Brain Injury In Infants Research Articles

DBAII-Net with multiscale feature aggregation and cross-modal attention for enhancing infant brain injury classification in MRI.

MRI is pivotal in diagnosing brain injuries in infants. However, the dynamic development of the brain introduces variability in infant MRI characteristics, posing challenges for MRI-based classification in this population. Furthermore, manual data selection in large-scale studies is labor-intensive, and existing algorithms often underperform with thick-slice MRI data. To enhance research efficiency and classification accuracy in large datasets, we propose an advanced classification model. We introduce the Dual-Branch Attention Information Interactive Neural Network (DBAII-Net), a cutting-edge model inspired by radiologists' use of multiple MRI sequences. DBAII-Net features two innovative modules: (1) the Convolutional Enhancement Module (CEM), which leverages advanced convolutional techniques to aggregate multi-scale features, significantly enhancing information representation; and (2) the Cross-Modal Attention Module (CMAM), which employs state-of-the-art attention mechanisms to fuse data across branches, dramatically improving positional and channel feature extraction. Performances (accuracy, sensitivity, specificity, area under the curve, etc.) of DBAII-Net were compared with eight benchmark models for brain MRI classification in infants aged 6 months to 2 years. Utilizing a self-constructed dataset of 240 thick-slice brain MRI scans (122 with brain injuries, 118 without), DBAII-Net demonstrated superior performance. On a test set of approximately 50 cases, DBAII-Net achieved average performance metrics of 92.53% accuracy, 90.20% sensitivity, 94.93% specificity, and an area under the curve (AUC) of 0.9603. Ablation studies confirmed the effectiveness of CEM and CMAM, with CMAM significantly boosting classification metrics. DBAII-Net with CEM and CMAM outperforms existing benchmarks in enhancing the precision of brain MRI classification in infants, significantly reducing manual effort in infant brain research. Our code is available at https://github.com/jiazhen4585/DBAII-Net.

Outcomes after intranasal human milk therapy in preterm infants with intraventricular hemorrhage.

Intraventricular hemorrhage (IVH) is a common cause of brain injury in preterm infants. Fresh human milk (HM) contains stem cells (SCs) that could potentially be delivered via intranasal HM (IHM). In this IHM pilot study, we describe outcomes. Infants <33 weeks gestation with IVH were given IHM until maximum 28 days of age. Short-term neurologic outcomes and follow-up testing were compared to historic HM-fed infants. Longitudinal outcomes were plotted using linear mixed models. Weighted G-computation quantified treatment effects. Propensity score models calculated inverse probability weights for IVH grade, gestational age, and sex. 37 infants (35.1% grade 3-4 IVH) were compared to 191 historic controls (17.8% grade 3-4 IVH). Post-hemorrhagic ventricular dilatation was common (25.7% IHM patients). Most weighted outcomes, although not significant, favored IHM at 4-12 and 18 months corrected age. This phase 1 study suggests powered trials of IHM for brain injury are needed. CLINICAL TRIAL REGISTRY NAME: clinicaltrials.gov identifier NCT04225286.

Using heart rate variability to predict neurological outcomes in preterm infants: a scoping review.

Infants born preterm are at higher risk of neurological complications, including intraventricular haemorrhage and white matter injury. After discharge, these infants may experience adverse neurodevelopmental outcomes and exhibit lower educational attainment. Early detection of brain injury and accurate prediction of neurodevelopmental impairment would allow early intervention and support. Heart rate variability (HRV) describes the variation of time intervals between each subsequent heartbeat. HRV is controlled by the autonomic nervous system, which may be affected by hypoxia and compromised blood flow. While HRV has primarily been investigated in neonatal sepsis, the association between HRV, brain injury and neurodevelopmental outcomes in preterm infants is less established. The present scoping review examines the utility of HRV monitoring for predicting short-term and long-term neurological outcomes in preterm infants. Following systematic search of Medline, Embase, Web of Science and the Cochrane Library, 15 studies were included. Nine studies examined the relationship between HRV and brain injury, with all but two showed an association. Eight studies examined the relationship between HRV and long-term outcomes and all eight found an association. This scoping review suggests that decreased HRV in the neonatal period is associated with short- and long-term neurodevelopmental outcomes in preterm infants. IMPACT: Changes in heart rate variability correlate with the occurrence of intraventricular haemorrhage in preterm infants. A decrease in heart rate variability may precede the development of intraventricular haemorrhage. Alterations in heart rate variability correlate with long-term neurodevelopmental outcomes. Significant variability exists in metrics used in assessing heart rate variability.

