia phenotypic polarization in a neonatal rat model of hypoxia-ischemia-induced WMD and elucidated the underlying pathophysiological processes. We exposed 3-day-old (P3) Sprague−Dawley rats to hypoxia (8% oxygen) for 2.5 hr after unilateral common carotid artery ligation. The activation of NLRP3 inflammatory bodies, microglia M1/M2 polarization, myelination, and synaptic development in our model were monitored 7, 14, and 21 days after birth. In addition, the Morris water maze test was performed on postnatal Day 28. We confirmed myelination disturbance in the periventricular white matter, abnormal synaptic development, and behavioral changes in the periventricular area during the development of HI WMD. In addition, we found an association between the occurrence and development of HI WMD and activation of the NLRP3 inflammasome, microglial M1/M2 polarization, and the release of inflammatory factors. NLRP3 inhibition can play an anti-inflammatory role by inhibiting the differentiation of microglia into the M1 phenotype, thereby improving myelination and synapse formation. In conclusion, microglia are key mediators of the inflammatory response and exhibit continuous phenotypic polarization 7–21 days after HI-induced WMD. This finding can potentially lead to a new treatment regimen targeting the phenotypic polarization of microglia early after HI-induced brain injury.
... Within these windows, adverse events can significantly alter developmental trajectories and increase the risk of disease (74). For these reasons, infants born prematurely at the verge of the second and third trimesters represent a particularly vulnerable population (Figure 1), as they are at increased risk of perinatal white matter injury (PWMI), which may present with intraventricular hemorrhage, periventricular leukomalacia, or diffuse white matter injury (75). Perinatal inflammation and infections have been implicated in the pathogenesis of PWMI and may further worsen the neurological outcome (39). ...
Infants born preterm are at a high risk of both gut microbiota (GM) dysbiosis and neurodevelopmental impairment. While the link between early dysbiosis and short-term clinical outcomes is well established, the relationship with long-term infant health has only recently gained interest. Notably, there is a significant overlap in the developmental windows of GM and the nervous system in early life. The connection between GM and neurodevelopment was first described in animal models, but over the last decade a growing body of research has also identified GM features as one of the potential mediators for human neurodevelopmental and neuropsychiatric disorders. In this narrative review, we provide an overview of the developing GM in early life and its prospective relationship with neurodevelopment, with a focus on preterm infants. Animal models have provided evidence for emerging pathways linking early-life GM with brain development. Furthermore, a relationship between both dynamic patterns and static features of the GM during preterm infants’ early life and brain maturation, as well as neurodevelopmental outcomes in early childhood, was documented. Future human studies in larger cohorts, integrated with studies on animal models, may provide additional evidence and help to identify predictive biomarkers and potential therapeutic targets for healthy neurodevelopment in preterm infants.
... The primary outcome was survival without severe neonatal morbidity at discharge. Severe neonatal morbidity was a composite endpoint defined as at least one adverse outcome among the following: severe bronchopulmonary dysplasia, defined as a need for oxygen for at least 28 days plus a need for oxygen concentration 30 % or greater, mechanical ventilator support, or continuous positive airway pressure at 36 weeks postmenstrual age [17]; severe cerebral lesions, defined as grade 3 or higher intraventricular hemorrhage [18]; grade 3 or higher retinopathy of prematurity according to the international classification (International Committee for the Classification of Retinopathy of Prematurity) [19]; and grade II and III necrotizing enterocolitis according to Bell staging [ 20]. ...
Objective:
To determine the prevalence, short-term prognosis and pharmacologic management of pulmonary hypertension (PH) among very preterm infants born before 32 weeks gestation (WG).
Study design:
In the EPIPAGE-2 French national prospective population-based cohort of preterm infants born in 2011, those presenting with PH were identified and prevalence was estimated using multiple imputation. The primary outcome was survival without severe morbidity at discharge and was compared between infants with or without PH after adjusting for confounders, using generalized estimating equations models. Subgroup analysis was performed according to gestational age (GA) groups.
Results:
Among 3383 eligible infants, 3222 were analyzed. The prevalence of PH was 6.0 % (95 % CI, 5.2-6.9), 14.5 % in infants born at 22-27+6 WG vs 2.7 % in infants born at 28-31+6 WG (P < .001). The primary outcome (survival without severe morbidity at discharge) occurred in 30.2 % of infants with PH vs 80.2 % of infants without PH (P < .001). Adjusted incidence rate ratios for survival without severe morbidity among infants with PH were 0.42 (0.32-0.57) and 0.52 (0.39-0.69) in infants born at 22-27+6 weeks gestation and those born at 28-31+6 weeks, respectively. Among infants with PH, 92.2 % (95 % CI, 87.7-95.2) received sedation and/or analgesia, 63.5 % (95 % CI, 56.6-69.9) received inhaled NO and 57.6 % (95 % CI, 50.9-64.0) received hemodynamic treatments.
Conclusion:
In this population-based cohort of very preterm infants, the prevalence of PH was 6 %. PH was associated with a significant decrease of survival without severe morbidity in this population.
... 5 It is characterized histopathologically by necrosis of premyelinating oligodendroglia in the periventricular white matter, which are extremely vulnerable to death. [6][7][8][9][10] The pattern of perinatal brain injury is highly dependent on gestational age. For example, in term infants, injuries primarily affect cerebral cortical parenchyma, especially posterior watershed regions or strokelike distributions. ...
Purpose: To assess the diagnostic value of the thalamus L-sign on magnetic resonance imaging (MRI) in distinguishing between periventricular leukomalacia and neurometabolic disorders in pediatric patients. Methods: In this retrospective study, clinical and imaging information was collected from 50 children with periventricular leu-komalacia and 52 children with neurometabolic disorders. MRI was used to evaluate the L-sign of the thalamus (ie, injury to the posterolateral thalamus) and the lobar distribution of signal intensity changes. Age, sex, gestational age, and level of Gross Motor Function Classification System (only for periventricular leukomalacia) constituted the clinical parameters. Statistical evaluation of group differences for imaging and clinical variables were conducted using univariable statistical methods. The intra-and inter-observer agreement was evaluated using Cohen's kappa. Univariable or multivariable logistic regression was employed for selection of variables, determining independent predictors, and modeling. Results: The thalamus L-sign was observed in 70% (35/50) of patients in the periventricular leukomalacia group, but in none of the patients with neurometabolic disorder (P < .001). The gestational age between groups varied significantly (P < .001). Involvement of frontal, parietal, and occipital lobes differed significantly between groups (P < .001). In the logistic regression, the best model included negative thalamus L-sign and gestational age, yielding an area under the curve, accuracy, sensitivity, spe-cificity, and precision values of 0.995, 96.1%, 96%, 96.2%, and 96%, respectively. Both the lack of thalamus L-sign and gestational age were independent predictors (P < .001). Conclusions: The thalamus L-sign and gestational age may be useful in distinguishing between periventricular leukomalacia and neurometabolic disorders.
