Perinatal Brain Research Articles

Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia–ischemia

BackgroundPerinatal inflammation combined with hypoxia–ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown.MethodsTwelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1–25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured.ResultsTwo HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT.ConclusionsWe did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI.ImpactAcute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy.Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown.In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death.Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.

Chorioamnionitis Precipitates Perinatal Alterations of Heme-Oxygenase-1 (HO-1) Homeostasis in the Developing Rat Brain.

Chorioamnionitis (CHORIO), placental insufficiency, and preterm birth are well-known antecedents of perinatal brain injury (PBI). Heme-oxygenase-1 (HO-1) is an important inducible enzyme in oxidative and inflammatory conditions. In the brain, HO-1 and the iron regulatory receptor, transferrin receptor-1 (TfR1), are known to be involved in iron homeostasis, oxidative stress, and cellular adaptive mechanisms. However, the role of HO pathway in the pathophysiology of PBI has not been previously studied. In this study, we set out to define the ontogeny of the HO pathway in the brain and determine if CHORIO changed its normal developmental regulation. We also aimed to determine the role of HO-1/TfR1 in CHORIO-induced neuroinflammation and peripheral inflammation in a clinically relevant rat model of PBI. We show that HO-1, HO-2, and TfR1 expression are developmentally regulated in the brain during the perinatal period. CHORIO elevates HO-1 and TfR1 mRNA expression in utero and in the early postnatal period and results in sustained increase in HO-1/TfR1 ratios in the brain. This is associated with neuroinflammatory and peripheral immune phenotype supported by a significant increase in brain mononuclear cells and peripheral blood double negative T cells suggesting a role of HO-1/TfR1 pathway dysregulation in CHORIO-induced neuroinflammation.

Neuroprotection of the Perinatal Brain by Early Information of Cerebral Oxygenation and Perfusion Patterns.

Abnormal patterns of cerebral perfusion/oxygenation are associated with neuronal damage. In preterm neonates, hypoxemia, hypo-/hypercapnia and lack of cerebral autoregulation are related to peri-intraventricular hemorrhages and white matter injury. Reperfusion damage after perinatal hypoxic ischemia in term neonates seems related with cerebral hyperoxygenation. Since biological tissue is transparent for near infrared (NIR) light, NIR-spectroscopy (NIRS) is a noninvasive bedside tool to monitor brain oxygenation and perfusion. This review focuses on early assessment and guiding abnormal cerebral oxygenation/perfusion patterns to possibly reduce brain injury. In term infants, early patterns of brain oxygenation helps to decide whether or not therapy (hypothermia) and add-on therapies should be considered. Further NIRS-related technical advances such as the use of (functional) NIRS allowing simultaneous estimation and integrating of heart rate, respiration rate and monitoring cerebral autoregulation will be discussed.

Usability and inter-rater reliability of the NeuroMotion app: A tool in General Movements Assessments.

Early intervention after perinatal brain insults requires early detection of infants with cerebral palsy (CP). General Movements Assessments (GMA) in the fidgety movement period has a high predictive value for CP. To investigate the NeuroMotion™ app's usability regarding film quality and user experience and to assess the inter-rater reliability of GMA in a neonatal risk group. GMA, inter-rater reliability and film quality was assessed in a cohort consisting of 37 infants enrolled in a multicentre study of GMA as part of the Swedish neonatal follow-up program for high-risk infants. Some of these infants were filmed twice. For evaluation of user experience 95 parents of 52 infants were addressed with a web-based questionnaire. A GMA expert assessed film quality and performed GMA and three on-site assessors, individually performed GMA. Inter-rater reliability was computed using Krippendorff's alpha (k-alpha). In all, 45 films showed good or excellent quality. The response rate of the questionnaire survey was 40% and revealed predominantly positive perceptions of the NeuroMotion™ app. GMA in 36 infants resulted in substantial agreement (k-alpha=0.72, 95%CI=0.3-1.0) between the three on-site assessors' consensus and the GMA expert. Inter-rater reliability for GMA between the on-site assessors was moderate (k-alpha=0.48, 0.18-0.74). The NeuroMotion™ app produces good technical quality films and the app user experience was overall positive. High agreement was observed between the on-site assessors and the GMA expert. The study design is feasible for more extensive GMA studies in cohorts of infants at risk of CP.

Relationship between resting-state fMRI functional connectivity with motor and language outcome after perinatal brain injury - A systematic review.

Perinatal brain injury is a significant cause of adverse neurodevelopmental outcomes. The objective of this systematic review was to identify patterns of altered brain function, quantified using functional connectivity (FC) changes in resting-state fMRI (rs-fMRI) data, that were associated with motor and language outcomes in individuals with a history of perinatal brain injury. A systematic search using electronic databases was conducted to identify relevant studies. A total of 10 studies were included in the systematic review, representing 260 individuals with a history of perinatal brain injury. Motor and language outcomes were measured at time points ranging from 4 months to 29 years 1 month. Relations between FC and motor measures revealed increased intra-hemispheric FC, reduced inter-hemispheric FC and impaired lateralization of motor-related brain regions associated with motor outcomes. Altered FC within sensorimotor, visual, cerebellum and frontoparietal networks, and between sensorimotor, visual, auditory and higher-order networks, including cerebellum, frontoparietal, default-mode, salience, self-referential and attentional networks were also associated with motor outcomes. In studies assessing the relationship between rs-fMRI and language outcome, reduced intra-hemispheric FC, increased inter-hemispheric FC and right-hemisphere lateralization of language-related brain regions correlated with language outcomes. Evidence from this systematic review suggests a possible association between diaschisis and motor and language impairments in individuals after perinatal brain lesions. These findings support the need to explore the contributions of additional brain regions functionally connected but remote from the primary lesioned brain area for targeted treatments and appropriate intervention, though more studies with increased standardization across neuroimaging and neurodevelopmental assessments are needed.