Evaluation of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in preterm infants with brain injury

BackgroundPrematurity-related brain injury is a common and serious complication that has long-term effects on the survival and development of affected infants. Currently, the roles of certain biomarkers such as the protein hydrolysis product SBDP145, melatonin, soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), high mobility group box 1 protein (HMGB1), and hypoxia-inducible factor 1-alpha (HIF-1α) in prematurity-related brain injury remain not fully elucidated. Our study aims to assess the significance of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in preterm infants with brain injury.Methods135 preterm infants admitted to our hospital from January 2020 to February 2022 were selected and divided into 78 cases in a prematurity-associated brain injury group, and 57 cases in another group of preterm infants without brain injury or other diseases according to the magnetic resonance imaging results. The levels of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in the two groups were analyzed. The serum concentrations of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in newborns with different severity of ventricular hemorrhage were observed, and the levels of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in those with different severity of white matter brain injury were compared.ResultsThe levels of SBDP145, sLOX-1, HMGB1 and HIF-1α were significantly higher in the preterm combined brain injury group than in the preterm group, and melatonin levels were significantly lower than in the preterm group(P < 0.05). The levels of SBDP145, sLOX-1, HMGB1 and HIF-1α were higher in the moderate to severe group and melatonin levels were lower in the mild group of newborns with ventricular hemorrhage (P < 0.05). The levels of SBDP145, sLOX-1, HMGB1 and HIF-1α were higher in the moderate-severe group and melatonin levels were lower in the mild group in newborns with cerebral white matter injury (P < 0.05). The independent variables were SBDP145, melatonin, sLOX-1, HMGB1, HIF-1α, and the dependent variable was the prognosis of neonates with brain injury. Univariate logistic regression analysis and multivariate logistic regression analysis were performed. The results showed that the influencing factors of newborns with brain injury were SBDP145, melatonin, sLOX-1, HMGB1, HIF-1α.ConclusionThe levels of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α were highly expressed in preterm newborns with brain injury, and the levels were higher when the condition of the newborns was more severe. These findings suggest the potential clinical utility of these biomarkers in predicting and monitoring brain injury in preterm infants, which could aid in early intervention and improve long-term outcomes.

Progesterone improves motor coordination impairments caused by postnatal hypoxic-ischemic brain insult in neonatal male rats

BackgroundHypoxic-ischemic (HI) insult in infants induces brain injury and results in motor coordination impairments associated with cerebral palsy; however, preventive measures for HI brain injury in preterm infants remain unclear. We investigated the impact of progesterone (P4) in a rat HI insult model that mimics HI brain injury in preterm infants. MethodsNeonatal male rats with their right common carotid artery coagulated were exposed to a 1-h hypoxia (6% oxygen) on postnatal day (PND) 3. P4 (0.2 mg) was subcutaneously administered daily from PND4–12. Motor coordination function and muscular strength were evaluated on PND50 using rotarod and grip strength tests, respectively. Brain histology was evaluated via immunohistochemistry using anti-NeuN, anti-Olig2, and anti-IbaI antibodies on PND15 and PND50. ResultsIn male rats, P4 significantly improved the latency-to-fall off on the rotarod test in the insult rats to the levels of the sham-operation rats. Neither the insult nor P4 administration impacted the grip strength results. No significant differences were observed in the number of neurons, oligodendrocyte progenitor cells (OPCs), and microglia in the motor and somatosensory area of the cortex between the insult and insult followed by P4-administered rats on PND50. The number of OPCs in the corpus callosum was significantly increased in the ipsilateral side compared with the contralateral side of the insult in the P4-administered rats, indicating that P4 facilitates recruitment of OPCs to the corpus callosum. HI insult accelerated neuronal differentiation in rats on PND15, which was abrogated in the P4-administerd group, suggesting that P4 suppresses transient neuronal differentiation caused by the insult. ConclusionP4 administration restored motor coordination impairments caused by postnatal HI insult in male rats. The insult timing corresponds to that of human preterm infants, indicating P4’s potential for protecting HI brain injury in preterm male infants.