Machine learning and deep learning are two subsets of artificial intelligence that involve teaching computers to learn and make decisions from any sort of data. Most recent developments in artificial intelligence are coming from deep learning, which has proven revolutionary in almost all fields, from computer vision to health sciences. The effects of deep learning in medicine have changed the conventional ways of clinical application significantly. Although some sub-fields of medicine, such as pediatrics, have been relatively slow in receiving the critical benefits of deep learning, related research in pediatrics has started to accumulate to a significant level, too. Hence, in this paper, we review recently developed machine learning and deep learning-based solutions for neonatology applications. We systematically evaluate the roles of both classical machine learning and deep learning in neonatology applications, define the methodologies, including algorithmic developments, and describe the remaining challenges in the assessment of neonatal diseases by using PRISMA 2020 guidelines. To date, the primary areas of focus in neonatology regarding AI applications have included survival analysis, neuroimaging, analysis of vital parameters and biosignals, and retinopathy of prematurity diagnosis. We have categorically summarized 106 research articles from 1996 to 2022 and discussed their pros and cons, respectively. In this systematic review, we aimed to further enhance the comprehensiveness of the study. We also discuss possible directions for new AI models and the future of neonatology with the rising power of AI, suggesting roadmaps for the integration of AI into neonatal intensive care units.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders and is accompanied by significant multidomain impairment. While genetic influences on the development of ADHD are strong (heritability of 0.70–0.80), there is increasing evidence suggesting that environmental factors may also play an etiological role. This chapter summarizes the literature investigating associations between various prenatal, perinatal/childbirth-related, and postnatal environmental risk factors and categorical ADHD diagnoses, as well as dimensionally measured ADHD symptoms. The complex interplay between genes and environment, as well as the role of protective factors, are also discussed. Overall, there appears to be stronger evidence for some factors (e.g., prematurity, low birth weight, parental age, maternal cigarette smoking, exposure to environmental toxins, and extreme early deprivation) than others (e.g., maternal diet, method of delivery, and screen time), and that certain protective factors such as family cohesion, community support, and maternal breastfeeding may play a role in promoting positive outcomes among individuals with ADHD, in some cases potentially reducing risk for ADHD. Methodological limitations and guidelines for future research are proposed. Examining the impact of environmental risk factors and protective factors, as well as gene–environment interactions, will be crucial to efforts aimed at uncovering etiological pathways to ADHD.
Myelination is a process tightly regulated by a variety of neurotrophic factors. Here, we show—by analyzing two transgenic mouse lines, one overexpressing EPO selectively in the brain Tg21(PDGFB-rhEPO) and another with targeted removal of EPO receptors (EPORs) from oligodendrocyte progenitor cells (OPC)s (Sox10-cre;EpoRfx/fx mice)—a key function for EPO in regulating developmental brain myelination. Overexpression of EPO resulted in faster postnatal brain growth and myelination, an increased number of myelinating oligodendrocytes, faster axonal myelin ensheathment, and improved motor coordination. Conversely, targeted ablation of EPORs from OPCs reduced the number of mature oligodendrocytes and impaired motor coordination during the second postnatal week. Furthermore, we found that EPORs are transiently expressed in the subventricular zone (SVZ) during the second postnatal week and EPO increases the postnatal expression of essential oligodendrocyte pro-differentiation and pro-maturation (Nkx6.2 and Myrf) transcripts, and the Nfatc2/calcineurin pathway. In contrast, ablation of EPORs from OPCs inactivated the Erk1/2 pathway and reduced the postnatal expression of the transcripts. Our results reveal developmental time windows in which EPO therapies could be highly effective for stimulating oligodendrocyte maturation and myelination.
Aim:
We investigated the historical origins of developmental care for newborn infants using Reference Publication Year Spectroscopy (RPYS), an innovative method of bibliometric analysis.
Methods:
A Web of Science search query that combined infant and intervention-related synonyms was performed on 2 February 2022. RPYS analysis was performed on this dataset to identify the most referenced historical publications for developmental care in newborn infants. Median deviation analysis identified the peak publication years, including the most cited historical references. Landmark publications were defined as those belonging to the top 10% of the most frequently referenced publications for at least 20 years.
Results:
The RPYS peaks showed an early phase (1936-1986), during which infant development was studied and analysed, leading to a conceptualisation of developmental care for newborn infants. The following years (1987-2020), showed an explosion of interest in developmental care and highlighted two main programmes. The Neonatal Individualized Developmental Care Assessment Program (NIDCAP) and the Infant Health and Development Program (IHDP) inspired numerous publications during those years, which strove to demonstrate evidence of their clinical benefits.
Conclusion:
Developmental care has become increasingly important, thanks to the implementation of NIDCAP and IHDP.
The development of the human brain and spinal cord may be divided into several phases, each of which is characterized by particular developmental disorders. After implantation, formation and separation of the germ layers occur, followed by dorsal and ventral induction phases, and phases of neurogenesis, migration, organization and myelination. With the transvaginal ultrasound technique, a detailed description of the living embryo and foetus has become possible. With magnetic resonance imaging, foetal development of the brain can now be studied in detail from about the beginning of the second half of pregnancy. In recent years, much progress has been made in elucidating the mechanisms by which the central nervous system (CNS) develops, and also in our understanding of its major developmental disorders, such as neural tube defects, cerebellar malformations, holoprosencephaly and malformations of cortical development. Molecular genetic data, that explain programming of development aetiologically, can now be incorporated.In this chapter, an overview is presented of major stages in the development of the human CNS (► Sect. 1.2), the first three weeks of development (► Sect. 1.3), neurulation (► Sect. 1.4), development of the spinal cord (► Sect. 1.5), pattern formation of the brain (► Sect. 1.6), early development of the brain (► Sect. 1.7), foetal development of the brain (► Sect. 1.8), development of the meninges and choroid plexuses (► Sect. 1.9), development of the blood supply of the brain (► Sect. 1.10), development of fibre tracts and their myelination (► Sect. 1.11) and the foetal connectome (► Sect. 1.12).KeywordsDevelopment of human brainDevelopment of human spinal cordPhases of developmentUltrasound imagingMagnetic resonance imagingDevelopment of myelinationDevelopment of fibre tracts
Congenital malformations are structural abnormalities due to faulty development, present at birth, and amongst the major causes of prenatal, perinatal and infant mortality and morbidity. They include gross and microscopic malformations, inborn errors of metabolism, intellectual disability and cellular and molecular abnormalities. About 3% of newborns have a single major malformation, and 0.7% have multiple major defects. The frequency is much higher prenatally, the majority aborting spontaneously. More than 80% of malformed conceptuses are lost during the embryonic period, and more than 90% before birth. The importance of congenital malformations as a cause of perinatal mortality has increased as deaths from intrapartum problems and infectious diseases have declined, and better neonatal care has improved the survival of normally developed low-birthweight babies. During the last decades, there has been a rapid expansion of methods for detecting many different types of disorders prenatally.In this introductory chapter, the known causes of congenital malformations (► Sect. 3.2), and possibilities to detect them prenatally (► Sect. 3.3), will be outlined. Some emphasis is given to the increasing group of inborn errors of metabolism affecting the central nervous system (CNS; ► Sect. 3.4), disorders of white matter (► Sect. 3.5), vascular disorders (► Sect. 3.6) and congenital tumours (► Sect. 3.7). Several Clinical cases illustrate these disorders. In ► Sect. 3.8, classifications of CNS malformations are discussed.KeywordsCongenital malformationsInborn errors of metabolismPrenatal detectionDisorders of white matterVascular disordersCongenital tumoursClassification of malformations
