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The human preterm brain is particularly susceptible to cerebral white matter injury (WMI) that disrupts the normal progression of developmental myelination. Advances in the care of preterm infants have resulted in a sustained reduction in the severity of WMI that has shifted from more severe focal necrotic lesions to milder diffuse WMI. Nevertheless, WMI remains a global health problem and the most common cause of chronic neurological morbidity from cerebral palsy and diverse neurobehavioral disabilities. Diffuse WMI involves maturation-dependent vulnerability of the oligodendrocyte (OL) lineage with selective degeneration of late oligodendrocyte progenitors (preOLs) triggered by oxidative stress and other insults. The magnitude and distribution of diffuse WMI are related to both the timing of appearance and regional distribution of susceptible preOLs. Diffuse WMI disrupts the normal progression of OL lineage maturation and myelination through aberrant mechanisms of regeneration and repair. PreOL degeneration is accompanied by early robust proliferation of OL progenitors that regenerate and augment the preOL pool available to generate myelinating OLs. However, newly generated preOLs fail to differentiate and initiate myelination along their normal developmental trajectory despite the presence of numerous intact-appearing axons. Disrupted preOL maturation is accompanied by diffuse gliosis and disturbances in the composition of the extracellular matrix and is mediated in part by inhibitory factors derived from reactive astrocytes. Signaling pathways implicated in disrupted myelination include those mediated by Notch, WNT-beta catenin, and hyaluronan. Hence, there exists a potentially broad but still poorly defined developmental window for interventions to promote white matter repair and myelination and potentially reverses the widespread disturbances in cerebral gray matter growth that accompanies WMI.

To review and synthesize the literature on human milk and structural brain development and injury in preterm infants, focusing on the application of quantitative brain magnetic resonance imaging (MRI) in this field. For this narrative review, we searched PubMed for articles published from 1990 to 2021 that reported observational or interventional studies of maternal milk or donor milk in relation to brain development and/or injury in preterm infants assessed with quantitative MRI at term equivalent age. Studies were characterized with respect to key aspects of study design, milk exposure definition, and MRI outcomes. We identified 7 relevant studies, all of which were observational in design and published between 2013 and 2021. Included preterm infants were born at or below 33 weeks’ gestation. Sample sizes ranged from 22 to 377 infants. Exposure to human milk included both maternal and donor milk. No study included a full-term comparison group. Main MRI outcome domains were white matter integrity (assessed with diffusion tensor imaging, resting state functional connectivity, or semiautomated segmentation of white matter abnormality) and total and regional brain volumes. Studies revealed that greater exposure to human milk versus formula was associated with favorable outcomes, including more mature and connected cerebral white matter with less injury and larger regional brain volumes, notably in the deep nuclear gray matter, amygdala-hippocampus, and cerebellum. No consistent signature effect of human milk exposure was found; instead, the beneficial associations were regional and tissue-specific neuroprotective effects on the areas of known vulnerability in the preterm infant. Evidence to date suggests that human milk may protect the preterm infant from the white matter injury and dysmaturation to which this population is vulnerable. Brain MRI at term equivalent age is emerging as a useful tool to investigate the effects of human milk on the preterm brain. When grounded in neurobiological knowledge about preterm brain injury and development, this approach holds promise for allowing further insight into the mechanisms and pathways underlying beneficial associations of human milk with neurodevelopmental outcomes in this population and in the investigation of specific milk bioactive components with neuroprotective or neurorestorative potential.