Utility of Diffusion Tensor Imaging in Preterm Infants with Germinal Matrix Hemorrhage and Intraventricular Hemorrhage: A Systematic Review

IntroductionIntraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH) are the most common brain injuries in preterm infants. Neonates with these injuries are at greater risk of impaired neurodevelopmental outcome. Current guidelines recommend screening infants with cranial ultrasound (CUS), although this is prone to missing subtle injury patterns, particularly within the posterior fossa. The present report sought to discuss the utility of diffusion tensor imaging (DTI) in preterm infants. MethodsA systematic review of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Included manuscripts were methodically scrutinized for quality; DTI use; neurologic outcome. ResultsTwenty studies with 1574 infants who underwent DTI were included. There were 574 preterm infants with GMH-IVH on DTI. Twelve studies documented decreased fractional anisotropy (FA) while six demonstrated structural segregation and asymmetrical white matter myelination in these infants. Seven studies documented concurrent CUS use with two studies comparing DTI findings to CUS findings. In both studies, DTI more accurately detected presence of GMH, especially within the cerebellum. Among GMH-IVH preterm infants, 58.5% demonstrated cognitive, intellectual, and language delays at follow-up (mean: 32.4 months). Additionally, lower FA values on initial DTI were associated with cognitive, language, and motor delays. ConclusionAlthough DTI is more sensitive for picking up subtle injury patterns, CUS remains the standard of care when screening for injuries that would necessitate surgical intervention. DTI offers a refined understanding of the sequelae of GMH-IVH with microstructural changes found on DTI being associated with childhood motor and cognitive outcomes.

Regional cerebral oxygen saturation variability and brain injury in preterm infants.

To examine whether variation of regional cerebral oxygen saturation (rScO2) within three days after delivery predicts development of brain injury (intraventricular/cerebellar hemorrhage or white matter injury) in preterm infants. A prospective study of neonates <32 weeks gestational age with normal cranial ultrasound admitted between 2018 and 2022. All received rScO2 monitoring with near-infrared spectroscopy at admission up to 72 h of life. To assess brain injury a magnetic resonance imaging was performed at term-equivalent age. We assessed the association between rScO2 variability (short-term average real variability, rScO2ARV, and standard deviation, rScO2SD), mean rScO2 (rScO2MEAN), and percentage of time rScO2 spent below 60% (rScO2TIME<60%) during the first 72 h of life and brain injury. The median [IQR] time from birth to brain imaging was 68 [59-79] days. Of 81 neonates, 49 had some form of brain injury. Compared to neonates without injury, in those with injury rScO2ARV was higher during the first 24 h (P = 0.026); rScO2SD was higher at 24 and 72 h (P = 0.029 and P = 0.030, respectively), rScO2MEAN was lower at 48 h (P = 0.042), and rScO2TIME<60% was longer at 24, 48, and 72 h (P = 0.050, P = 0.041, and P = 0.009, respectively). Similar results were observed in multivariable logistic regression. Although not all results were statistically significant, increased rScO2 variability (rScO2ARV and rScO2SD) and lower mean values of rScO2 were associated with increased likelihood of brain injury. In preterm infants increased aberration of rScO2 in early postdelivery period was associated with an increased likelihood of brain injury diagnosis at term-equivalent age.

Comparative utility of MRI and EEG for early detection of cortical dysmaturation after postnatal systemic inflammation in the neonatal rat