The cerebral cortex can be divided into a large isocortex, a much smaller allocortex (the hippocampal formation and the olfactory cortex), and a transition zone (the mesocortex) in between. Although many individual variations exist in the sulcal pattern and in the extent of the various cortical areas, the remarkable conservation of the pattern of areal divisions within the human brain suggests the existence of a highly conserved and rather rigidly regulated regional specification programme that controls their development. Histogenesis of the cerebral cortex progresses through three major phases: cell production, cell migration, and cortical differentiation and maturation. Migrating cells from the ventricular zone to the cortical plate form ontogenetic radial cell columns. An important role in neurogenesis for the outer part of the subventricular zone became evident.During the last decades, analysis of the genetic control of cortical development became possible. Mechanisms for induction and regionalization of the cerebral cortex are being unravelled and genes that are implicated in controlling regionalization, arealization, and differentiation have been discovered in the mouse brain. This neurogenetic approach has given a great impetus to the study of neuronal migration disorders (NMDs). Advances in neurogenetics and the increasing application of magnetic resonance imaging (MRI) resulted in the distinction of a growing number of NMDs, of many of which the gene involved has been discovered. In this chapter, after a brief overview of the cerebral cortex (► Sect. 10.2) and its main connections (► Sect. 10.3), the development of the isocortex (► Sect. 10.4), the hippocampus (► Sect. 10.5), and their main fibre systems, including diffusion tensor imaging data in the fetal brain (► Sect. 10.6), are discussed, followed by an overview of developmental disorders of the cerebral cortex. Malformations of cortical development (MCDs) include malformations due to abnormal cell production (► Sect. 10.7.1), abnormal migration (► Sect. 10.7.2), abnormal cortical organization (► Sect. 10.7.3), vascular disorders (► Sect. 10.7.5), and disorders of cortical connectivity (► Sect. 10.7.6). Many of these result in epilepsy (► Sect. 10.7.4) and/or intellectual disability (► Sect. 10.7.7). In ► Sect. 10.7.8, some neurobehavioural disorders are briefly reviewed, followed by a brief discussion of the development of language and some congenital language disorders (► Sect. 10.8). Throughout the chapter, clinical cases are presented and illustrated with MRI and autopsy data.KeywordsDevelopment cerebral cortexDevelopment isocortexSubventricular zoneRegionalization cerebral cortexDevelopment hippocampusDevelopment main fibre connectionsNeuronal migration disordersMalformations of cortical developmentEpilepsyIntellectual disabilityNeurobehavioural disordersDevelopment of languageCongenital language disorders
The developing central nervous system (CNS) is exquisitely vulnerable to injury due to unique social, biomechanical, and biological circumstances. This entry outlines the major causes of CNS injury in young people and discusses the most common underlying biological phenomena that lead to CNS tissue damage and dysfunction. Injury to the developing CNS can deplete fragile precursor cell populations, leading to disruption of normal development. However, the young CNS has a remarkable ability to recover from injury. Proper acute management and rehabilitation care of children with CNS injury can lead to good outcomes even after severe injuries.
Myelination is a process that is tightly regulated by a variety of neurotrophic factors. Here, we show - by analyzing two transgenic mouse lines, one overexpressing EPO selectively in the brain Tg21 ( PDGFB-rhEPO ), and another with targeted removal of EPO receptors (EPORs) from oligodendrocyte progenitor cells (OPC)s ( Sox10-cre;EPOR fl/fl mice ) – a key function for EPO in regulating developmental brain myelination. Overexpression of EPO resulted in faster postnatal brain growth and myelination, an increased number of myelinating oligodendrocytes, faster axonal myelin ensheathment, and improved motor coordination. Inversely, targeted ablation of EPORs from OPCs reduced the number of mature oligodendrocytes and impaired motor coordination during the second postnatal week. Further, we found that EPORs are transiently expressed in the subventricular zone (SVZ) during the second postnatal week, and they stimulate the Erk1/2 pathway as well as the expression of essential oligodendrocyte pro-differentiation and pro-maturation transcripts (Nkx6.2 and Myrf), and the Nfatc2/calcineurin pathway. Our results reveal developmental time windows in which EPORs are expressed when therapies could be highly effective for stimulating oligodendrocyte maturation and myelination.
Background:
Intraamniotic inflammation is associated with preterm birth, especially in cases occurring before 32 weeks' gestation, and is causally-linked with increased risk of neonatal mortality and morbidity. Targeted anti-inflammatory interventions may assist in improving outcomes for pregnancies impacted by intrauterine inflammation. Interleukin (IL)-1 is a central upstream mediator of inflammation. Accordingly, IL-1 is a promising candidate target for intervention therapies, and has previously been targeted using the IL-1 receptor antagonist, anakinra. Recent studies have shown that the novel non-competitive allosteric IL-1 receptor inhibitor, rytvela, partially resolved inflammation associated with preterm birth and fetal injury. In the present study, we used a preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela and anakinra, administered to the amniotic fluid in the setting of intraamniotic E. coli lipopolysaccharides (LPS) exposure.
Objective:
We hypothesized that both rytvela and anakinra would reduce LPS-induced intrauterine inflammation and protect the fetal brain.
Study design:
Ewes with a singleton fetus at 105 days of gestation (GA; term is ∼150 days) were randomized to one of the following groups: i) Intraamniotic (IA) injections of 2 ml saline at time = 0 and time = 24 hours as a negative control group (Saline Group, n=12); ii) IA injection of 10 mg E.coli LPS in 2 ml saline and IA injections of 2 ml saline at time = 0 hours and time = 24 hours as an inflammation positive control group (LPS Group, n=11); iii) IA injection of E.coli LPS in 2 ml saline and IA injections of 2.5 mg rytvela at time = 0 hours and time = 24 hours to test the anti-inflammatory efficacy of rytvela (LPS + rytvela Group, n=10); or iv) IA injection of E.coli LPS in 2 ml saline and IA injections of 100 mg anakinra at time = 0 hours and time = 24 hours to test the anti-inflammatory efficacy of anakinra (LPS + anakinra Group, n=12). Amniotic fluid was sampled at time = 0, 24 and 48 hours (i.e. at each intervention and at delivery). Fetal cord blood was collected at delivery for differential blood counts and chemical studies. Inflammation was characterized by the analysis of fetal tissue cytokine/chemokine levels using quantitative polymerase chain reaction (qPCR), enzyme-linked inmmunosorbent assay (ELISA), and histology. The primary study outcome of interest was the assessment of anakinra and rytvela brain-protective effects in the setting of E.coli LPS-induced intrauterine inflammation. Secondary outcomes of interest were to assess protection from fetal and intrauterine (i.e. amniotic fluid, chorioamnion) inflammation.
Results:
IA administration of LPS caused inflammation of the fetal lung, brain and chorioamnionitis in preterm fetal sheep. Relative to treatment with saline only in the setting of LPS exposure, IA administration of both rytvela and anakinra both significantly prevented periventricular white matter injury, microglial activation, and histologic chorioamnionitis. anakinra showed additional efficacy in inhibiting fetal lung MPO activity, but its use was associated with metabolic acidaemia and reduced fetal plasma IGF-1 levels at delivery.
Conclusion:
IA administration of rytvela or anakinra significantly inhibited fetal brain inflammation and chorioamnionitis in preterm fetal sheep exposed to intraamniotic LPS animals. Additionally, anakinra treatment was associated with potential negative impacts on the developing fetus.
White matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment. Neonates present a unique opportunity to repair WMIs due to a transient abundance of neural stem/progenitor cells (NSPCs) present in the germinal matrix with oligodendrogenic potential. We identified an endogenous oxysterol, 20-αHydroxycholesterol (20HC), in human maternal breast milk that induces oligodendrogenesis through a sonic hedgehog (shh), Gli-dependent mechanism. Following WMI in neonatal mice, injection of 20HC induced subventricular zone-derived oligodendrogenesis and improved myelination in the periventricular white matter, resulting in improved motor outcomes. Targeting the oligodendrogenic potential of postnatal NSPCs in neonates with WMIs may be further developed into a novel approach to mitigate this devastating complication of preterm birth.
Objectives:
To investigate the predictability of synthetic relaxometry for neurodevelopmental outcomes in premature infants and to evaluate whether a combination of relaxation times with clinical variables or qualitative MRI abnormalities improves the predictive performance.
Methods:
This retrospective study included 33 premature infants scanned with synthetic MRI near or at term equivalent age. Based on neurodevelopmental assessments at 18-24 months of corrected age, infants were classified into two groups (no/mild disability [n = 23] vs. moderate/severe disability [n = 10]). Clinical and MRI characteristics associated with moderate/severe disability were explored, and combined models incorporating independent predictors were established. Ultimately, the predictability of relaxation times, clinical variables, MRI findings, and a combination of the two were evaluated and compared. The models were internally validated using bootstrap resampling.
Results:
Prolonged T1-frontal/parietal and T2-parietal periventricular white matter (PVWM), moderate-to-severe white matter abnormality, and bronchopulmonary dysplasia were significantly associated with moderate/severe disability. The overall predictive performance of each T1-frontal/-parietal PVWM model was comparable to that of individual MRI finding and clinical models (AUC = 0.71 and 0.76 vs. 0.73 vs. 0.83, respectively; p > 0.27). The combination of clinical variables and T1-parietal PVWM achieved an AUC of 0.94, sensitivity of 90%, and specificity of 91.3%, outperforming the clinical model alone (p = 0.049). The combination of MRI finding and T1-frontal PVWM yielded AUC of 0.86, marginally outperforming the MRI finding model (p = 0.09). Bootstrap resampling showed that the models were valid.
Conclusions:
It is feasible to predict adverse outcomes in premature infants by using early synthetic relaxometry. Combining relaxation time with clinical variables or MRI finding improved prediction.
Clinical relevance statement:
Synthetic relaxometry performed during the neonatal period may serve as a biomarker for predicting adverse neurodevelopmental outcomes in premature infants.
Key points:
• Synthetic relaxometry based on T1 relaxation time of parietal periventricular white matter showed acceptable performance in predicting adverse outcome with an AUC of 0.76 and an accuracy of 78.8%. • The combination of relaxation time with clinical variables and/or structural MRI abnormalities improved predictive performance of adverse outcomes. • Synthetic relaxometry performed during the neonatal period helps predict adverse neurodevelopmental outcome in premature infants.
Cerebral visual impairment (CVI) is a brain-based visual disorder associated with injury and/or maldevelopment of central visual pathways. Visuospatial processing impairments are a cardinal feature of the complex clinical profile of individuals with CVI. Here, we assessed visuospatial processing abilities using a classic conjunction search task. Twenty-three individuals previously diagnosed with CVI (mean age 18.55 years ± 4.98 SD) and 37 controls with neurotypical development (mean age 21.11 years ± 4.56 SD) participated in the study. Subjects were instructed to search for a two-feature target (a white or black letter “O” or “C”) presented among a varying number of surrounding distractors (set sizes ranging from 1 to 32 items). Behavioral outcomes collected were reaction time (RT), accuracy, as well as slope and intercept values derived from the RT × set size function. Overall, participants with CVI took longer and were less accurate in finding the target than controls. Analysis of RT × set size functions revealed a profile consistent with less efficient search and slower visual orienting responses as indexed by higher slope and intercept values, respectively. These results are consistent with clinical reports of impaired visuospatial processing abilities and deployment of visual selective attention in individuals with CVI.
Hypoxic-ischemic injury to the periventricular cerebral white matter [periventricular leukomalacia (PVL)] results in cerebral palsy and is the leading cause of brain injury in premature infants. The principal feature of PVL is a chronic disturbance of myelination and suggests that oligodendrocyte (OL) lineage progression is disrupted by ischemic injury. We determined the OL lineage stages at risk for injury during the developmental window of vulnerability for PVL (23–32 weeks, postconceptional age). In 26 normal control autopsy human brains, OL lineage progression was defined in parietal white matter, a region of predilection for PVL. Three successive OL stages, the late OL progenitor, the immature OL, and the mature OL, were characterized between 18 and 41 weeks with anti-NG2 proteoglycan, O4, O1, and anti-myelin basic protein (anti-MBP) antibodies. NG2+O4+ late OL progenitors were the predominant stage throughout the latter half of gestation. Between 18 and 27 weeks, O4+O1+ immature OLs were a minor population (9.9 ± 2.1% of total OLs; n = 9). Between 28 and 41 weeks, an increase in immature OLs to 30.9 ± 2.1% of total OLs ( n = 9) was accompanied by a progressive increase in MBP+ myelin sheaths that were restricted to the periventricular white matter. The developmental window of high risk for PVL thus precedes the onset of myelination and identifies the late OL progenitor as the major potential target. Moreover, the decline in incidence of PVL at ∼32 weeks coincides with the onset of myelination in the periventricular white matter and suggests that the risk for PVL is related to the presence of late OL progenitors in the periventricular white matter.
Periventricular leukomalacia (PVL), the major substrate of cerebral palsy in survivors of prematurity, is defined as focal periventricular necrosis and diffuse gliosis in immature cerebral white matter. We propose that nitrosative and/or oxidative stress to premyelinating oligodendrocytes complicating cerebral ischemia in the sick premature infant is a key mechanism of injury interfering with maturation of these cells to myelin-producing oligodendrocytes and subsequent myelination. Using immunocytochemical markers in autopsy brain tissue from 17 PVL cases and 28 non-PVL controls, we found in the PVL cases: 1) selective regionalization of white matter injury, including preferential involvement of the deep compared to intragyral white matter; 2) prominent activation of microglia diffusely throughout the white matter; 3) protein nitration and lipid peroxidation in premyelinating oligodendrocytes in the diffuse component; 4) preferential death of premyelinating oligodendrocytes diffusely; and 5) virtual sparing of the overlying cerebral cortex, as demonstrated by markers of activated astrocytes and microglia. These data establish that PVL is primarily a white matter disease that involves injury to premyelinating oligodendrocytes, potentially through activation of microglia and release of reactive oxygen and nitrogen species. Agents that prevent nitrosative and oxidative stress may play a key role in ameliorating PVL in premature infants in the intensive care nursery.
Infants born very preterm have an increased risk of brain injury. Given the great increase in the number of such infants that are surviving, it is important to establish whether any resultant brain abnormalities persist into adolescence and adult life. We therefore examined in vivo whole brain, grey matter, white matter and hip-pocampal volumes, ventricular size and grey/white matter ratios in a series of adolescents who had been born very preterm, and an age-matched full-term control group. Structural MRI was carried out on a cohort of 72 adolescents (mean age 15 years) who were born before 33 weeks, and 48 age-matched full-term controls. Brain measurements were made blind to group af®li-ation using stereological principles. After controlling for gender and height, the very preterm subjects showed a 6.0% decrease in whole brain volume, and an 11.8% decrease in cortical grey matter volume, as well as a 15.6% decrease in right and a 12.1% decrease in left hippocampal volumes; they also had a 42.0% increase in the size of the lateral ventricles. Therefore, individuals who were born very preterm continue to show noticeable decrements in brain volumes and striking increases in lateral ventricular volume into adolescence. The functional signi®cance of these abnormalities merits further investigation.