Currently, we have an incomplete understanding of the mechanisms underlying infantile epileptic spasms syndrome (IESS). However, over the past decade, significant efforts have been made to develop IESS animal models to provide much-needed mechanistic information for therapy development. Our laboratory has focused on the TTX model and in this paper, we review some of our findings. To induce spasms, tetrodotoxin (TTX) is infused into the neocortex of infant rats. TTX produces a lesion at its infusion site and thus mimics IESS resulting from acquired structural brain abnormalities. Subsequent electrophysiological studies showed that the epileptic spasms originate from neocortical layer V pyramidal cells. Importantly, experimental maneuvers that increase the excitability of these cells produce focal seizures in non-epileptic control animals but never produce them in TTX-infused epileptic rats; instead, epileptic spasms are produced in epileptic rats, indicating a significant transformation in the operations of neocortical networks. At the molecular level, studies showed that the expression of insulin-like growth factor 1 was markedly reduced in the cortex and this corresponded with a loss of presynaptic GABAergic nerve terminals. Very similar observations were made in surgically resected tissue from IESS patients with a history of perinatal strokes. Other experiments in conditional knockout mice indicated that IGF-1 plays a critical role in the maturation of neocortical inhibitory connectivity. This finding led to our hypothesis that the loss of IGF-1 in epileptic animals impairs inhibitory interneuron synaptogenesis and is responsible for spasms. To test this idea, we treated epileptic rats with the IGF-1-derived tripeptide (1-3)IGF-1, which was shown to act through IGF-1's receptor. (1-3)IGF-1 rescued inhibitory interneuron connectivity, restored IGF-1 levels, and abolished spasms. Thus, (1-3)IGF-1 or its analogs are potential novel treatments for IESS following perinatal brain injury. We conclude by discussing our findings in the broader context of the often-debated final common pathway hypothesis for IESS. PLAIN LANGUAGE SUMMARY: We review findings from the TTX animal model of infantile epileptic spasms syndrome, which show that these seizures come from an area of the brain called the neocortex. In this area, the amount of an important growth factor called IGF-1 is reduced, as is the number of inhibitory synapses that play an important role in preventing seizures. Other results indicate that the loss of IGF-1 prevents the normal development of these inhibitory synapses. Treatment of epileptic animals with (1-3)IGF-1 restored IGF-1 levels and inhibitory synapses and abolished spasms. Thus, (1-3)IGF-1 or an analog is a potential new therapy for epileptic spasms.

Objective: Term congenital heart disease (CHD) neonates display abnormalities of brain structure and maturation, which are possibly related to underlying patient factors and perioperative insults. Our primary goal was to delineate associations between clinical factors and postnatal brain microstructure in term CHD neonates using diffusion tensor imaging (DTI) magnetic resonance (MR) acquisition combined with complementary data-driven connectome and seed-based tractography quantitative analysis. Our secondary goal was to delineate associations between mild dysplastic structural abnormalities and connectome and seed-base tractography as our primary goal. Methods: Neonates undergoing cardiac surgery for CHD were prospectively recruited from two large centers. Both pre- and postoperative magnetic resonance (MR) brain scans were obtained. DTI in 42 directions was segmented to 90 regions using neonatal brain template and three weighted methods. Seed- based tractography was performed in parallel. Clinical data :18 patient-specific and 9 preoperative variables associated with preoperative scan and 6 intraoperative and 12 postoperative variables associated with postoperative scan. A composite Brain Dysplasia Score (BDS) was created including cerebellar, olfactory bulbs, and hippocampus abnormalities. The outcomes included (1) connectome metrics: cost and global/nodal efficiency (2) seed-based tractography: fractional anisotropy. Statistics: multiple regression with false discovery rate correction (FDR). Results: A total of 133 term neonates with complex CHD were prospectively enrolled and 110 had analyzable DTI. Multiple patient-specific factors including d-transposition of the great arteries physiology and severity of impairment of fetal cerebral substrate delivery were predictive of preoperative reduced cost (p<0.0073), reduced global/nodal efficiency (p <0.03). Multiple postoperative factors (extracorporeal membrane oxygenation [ECMO], seizures, cardiopulmonary resuscitation) were predictive of postoperative reduced cost, reduced global/nodal efficiency (p < 0.05). All three subcortical structures of the BDS (including olfactory bulb/sulcus, cerebellum, and hippocampus) predicted distinct patterns of altered nodal efficiency (p<0.05). Conclusion: Patient-specific and postoperative clinical factors were most predictive of diffuse postnatal microstructural dysmaturation in term CHD neonates. In contrast, subcortical components of a structurally based- brain dysplasia score, predicted more regional based postnatal microstructural differences. Collectively, these findings suggest that brain DTI connectome may facilitate deciphering the mechanistic relative contribution of clinical and genetic risk factors related to poor neurodevelopmental outcomes in CHD.

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 encephalopathy 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.