BackgroundExposure to postnatal systemic inflammation is associated with increased risk of brain injury in preterm infants, leading to impaired maturation of the cerebral cortex and adverse neurodevelopmental outcomes. However, the optimal method for identifying cortical dysmaturation is unclear. Herein, we compared the utility of electroencephalography (EEG), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) at different recovery times after systemic inflammation in newborn rats. MethodsSprague Dawley rat pups of both sexes received single-daily lipopolysaccharide (LPS; 0.3 mg/kg i.p.; n = 51) or saline (n = 55) injections on postnatal days (P)1, 2, and 3. A subset of these animals were implanted with EEG electrodes. Cortical EEG was recorded for 30 min from unanesthetized, unrestrained pups at P7, P14, and P21, and in separate groups, brain tissues were collected at these ages for ex-vivo MRI analysis (9.4 T) and Golgi–Cox staining (to assess neuronal morphology) in the motor cortex. ResultsPostnatal inflammation was associated with reduced cortical pyramidal neuron arborization from P7, P14, and P21. These changes were associated with dysmature EEG features (e.g., persistence of delta waveforms, higher EEG amplitude, reduced spectral edge frequency) at P7 and P14, and higher EEG power in the theta and alpha ranges at P21. By contrast, there were no changes in cortical DTI or NODDI in LPS rats at P7 or P14, while there was an increase in cortical fractional anisotropy (FA) and decrease in orientation dispersion index (ODI) at P21. ConclusionsEEG may be useful for identifying the early evolution of impaired cortical development after early life postnatal systemic inflammation, while DTI and NODDI seem to be more suited to assessing established cortical changes.

Extracellular Vesicle ASC: A Novel Mediator for Lung-Brain Axis in Preterm Brain Injury.

Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in interorgan communication in diverse pathological processes. ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of the alveolar macrophage (AM) markers CD11b, CD11c, and CD206 as well as ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction of inspired oxygen therapy (HO2⩾30%) had increased concentrations of AM-derived EV-ASC compared with infants on lower fraction of inspired oxygen (LO2<30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO2 had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood-brain barrier, and the EVs from infants on HO2 caused inflammation, reduced cell survival, and increased cell death, with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain cross-talk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants.

Developmental Outcomes of Traumatic Brain Injury in Infants and Children: A Prospective Study

Abstract Background Traumatic brain injury (TBI) in children is a significant health burden worldwide. Children aged 0 to 4 years have the highest incidence of TBI among the non-elderly. These children suffer from long term neurological deficits that compromise their quality of life and daily living activities. Objective To determine the developmental outcomes of infants and children with TBI. Subjects and Methods A prospective descriptive study on infants and children with TBI was conducted. Developmental outcomes by Age and Stage Questionnaire 3rd edition (ASQ-3) was assessed twice; once at hospital discharge and another time 3 months later. Further, Bayley scales of infants and toddlers’ development III was assessed only once in the second visit. Results at discharge and follow up were compared and correlated. Results Eighty -five patients were included in the study with 63.5% were males and the median age was 24(12-34) months, range (1- 42 months). There were statistically significant difference between ASQ-3 at discharge and follow up which was higher at follow up than at discharge indicating better developmental outcomes(P &amp;lt; 0.001 for all aspects). Comparison between ASQ-3 (problem solving) and Bayley Scale (cognitive) at follow up shows that there was no statistically significant difference between them with kappa agreement and 95% CI of 0.527 (0.218–0.837). Also, comparison between ASQ-3 (motor) at follow-up and Bayley Scale (motor)at follow up shows that there was no statistically significant difference between them with kappa agreement and 95% CI of 0.285 (0.001 - 0.569). Also, comparison between ASQ-3 (communication) and Bayley Scale (language) at follow up shows that there was no statistically significant difference between them with kappa agreement and 95% CI 0.501 (0.235 - 0.766). this means that both tests were comparable Conclusions ASQ-3 can be used as a screening tool for infants and children after TBI before referral to Bayley scale. Developmental milestones improved at follow up in most infants and children after TBI.

Effect of Cerebral Oximetry-Guided Treatment on Brain Injury in Preterm Infants as Assessed by Magnetic Resonance Imaging at Term Equivalent Age: An Ancillary SafeBoosC-III Study

Plain Language SummaryOur study looked at whether monitoring the cerebral oxygenation by a specific tool can help protect the brains of very premature babies. We wanted to see if this tool could reduce the chances of any degree of brain injury in these tiny babies. The SafeBoosC-III was a big multicenter trial that found that using cerebral oximetry did not make a big difference in preventing severe brain injuries or saving lives in these babies. To study in more depth a representative group of babies in this big trial, we used advanced brain scans like MRI to check babies’ brain health. Even though we noticed a small improvement in overall brain health when using cerebral oximetry, it was not enough to show a clear benefit. It is important to note that only one baby out of every five had severe brain injuries in the study. Our research shows that while cerebral oximetry is helpful for monitoring brain oxygen levels, it did not lead to noticeable changes in how often brain injuries happened in premature babies. This tells us that we still have more to learn about protecting these fragile babies’ brains, and we need to keep looking for better ways to help them. In conclusion, our study highlights the challenges in using cerebral oximetry to prevent brain injuries in very premature babies, urging doctors and researchers to keep exploring new ideas to improve their brain health.