Preterm infants have a high prevalence of long-term cognitive and behavioral disturbances. However, it is not known whether the stresses associated with premature birth disrupt regionally specific brain maturation or whether abnormalities in brain structure contribute to cognitive deficits.
To determine whether regional brain volumes differ between term and preterm children and to examine the association of regional brain volumes in prematurely born children with long-term cognitive outcomes.
Case-control study conducted in 1998 and 1999 at 2 US university medical schools.
A consecutive sample of 25 eight-year-old preterm children recruited from a longitudinal follow-up study of preterm infants and 39 term control children who were recruited from the community and who were comparable with the preterm children in age, sex, maternal education, and minority status.
Volumes of cortical subdivisions, ventricular system, cerebellum, basal ganglia, corpus callosum, amygdala, and hippocampus, derived from structural magnetic resonance imaging scans and compared between preterm and term children; correlations of regional brain volumes with cognitive measures (at age 8 years) and perinatal variables among preterm children.
Regional cortical volumes were significantly smaller in the preterm children, most prominently in sensorimotor regions (difference: left, 14.6%; right, 14.3% [P<.001 for both]) but also in premotor (left, 11.2%; right, 12.6% [P<.001 for both]), midtemporal (left, 7.4% [P =.01]; right, 10.2% [P<.001]), parieto-occipital (left, 7.9% [P =.01]; right, 7.4% [P =.005]), and subgenual (left, 8.9% [P =.03]; right, 11.7% [P =.01]) cortices. Preterm children's brain volumes were significantly larger (by 105. 7%-271.6%) in the occipital and temporal horns of the ventricles (P<. 001 for all) and smaller in the cerebellum (6.7%; P =.02), basal ganglia (11.4%-13.8%; P</=.005), amygdala (left, 20.2% [P =.001]; right, 30.0% [P<.001]), hippocampus (left, 16.0% [P =.001]; right, 12.0% [P =.007]), and corpus callosum (13.1%-35.2%; P</=.01 for all). Volumes of sensorimotor and midtemporal cortices were associated positively with full-scale, verbal, and performance IQ scores (P<.01 for all).
Our data indicate that preterm birth is associated with regionally specific, long-term reductions in brain volume and that morphological abnormalities are, in turn, associated with poorer cognitive outcome. JAMA. 2000;284:1939-1947.
Little is known of the molecular mechanisms that trigger oligodendrocyte death and demyelination in many acute central nervous system insults. Since oligodendrocytes express functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type glutamate receptors, we examined the possibility that oligodendrocyte death can be mediated by glutamate receptor overactivation. Oligodendrocytes in primary cultures from mouse forebrain were selectively killed by low concentrations of AMPA, kainate or glutamate, or by deprivation of oxygen and glucose. This toxicity could be blocked by the AMPA/kainate receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX). In vivo, differentiated oligodendrocytes in subcortical white matter expressed AMPA receptors and were selectively injured by microstereotaxic injection of AMPA but not NMDA. These data suggest that oligodendrocytes share with neurons a high vulnerability to AMPA/kainate receptor-mediated death, a mechanism that may contribute to white matter injury in CNS disease.
The neurons of layer 4 in the adult cerebral cortex receive their major ascending inputs from the thalamus. In development, however, thalamic axons arrive at the appropriate cortical area long before their target layer 4 neurons have migrated into the cortical plate. The axons accumulate and wait in the zone below the cortical plate, the subplate, for several weeks before invading the cortical plate. The subplate is a transient zone that contains the first postmitotic neurons of the telencephalon. These neurons mature well before other cortical neurons, and disappear by cell death after the thalamic axons have grown into the overlying cortical plate. The close proximity of growing thalamocortical axons and subplate neurons suggests that they might be involved in interactions important for normal thalamocortical development. Here we show that early in development the deletion of subplate neurons located beneath visual cortex prevents axons from the lateral geniculate nucleus of the thalamus from recognizing and innervating visual cortex, their normal target. In the absence of subplate neurons, lateral geniculate nucleus axons continue to grow in the white matter past visual cortex despite the presence of their target layer 4 neurons. Thus the transient subplate neurons are necessary for appropriate cortical target selection by thalamocortical axons.
The effects of perivascular blood on pial arteriolar vasoreactivity to selected vasodilators and vasoconstrictors were examined in vivo in a newborn pig model. alpha-Chloralose-anesthetized newborn pigs were fitted with closed cranial windows 4 d after cortical subarachnoid injections of autologous blood. The responsiveness of pial arterioles to topical application of dilator agents [iloprost, prostaglandin E2 (PGE2), histamine, and sodium nitroprusside (SNP)] and vasoconstrictor agents [leukotriene C4 and endothelin-1 (ET-1) in artificial cerebrospinal fluid was studied in control and blood-injected piglets. Pial arterioles dilated dose dependently in response to topical application of iloprost, PGE2, histamine, and SNP in the control group, with increases in diameter of 54, 44, 67, and 50% at 10(-8) M, 10(-5) M, 10(-5) M, and 10(-5) M, respectively. These dilations in response to iloprost, PGE2, and histamine in the blood-injected piglets were significantly attenuated to 23, 18, and 34%, respectively, whereas the dilation in response to SNP was not changed (64%). Constrictions in response to 10(-8) M leukotriene C4 and ET-1 were 16 and 26% and were potentiated by hematoma to 36 and 43%, respectively. The lowest dose of ET-1 (10(-12) M) significantly dilated pial arterioles in the control but not in the blood-treated group. We conclude that prolonged exposure of pial arterioles to perivascular blood attenuates cerebrovascular dilation in response to selected vasoactive agents (iloprost, PGE2, and histamine) but not to SNP, suggesting that blood-induced attenuation of vasodilation and the generalized vasoconstriction may involve inhibiting the prostanoid/cAMP signaling pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
In recent years there has been an increasing interest in a new kind of vulnerability of the developing brain which is concerned with disturbances and distortion of its later growth program, rather than with gross morphological anomaly, destructive lesions, or metabolic error. Thus there has grown up the concept of heightened sensitivity of the brain to growth retardation during its "growth spurt," a period arbitrarily defined as the time when the brain is passing through its most rapid phase of growth. The following remarks represent a personal view of the present situation and are amplified fled elsewhere.
Almost all the evidence for the special vulnerability of the brain growth spurt comes from experimental animals, usually rats, in whom nutritional growth restriction has been imposed during gestational, suckling and postweaning periods, or selectively in any one or two of these.
Death of oligodendrocyte (OL) precursors can be triggered in vitro by cystine deprivation, a form of oxidative stress that involves depletion of intracellular glutathione. We report here that OLs demonstrate maturation-dependent differences in survival when subjected to free radical-mediated injury induced by glutathione depletion. Using immunopanning to isolate rat preoligodendrocytes (preOLs), we generated highly enriched populations of preOLs and mature OLs under chemically defined conditions. Cystine deprivation caused a similar decrease in glutathione levels in OLs at both stages. However, preOLs were completely killed by cystine deprivation, whereas mature OLs remained viable. Although the glutathione-depleting agents buthionine sulfoximine and diethylmaleate were more potent in depleting glutathione in mature OLs, both agents were significantly more toxic to preOLs. Glutathione depletion markedly increased intracellular free radical generation in preOLs, but not in mature OLs, as indicated by oxidation of the redox-sensitive probe dihydrorhodamine 123. The antioxidants alpha-tocopherol, idebenone, and glutathione monoethylester prevented the oxidation of dihydrorhodamine in cystine-depleted preOLs and markedly protected against cell death. When the intracellular glutathione level was not manipulated, preOLs were also more vulnerable than mature OLs to exogenous free radical toxicity generated by a xanthine-xanthine oxidase system. Ultrastructural features of free radical-mediated injury in glutathione-depleted preOLs included nuclear condensation, margination of chromatin, and mitochondrial swelling. These observations indicate that preOLs are significantly more sensitive to the toxic effects of glutathione depletion and that oligodendroglial maturation is associated with decreased susceptibility to oxidative stress.
Glutamate-mediated damage to oligodendrocytes contributes to mental or physical impairment in periventricular leukomalacia (pre- or perinatal white matter injury leading to cerebral palsy), spinal cord injury, multiple sclerosis and stroke(1-4). Unlike neurons(5), white matter oligodendrocytes reportedly lack NMDA (N-methyl-D- aspartate) receptors(6,7). It is believed that glutamate damages oligodendrocytes, especially their precursor cells, by acting on calcium-permeable AMPA (alpha-amino-3-hydroxy-5-methyl- 4-isoxazole propionic acid)/kainate receptors alone(1-4) or by reversing cystine - glutamate exchange and depriving cells of antioxidant protection(8). Here we show that precursor, immature and mature oligodendrocytes in the white matter of the cerebellum and corpus callosum exhibit NMDA-evoked currents, mediated by receptors that are blocked only weakly by Mg2+ and that may contain NR1, NR2C and NR3 NMDA receptor subunits. NMDA receptors are present in the myelinating processes of oligodendrocytes, where the small intracellular space could lead to a large rise in intracellular ion concentration in response to NMDA receptor activation. Simulating ischaemia led to development of an inward current in oligodendrocytes, which was partly mediated by NMDA receptors. These results point to NMDA receptors of unusual subunit composition as a potential therapeutic target for preventing white matter damage in a variety of diseases.
Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30-50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular leukomalacia (PVL), characterized by periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants. We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e. mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5 +/- 4.8 wk) and 16 non-PVL controls (36.7 +/- 5.2 wk) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared with controls (19%; 3/16) (p = 0.01), with substantial involvement of the mediodorsal, and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL. (Pediatr Res 65: 524-529, 2009)
Periventricular leukomalacia (PVL), the major lesion underlying cerebral palsy in survivors of prematurity, is characterized by focal periventricular necrosis and diffuse gliosis of immature cerebral white matter. Causal roles have been ascribed to hypoxia-ischemia and maternal-fetal infection, leading to cytokine responses, inflammation, and oligodendrocyte cell death. Because interferon-gamma (IFN-gamma) is directly toxic to immature oligodendrocytes, we tested the hypothesis that it is expressed in PVL (N = 13) compared to age-adjusted controls (N = 31) using immunocytochemistry. In PVL, IFN-gamma immunopositive macrophages were clustered in necrotic foci, and IFN-gamma immunopositive reactive astrocytes were present throughout the surrounding white matter (WM). The difference in the number of IFN-gamma immunopositive glial cells/high power field (IFN-gamma score, Grades 0-3) between PVL cases (age-adjusted mean 2.59 +/- 0.25) and controls (age-adjusted mean 1.39 +/- 0.16) was significant (p<0.001). In the gliotic WM, the IFN-gamma score correlated with markers for lipid peroxidation, but not nitrative stress. A subset of premyelinating (O4(+)) oligodendrocytes expressed IFN-gamma receptors in PVL and control cases, indicating that these cells are vulnerable to IFN-gamma toxicity via receptor-mediated interactions. In PVL, IFN-gamma produced by macrophages and reactive astrocytes may play a role in cytokine-induced toxicity to premyelinating oligodendrocytes as part of a cytokine response stimulated by ischemia and/or infection.
Oligodendrocyte-like cells (OLD) derived from the rat oligodendroglial precursor line, CG-4, express Ca(2+)-permeable non-methyl-D-aspartate glutamate receptor channels (GluR). Exposure to kainate, an L-glutamate analogue, markedly elevates OLC Ca2+ influx and cytosolic [Ca2+], and results in damage to both OLC plasma membrane and OLC nuclear DNA. Two observations indicate that kainate-induced OLC internucleosomal DNA nicking is not simply a delayed consequence of cell necrosis: 1) there is no temporal lag between onset of plasma membrane injury and of DNA nicking; and 2) aurintricarboxylic acid, an endonuclease inhibitor, blocks kainate-induced damage to the plasma membrane. N-acetyl-L-cysteine also inhibits OLC kainate injury, suggesting that reactive oxygen species participate in OLC excitotoxicity. Kainate-induced OLC Ca2+ influx and excitotoxicity are blocked by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), indicating that these kainate effects are mediated by AMPA-GluR. AMPA and L-glutamate fail to elicit OLC damage unless cyclothiazide, an AMPA-GluR desensitization blocker, is present. OLC express both the "flip" and "flop" forms of GluR2, GluR3, and GluR4 mRNAs, but neither flip nor flop GluR1 mRNA. These data, together with the restriction of the desensitization-blocking activity of cyclothiazide to GluR containing flip-encoded GluR subunits, and the sharply diminished Ca2+ permeability of GluR containing edited GluR2, suggest OLC excitotoxicity is mediated by AMPA-GluR that contain flip GluR3 and/or flip GluR4 protein subunits, but neither flip nor flop GluR2 protein subunits. Rapid desensitization of these GluR is likely to be important in protecting cells of the oligodendroglial lineage from excitotoxicity.
This thoroughly revised new edition of a classic book provides a clinically inspired but scientifically guided approach to the biological foundations of human mental function in health and disease. It includes authoritative coverage of all the major areas related to behavioral neurology, neuropsychology, and neuropsychiatry. Each chapter, written by a world-renowned expert in the relevant area, provides an introductory background as well as an up-to-date review of the most recent developments. Clinical relevance is emphasized but is placed in the context of cognitive neuroscience, basic neuroscience, and functional imaging. Major cognitive domains such as frontal lobe function, attention and neglect, memory, language, prosody, complex visual processing, and object identification are reviewed in detail. A comprehensive chapter on behavioural neuroanatomy provides a background for brain-behaviour interactions in the cerebral cortex, limbic system, basal ganglia, thalamus, and cerebullum. Chapters on temperolimbic epilepsy, major psychiatric syndromes, and dementia provide in-depth analyses of these neurobehavioral entities and their neurobiological coordinates. Changes for this second edition include the reflection throughout the book of the new and flourishing alliance of behavioral neurology, neuropsychology, and neuropsychiatry with cognitive science;major revision of all chapters; new authorship of those on language and memory; and the inclusion of entirely new chapters on psychiatric syndromes and the dementias. Both as a textbook and a reference work, the second edition of Principles of Behavioral and Cognitive Neurology represents an invaluable resource for behavioural neurologists, neuropsychologists, neuropsychiatrists, cognitive and basic neuroscientists, geriatricians, physiatrists, and their students and trainees.
Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Myelin and oligodendrocytes are considered the major targets of injury caused by a cell-mediated immune response. There is circumstantial evidence that proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) could have disease-promoting roles in multiple sclerosis (MS). In the present study, the cytotoxic effects of IFN-gamma and TNF-alpha on the human oligodendroglial cell lines human oligodendroglioma (HOG) and MO3.13 were analyzed. When the oligodendroglial cell lines were cultured in the presence of IFN-gamma or TNF-alpha, apoptotic cell death was observed in both cell lines after >24 hr incubation. Apoptosis was evidenced by a decrease in cell viability, apoptotic changes in cell and nucleus morphology, and disruption of the membrane asymmetry. Our data show that TNF-alpha and IFN-gamma induce apoptosis in a dose-dependent fashion in both oligodendroglial cell lines and that their synergistic effect results in enhanced cell death. Understanding the regulation of cell death pathways in oligodendrocytes is critical for protecting myelin-producing cells and their associated axons during injury in patients with MS. (C) 2004 Wiley-Liss, Inc.
•Intraventricular hemorrhage (IVH) occurs in 31% to 43% of infants weighing less than 1500g. Intraventricular hemorrhage is rarely an Isolated lesion at autopsy. To document associated cerebral abnormality, 24 brains of infants with a diagnosis of IVH and who survived for at least one week were examined. The diagnosis was verified in 20 infants. Choroid plexus hemorrhage and brain calcification had been misdiagnosed as IVH in two infants and in two other infants, IVH was not evident at autopsy. Eleven Infants (46%) had choroid plexus hemorrhage. Twenty-two infants (92%) had additional cerebral abnormalities: periventricular leukomalacia, brainstem necrosis, hydrocephalus, or cerebellar necrosis. This study demonstrates that IVH is rarely an isolated abnormality in the preterm Infant brain. The associated brain lesions should be considered in attempts to prevent or treat IVH and their presence should be suspected during clinical assessment of survivors.
(AJDC 1987;141:617-621)
Introduction
The purpose of this report is to draw attention to a unique disease of cerebral white matter which has been encountered with great frequency among infants who died at the Children's Hospital Medical Center, Boston. Despite the remarkably high incidence of periventricular leukomalacia, which is the name that has been chosen for this pathological entity, it has been the subject of relatively little investigation, particularly in respect to the importance of prenatal and neonatal factors in its production and in respect to the clinical manifestations and to the nature of the pathological changes.
Historical Review
In 1843, in a lecture concerning the deformities of the human frame, W. J. Little1 described universal spasmodic contractures of the limbs which he attributed to abnormal factors in the perinatal period. He emphasized that the majority of these infants were born prematurely and had suffered some form of asphyxia at birth and
To evaluate the prevalence of cranial ultrasound abnormalities in very preterm infants as a function of gestational age, plurality, intrauterine growth restriction, and death before discharge.
A prospective, population-based cohort of 2667 infants born between 22 and 32 weeks of gestation in 1997 in nine regions of France, transferred to a neonatal intensive care unit, for whom at least one cranial ultrasound scan was available.
The frequencies of white matter damage (WMD), major WMD, cystic periventricular leukomalacia (PVL), periventricular parenchymal hemorrhagic involvement, and intraventricular hemorrhage with ventricular dilatation were 21%, 8%, 5%, 3%, and 3%, respectively. The risk of WMD increased with decreasing gestational age. Mean age at diagnosis of cystic PVL was older for the most premature infants. Intraventricular hemorrhage with ventricular dilatation was associated with a higher risk of cystic PVL. Intrauterine growth restriction was not associated with a lower prevalence of cystic PVL.
The frequency of WMD is high in very preterm babies and is strongly related to gestational age. The incidence of cystic PVL did not differ between babies with intrauterine growth restriction and babies who were appropriate for gestational age.
Oligodendrocytes in multiple sclerosis brain may be under a direct attack by proinflammatory cytokines, particularly tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ). In this study, we have examined the in vitro cytotoxic effects of the two cytokines, individually and in combination, on oligodendrocyte lineage cells using morphological criteria, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction assay (MTT), terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL), and agarose-gel electrophoretic analysis of fragmented DNA. IFNγ exerted a dose-dependent cytotoxic effect on cultured CG4 cells, an oligodendrocyte progenitor cell line, and in primary cultures of purified oligodendrocyte progenitors. TNFα, while by itself being only mildly toxic, greatly potentiated the cytotoxicity of IFNγ. The cytokine effects were developmentally modified in that their cytotoxic and cooperative effects became less evident in more differentiated cells. A cell-permeable peptide inhibitor (i.e., z-VAD.fmk) of caspases partially suppressed apoptotic changes elicited by the cytokine combination in CG4 cells but not in primary oligodendrocytes. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis of mRNA prepared from cytokine-treated cultures revealed an increased expression of the death receptor, Fas. The results suggest particular vulnerability of oligodendrocyte progenitors to a combination of TNFα and IFNγ involving an activation of the cell death program. J. Neurosci. Res. 54:574–583, 1998. © 1998 Wiley-Liss, Inc.
Periventricular white matter injury has a high incidence, particularly in the premature infant. A prominent feature of the pathogenesis of this injury, which ultimately results in disrupted myelination of periventricular white matter tracts, is a loss of oligodendrocytes (OLs). The timing of injury corresponds to the period in white matter development when OL precursors predominate. This article focuses on current understanding of the cellular and molecular basis for the developmental vulnerability of OL precursors that may predispose to their loss in periventricular leukomalacia (PVL). Recent advances in the cellular neurobiology of OL development have permitted study of the processes that regulate survival of developing OLs. Several potentially complementary etiologies for the developmental vulnerability of OL precursors are reviewed: (1) free-radical–mediated toxicity in the setting of oxidative stress, (2) cytotoxic cytokines, and (3) a critical dependence on selected trophic factors during certain periods in OL development. Recent work indicates that these causes of cell death are mediated by a common mechanism involving apoptosis. Potential therapeutic interventions for interruption of the pathways mediating OL death are examined. MRDD Research Reviews 3:96–107, 1997. © 1997 Wiley-Liss, Inc.
Myelination in the peripheral nervous system is considered to increase the phosphorylation level of neurofilament proteins in the axon, resulting in an increase in axonal calibre. To understand the relationship between myelination and neurofilament proteins in axons, we examined jimpy mutant mice with a point mutation in the proteolipid protein gene and dysmyelination in the central nervous system. The jimpy mice exhibited a characteristic similarity in neurofilament nature to the myelin-deficient mice in the peripheral nervous system reported previously. The following novel results were obtained in the jimpy mice: dysmyelinated axons, in which the amount of non-phosphorylated neurofilament-H was drastically increased without a significant reduction of the phosphorylated form, compared with the control myelinated axons, did not suffer any decrease in their diameters. Expression levels of all neurofilament subunit proteins and their mRNAs were enhanced in the central nervous system tissue. Because the above biochemical data were obtained from the cytoskeletal fraction, at least some of the increased neurofilament-H and -M proteins appeared to be coassembled into neurofilaments but remained non-phosphorylated. Axonal neurofilaments of the jimpy were, probably due to this abnormal stoichiometry and phosphorylation state in neurofilaments, more compact and random in alignment with less prominent cross-bridges than those of the control, providing possible evidence for disturbing the axonal transport of other organelles. These results suggest that myelination regulates both the expression and phosphorylation of neurofilament proteins, and is essential for the cytoplasmic organization of myelinated axons.