Hypertensive Disorders of Pregnancy and Risk of Early Brain Abnormalities on Magnetic Resonance Imaging at Term among Infants Born at ≤32 Weeks’ Gestational Age

To evaluate the proximal effects of hypertensive disorders of pregnancy (HDP) on a validated measure of brain abnormalities in infants born at ≤32 weeks' gestational age (GA) using magnetic resonance imaging (MRI) at term-equivalent age. In a multisite prospective cohort study, 395 infants born at ≤32 weeks' GA, underwent 3T MRI scan between 39 through 44 weeks' postmenstrual age. A single neuroradiologist, blinded to clinical history, evaluated the standardized Kidokoro global brain abnormality score as the primary outcome. We classified infants as HDP-exposed by maternal diagnosis of chronic hypertension, gestational hypertension, preeclampsia, or eclampsia. Linear regression analysis identified the independent effects of HDP on infant brain abnormalities, adjusting for histologic chorioamnionitis, maternal smoking, antenatal steroids, magnesium sulfate, and infant sex. Mediation analyses quantified the indirect effect of HDP mediated via impaired intrauterine growth and prematurity and remaining direct effects on brain abnormalities. 170/395 infants (43%) were HDP-exposed. Adjusted multivariable analyses revealed HDP-exposed infants had 27% (95% CI 5-53%) higher brain abnormality scores than those without HDP exposure (p=0.02), primarily driven by increased white matter injury/abnormality scores (p=0.01). Mediation analyses showed HDP-induced impaired intrauterine growth significantly (p=0.02) contributed to brain abnormality scores (22% of the total effect). Maternal hypertension independently increased the risk for early brain injury and/or maturational delays in infants born at ≤32 weeks' GA with an indirect effect of 22% resulting from impaired intrauterine growth. Enhanced prevention/treatment of maternal hypertension may mitigate the risk of infant brain abnormalities and potential neurodevelopmental impairments.

Traumatic brain injury in infants and little children (a literature review)

Traumatic brain injury in infants and little children (a literature review)

Intrauterine inflammation and postnatal intravenous dopamine alter the neurovascular unit in preterm newborn lambs

BackgroundIntrauterine inflammation is considered a major cause of brain injury in preterm infants, leading to long-term neurodevelopmental deficits. A potential contributor to this brain injury is dysregulation of neurovascular coupling. We have shown that intrauterine inflammation induced by intra-amniotic lipopolysaccharide (LPS) in preterm lambs, and postnatal dopamine administration, disrupts neurovascular coupling and the functional cerebral haemodynamic responses, potentially leading to impaired brain development. In this study, we aimed to characterise the structural changes of the neurovascular unit following intrauterine LPS exposure and postnatal dopamine administration in the brain of preterm lambs using cellular and molecular analyses.MethodsAt 119–120 days of gestation (term = 147 days), LPS was administered into the amniotic sac in pregnant ewes. At 126-7 days of gestation, the LPS-exposed lambs were delivered, ventilated and given either a continuous intravenous infusion of dopamine at 10 µg/kg/min or isovolumetric vehicle solution for 90 min (LPS, n = 6; LPSDA, n = 6). Control preterm lambs not exposed to LPS were also administered vehicle or dopamine (CTL, n = 9; CTLDA, n = 7). Post-mortem brain tissue was collected 3–4 h after birth for immunohistochemistry and RT-qPCR analysis of components of the neurovascular unit.ResultsLPS exposure increased vascular leakage in the presence of increased vascular density and remodelling with increased astrocyte “end feet” vessel coverage, together with downregulated mRNA levels of the tight junction proteins Claudin-1 and Occludin. Dopamine administration decreased vessel density and size, decreased endothelial glucose transporter, reduced neuronal dendritic coverage, increased cell proliferation within vessel walls, and increased pericyte vascular coverage particularly within the cortical and deep grey matter. Dopamine also downregulated VEGFA and Occludin tight junction mRNA, and upregulated dopamine receptor DRD1 and oxidative protein (NOX1, SOD3) mRNA levels. Dopamine administration following LPS exposure did not exacerbate any effects induced by LPS.ConclusionLPS exposure and dopamine administration independently alters the neurovascular unit in the preterm brain. Alterations to the neurovascular unit may predispose the developing brain to further injury.