Programmed cell death (PCD) in the form of apoptosis is recognized as one of the central events in the development of the central nervous system. To study the time of onset, extent and distribution of PCD in the human telencephalon, embryos and fetuses from 4.5 to 27 gestational weeks (g.w.) were examined using the TUNEL (TdT-mediated dUTP-biotin nick-end labelling) in situ method. At 4.5 g.w. sparse TUNEL(+) nuclei were observed in the ventricular zone of the neural tube. With the formation of the cortical plate at 7–8 g.w., TUNEL(+) nuclei were seen in all developmental layers of the cortical anlage, as well as in the subcortical regions such as the ganglionic eminence and the internal capsule. The proliferative zones (the ventricular zone, the subventricular zone and the ganglionic eminence) contained the majority of all apoptotic nuclei observed in each specimen. However, the apoptotic index was highest in the subplate zone and in layer I. Double-labelling experiments suggested that neuronal precursors were the main population of cells undergoing PCD in the first trimester of gestation, whereas glial cells probably start dying around midgestation. The onset of labelling of microglial cells and apoptotic nuclei were synchronous, indicating the involvement of microglia in PCD. In conclusion, two distinct types of PCD were observed during human telencephalic development: embryonic apoptosis, which was synchronous with proliferation and migration of neuronal cells and probably not related to establishment of neuronal circuitry, and fetal apoptosis, which coincided with differentiation and synaptogenesis, and therefore may be related to the development of axonal-target connectivity.
Myelination provides extrinsic trophic signals that influence normal maturation and long-term survival of axons. The extent of axonal involvement in diseases affecting myelin or myelin forming cells has traditionally been underestimated. There are, however, many examples of axon damage as a consequence of dysmyelinating or demyelinating disorders. More than a century ago, Charcot described the pathology of multiple sclerosis (MS) in terms of demyelination and relative sparing of axons. Recent reports demonstrate a strong correlation between inflammatory demyelination in MS lesions and axonal transection, indicating axonal loss at disease onset. Disruption of axons is also observed in experimental allergic encephalomyelitis and in Theiler's murine encephalomyelitis virus disease, two animal models of inflammatory demyelinating CNS disease. A number of dysmyelinating mouse mutants with axonal pathology have provided insights regarding cellular and molecular mechanisms of axon degeneration. For example, the myelin-associated glycoprotein and proteolipid protein have been shown to be essential for mediating myelin-derived trophic signals to axons. Patients with the inherited peripheral neuropathy Charcot-Marie Tooth disease type 1 develop symptomatic progressive axonal loss due to abnormal Schwann cell expression of peripheral myelin protein 22. The data summarized in this review indicate that axonal damage is an integral part of myelin disease, and that loss of axons contributes to the irreversible functional impairment observed in affected individuals. Early neuroprotection should be considered as an additional therapeutic option for these patients.
Definition in the living premature infant of the anatomical and temporal characteristics of development of critical brain structures is crucial for insight into the time of greatest vulnerability of such brain structures. We used three-dimensional magnetic resonance imaging (3D MRI) and image-processing algorithms to quantitate total brain volume and total volumes of cerebral gray matter (GM), unmyelinated white matter (WM), myelinated WM, and cerebrospinal fluid (CSF) in 78 premature and mature newborns (postconceptional age, 29-41 weeks). Total brain tissue volume was shown to increase linearly at a rate of 22 ml/wk. Total GM showed a linear increase in relative intracranial volume of approximately 1.4% or 15 ml in absolute volume per week. The pronounced increase in total GM reflected primarily a fourfold increase in cortical GM. Unmyelinated WM was found to be the most prominent brain tissue class in the preterm infant younger than 36 weeks of postconceptional age. Although minimal myelinated WM was present in the preterm infant at 29 weeks, between 35 and 41 weeks an abrupt fivefold increase in absolute volume of myelinated WM was documented. Extracerebral and intraventricular CSF was readily quantitated by this technique and found to change minimally. The application of 3D MRI and tissue segmentation to the study of human infant brain from 29 to 41 weeks of postconceptional age has provided new insights into cerebral cortical development and myelination and has for the first time provided means of quantitative assessment in vivo of early human brain development.
Periventricular leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [beta-amyloid precursor protein (beta-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis. Using beta-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages, a finding consistent with others. Interestingly, GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. We conclude that diffuse axonal injury, as determined by apoptotic marker fractin, occurs in PVL and that its cause likely includes primary ischemia and trophic degeneration secondary to corticothalamic neuronal damage.
The central nervous system contains several populations of mononuclear phagocytes. Principal amongst these are the tissue-resident microglia. These cells are considered to derive from circulating blood progenitors that colonise the developing human nervous system in the second trimester of fetal life. They first appear as amoeboid forms and gradually differentiate to process-bearing 'ramified' forms with maturation. Signals driving this transformation are known to be partly derived from astrocytes in vitro, and amoeboid microglial cells progressively ramify when co-cultured with astrocytes, mirroring the 'differentiation' of microglia in situ during development. In the adult, microglia occupy distinct non-overlapping territories in their ramified conformations, and are capable of 'dedifferentiating' to their activated amoeboid morphological states in a number of pathological circumstances. This is in keeping with the capacity of these cells for a rapid response to inflammatory cues in the CNS. The interchangeable morphological continuum of these cells supports the view that microglia represent a single heterogeneous population of resident mononuclear phagocytes capable of marked plasticity. This review will discuss signals that drive the colonisation, differentiation and ramification of microglia, and examines hypothetical models for their spatial distribution in the adult nervous system.
Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30-50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular leukomalacia (PVL), characterized by periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants. We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e. mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5 +/- 4.8 wk) and 16 non-PVL controls (36.7 +/- 5.2 wk) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared with controls (19%; 3/16) (p = 0.01), with substantial involvement of the mediodorsal, and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL.
Survivors of preterm birth have a high incidence of neurodevelopmental impairment which is not explained by currently understood brain abnormalities. The aim of this study was to test the hypothesis that the neurodevelopmental abilities of 2-year-old children who were born preterm and who had no evidence of focal abnormality on conventional MR imaging were consistently linearly related to specific local changes in white matter microstructure. We studied 33 children, born at a median (range) gestational age of 28(+5) (24(+4)-32(+1)) weeks. The children were recruited as infants from the Neonatal Intensive Care Unit at Queen Charlotte's and Hammersmith Hospital in the early neonatal period and imaged at a median corrected age of 25.5 (24-27) months. The children underwent diffusion tensor imaging to measure fractional anisotropy (FA) as a measure of tissue microstructure, and neurodevelopmental assessment using the Griffiths Mental Development Scales [giving an overall developmental quotient (DQ) and sub-quotients scores for motor, personal-social, hearing-language, eye-hand coordination and performance scales] at 2 years corrected age. Tract-based spatial statistics with linear regression analysis of voxel-wise cross-subject statistics were used to assess the relationship between FA and DQ/sub-quotient scores and results confirmed by reduced major axis regression of regions with significant correlations. We found that DQ was linearly related to FA values in parts of the corpus callosum; performance sub-scores to FA values in the corpus callosum and right cingulum; and eye-hand coordination sub-scores to FA values in the cingulum, fornix, anterior commissure, corpus callosum and right uncinate fasciculus. This study shows that specific neurodevelopmental impairments in infants born preterm are precisely related to microstructural abnormalities in particular regions of cerebral white matter which are consistent between individuals. FA may aid prognostication and provide a biomarker for therapeutic or mechanistic studies of preterm brain injury.