Electroencephalographic Patterns on Follow-Up Visits in Extremely Premature Infants With Periventricular Leukomalacia: An Observational Study

BackgroundPeriventricular leukomalacia (PVL) is a common brain injury in premature infants, and epilepsy remains a significant complication. One concerning electroencephalographic (EEG) pattern found is developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS). This pattern is associated with persistent neuropsychological and motor deficits, even without a diagnosis of epilepsy. The purpose of this study is to identify the relationships between various PVL grades and EEG patterns in this population on follow-up visits, especially the occurrence of DEE-SWAS pattern on EEG. MethodsThis is a retrospective study of <36 weeks gestational age newborns who were followed in the neurodevelopmental clinic at Corewell Health East/Corewell Health Children's Hospital in Royal Oak, Michigan, between 2020 and 2022. Patients' demographics along with prematurity complications, diagnostic head ultrasound (HUS), and EEG studies were reviewed and graded. EEG studies are usually ordered when seizures were suspected. ResultsA total of 155 newborns met the inclusion criteria. Twenty-six patients had PVL. Nine patients had grade 2 to 3 PVL based on HUS review. EEG was performed on 15 patients with PVL at a mean age of 22 months. More severe PVL grades were significantly associated with worse EEG patterns (P = 0.005). Five patients had DEE-SWAS pattern on EEG, all of whom had grade 2 or 3 PVL. Epilepsy was eventually diagnosed in three infants with PVL. ConclusionsEEG can help identify important abnormal electrographic patterns in premature infants with PVL early in life; this might give a window of opportunity to intervene early and improve long-term developmental outcomes in this population.

Hypotension: a modifiable risk factor impacting surgical NEC-associated AKI and brain injury in preterm infants.

Hypotension: a modifiable risk factor impacting surgical NEC-associated AKI and brain injury in preterm infants.

Association between Early Basal Ganglia and Thalami Perfusion Assessed by Color Doppler Ultrasonography and Brain Injury in Infants with Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study

ObjectiveTo evaluate associations between neurologic outcomes and early measurements of basal ganglia (BG) and thalamic (Th) perfusion using color Doppler ultrasonography (CDUS) in infants with hypoxic-ischemic encephalopathy (HIE). Study designProspective study of infants with mild (n=18), moderate (n=17), and severe HIE (n=14) and controls (n=17). Infants with moderate-severe HIE received therapeutic hypothermia (TH). CDUS was performed at 24-36h and brain magnetic resonance imaging (MRI) at a median of 10 days. Development was followed through 2.5 to 5 years. The primary outcome was the association between BG and Th perfusion and brain MRI injury. Secondary analyses focused on associations between perfusion measurements and admission neurologic examinations, MRI scores in infants treated with TH, and motor and sensory disability, or death. An exploratory analysis assessed the accuracy of BG and Th perfusion to predict brain MRI injury in infants treated with TH. ResultsIncreased BG and Th perfusion on CDUS was observed in infants with severe MRI scores and those with significant motor and neurosensory disability or death through 2.5 to 5 years (p<0.05). Infants with severe HIE showed increased BG and Th perfusion (p< .005) compared with infants with moderate HIE. No differences were identified between the between the control and mild HIE groups. Th perfusion ≥ 0.237 cm/sec (AUC of 0.824) correctly classified 80% of infants with severe MRI scores. ConclusionEarly dynamic CDUS of the BG and Th is a potential biomarker of severe brain injury in infants with HIE and may be a useful adjunct to currently used assessments.

A biochemical feedback signal for hypothermia treatment for neonatal hypoxic-ischemic encephalopathy: focusing on central nervous system proteins in biofluids.

Hypothermia has been widely used to treat moderate to severe neonatal hypoxic-ischemic encephalopathy (HIE), yet evaluating the effects of hypothermia relies on clinical neurology, neuroimaging, amplitude-integrated electroencephalography, and follow-up data on patient outcomes. Biomarkers of brain injury have been considered for estimating the effects of hypothermia. Proteins specific to the central nervous system (CNS) are components of nervous tissue, and once the CNS is damaged, these proteins are released into biofluids (cerebrospinal fluid, blood, urine, tears, saliva), and they can be used as markers of brain damage. Clinical reports have shown that CNS-specific marker proteins (CNSPs) were early expressed in biofluids after brain damage and formed unique biochemical profiles. As a result, these markers may serve as an indicator for screening brain injury in infants, monitoring disease progression, identifying damage region of brain, and assessing the efficacy of neuroprotective measures. In clinical work, we have found that there are few reports on using CNSPs as biological signals in hypothermia for neonatal HIE. The aim of this article is to review the classification, origin, biochemical composition, and physiological function of CNSPs with changes in their expression levels after hypothermia for neonatal HIE. Hopefully, this review will improve the awareness of CNSPs among pediatricians, and encourage future studies exploring the mechanisms behind the effects of hypothermia on these CNSPs, in order to reduce the adverse outcome of neonatal HIE.

CNN-Based Pattern Classifiers for Precise Identification of Perinatal EEG Biomarkers of Brain Injury in Preterm Neonates

Electroencephalographic (EEG) monitoring is important for the diagnosis of hypoxic-ischemic (HI) brain injury in high-risk preterm infants. EEG monitoring is limited by the reliance on expert clinical observation. However, high-risk preterm infants often do not present observable symptoms due to their frailty. Thus, there is an urgent need to find better ways to automatically quantify changes in the EEG these high-risk babies. This article is a first step towards this goal. This innovative study demonstrates the effectiveness of deep Convolutional Neural Networks (CNN) pattern classifiers, trained on spectrally-detailed Wavelet Scalograms (WS) images derived from neonatal EEG sharp waves—a potential translational HI biomarker, at birth. The WS-CNN classifiers exhibit outstanding performance in identifying HI sharp waves within an exclusive clinical EEG recordings dataset of preterm infants immediately after birth. The work has impact as it demonstrates exceptional high accuracy of 99.34 ± 0.51% cross-validated across 13,624 EEG patterns over 48 h raw EEG at low 256 Hz clinical sampling rates. Furthermore, the WS-CNN pattern classifier is able to accurately identify the sharp-waves within the most critical first hours of birth (n = 8, 4:36 ± 1:09 h), regardless of potential morphological changes influenced by different treatments/drugs or the evolutionary ‘timing effects’ of the injury. This underscores its reliability as a tool for the identification and quantification of clinical EEG sharp-wave biomarkers at bedside.

Increased PLAGL1 Gene Methylation in Cord Blood is Positively Correlated with Brain Injury in Chorioamniotic Preterm Infants.

The study aims to explore the epigenetic mechanisms of neurodevelopmental impairment accompanied in chorioamniotic preterm infants. Our study included 16 full-term infants and 69 preterm infants. The methylation status of the pleomorphic adenoma gene-like 1 (PLAGL1) gene in the cord blood was determined by pyrosequencing. Brain B-ultrasonography and magnetic resonance imaging (MRI) were performed to diagnose brain injury. The activity of candidate fragments of PLAGL1 and the effect of methylation on PLAGL1 activity were evaluated by double luciferase reporter assay. The data showed that there were no differences in the methylation levels of each Cytosine-phosphate-Guanine (CpG) site of PLAGL1 between full-term and preterm infants. Within preterm infants, the methylation levels of the CpG2, CpG3, CpG4, and CpG5 sites were increased in the chorioamnionitis group compared with the no chorioamnionitis group. The areas under curves (AUCs) of the receiver operating characteristic (ROC) curves of CpG2, CpG3, CpG4, and CpG5 were 0.656, 0.653, 0.670, and 0.712, respectively. Meanwhile, the methylation level of the CpG2 site was increased in preterm babies with brain injury compared with those without brain injury, and the AUC of CpG2 was 0.648, with a sensitivity of 75.9% and a specificity of 50.0%. A double luciferase reporter assay revealed that PLAGL1 fragments had enhancer-like activity and that the methylated form of PLAGL1 weakened this activity. Thus, PLAGL1 hypermethylation in chorioamniotic preterm infants is positively correlated with brain injury. Our results suggest a potential use for PLAGL1 methylation as a biomarker in the diagnosis of brain injury.