Short\u2010term outcomes in infants with mild neonatal encephalopathy: a retrospective, observational study

BackgroundNeonatal encephalopathy due to acute perinatal asphyxia is a major cause of perinatal brain damage. Moderate to severe neonatal encephalopathy is associated with high mortality and morbidity rates. However, the neurodevelopmental outcomes in neonates with mild neonatal encephalopathy are unclear. The primary aim of this single-center observational study was to assess the short-term outcomes in term neonates with mild neonatal encephalopathy due to perinatal asphyxia. A secondary aim was to identify predictors of poor prognosis by identifying the characteristics of these infants according to their short-term outcomes.MethodsWe retrospectively investigated all infants with perinatal asphyxia at Tokyo Metropolitan Children’s Medical Center from January 2014 to December 2019. An abnormal short-term outcome was defined as any one of the following: seizures or abnormal electroencephalography, abnormal brain magnetic resonance imaging obtained within the first 4 weeks of life, and abnormal neurological examination findings at discharge.ResultsIn total, 110 term infants with perinatal asphyxia during the study period were screened and 61 were diagnosed with mild neonatal encephalopathy. Eleven (18 %) of these infants had an abnormal short-term outcome. The median Thompson score at admission was significantly higher in infants with abnormal short-term outcomes than in those with normal short-term outcomes (5 [interquartile range, 4-5.5] vs. 2 [interquartile range, 1–3], p < 0.01). Receiver operating characteristic curve analysis showed that a cutoff value of 4 had high sensitivity and specificity (90.9 and 83.0 %, respectively) for prediction of an abnormal short-term outcome.Conclusions18 % of infants with mild encephalopathy had an abnormal short-term outcome, such as abnormal brain magnetic resonance imaging findings. The Thompson score at admission may be a useful predictor of an abnormal short-term outcome in infants with mild neonatal encephalopathy.

The etiology of 340 infants with early-onset epilepsy

Objective: To investigate the etiology of epilepsy onset before 6 months old and improve clinical understanding. Methods: The medical history, electroencephalogram, brain imaging, genetic examination and other clinical data of 340 patients who were diagnosed with epilepsy with onset under 6 months of age and were hospitalized in the Department of Neurology, Beijing Children's Hospital, Capital Medical University between January 2017 and December 2018 were retrospectively analyzed. Rank sum test was used to compare the ages of onset of different etiologic groups. Results: Of the 340 patients, 196 were males and 144 were females. The age of onset was 90.5 (48.0, 135.5) days. In the 250 (73.5%) underwent genetic test, 103 (41.2%) had pathogenic or likely pathogenic variants, involving 43 single gene variants and 2 chromosomal abnormalities. Seventy-nine patients (23.2%) had genetic etiology, 66 (19.4%) had structural etiology, 19 (5.6%) had metabolic etiology, 13 (3.8%) had multiple etiologies, and 163 (47.9%) had unknown etiology. In the 79 cases with genetic etiology, 30 single gene variants were detected, including 19 cases of PRRT2, 10 cases of KCNQ2, 7 cases of SCN1A, 6 cases of SCN2A, 6 cases of STXBP1, 5 cases of CDKL5, 2 cases of ARX, and 1 case of each of 23 gene variants. Two cases had chromosomal abnormalities which were 21-trisomy and 16p11.2 microdeletion syndrome respectively. Among the 66 cases with structural etiologies, 37 cases had acquired factors such as perinatal brain injury, 28 cases had congenital factors such as cortical malformation and 1 case was perinatal brain injury combined megalencephaly. The onset age of genetic etiology was 95 (26, 128) days, that of structural etiology was 90 (58, 30) days, and that of metabolic etiology was 57 (30, 90) days. The onset age of metabolic etiology was earlier than that of structural etiology (U=436.500, P=0.044). Conclusions: Genetic etiology is the most common defined etiology of infants with early-onset epilepsy aged 0-6 months, and there are certain differences in the age of onset between different etiologies. Proper application of genetic test is helpful to identify the etiology and guide treatment.

High-frequency oscillations recorded with surface EEG in neonates with seizures

ObjectiveNeonatal seizures are often the first symptom of perinatal brain injury. High-frequency oscillations (HFOs) are promising new biomarkers for epileptogenic tissue and can be found in intracranial and surface EEG. To date, we cannot reliably predict which neonates with seizures will develop childhood epilepsy. We questioned whether epileptic HFOs can be generated by the neonatal brain and potentially predict epilepsy. MethodsWe selected 24 surface EEGs sampled at 2048 Hz with 175 seizures from 16 neonates and visually reviewed them for HFOs. Interictal epochs were also reviewed. ResultsWe found HFOs in thirteen seizures (7%) from four neonates (25%). 5025 ictal ripples (rate 10 to 1311/min; mean frequency 135 Hz; mean duration 66 ms) and 1427 fast ripples (rate 8 to 356/min; mean frequency 298 Hz; mean duration 25 ms) were marked. Two neonates (13%) showed interictal HFOs (285 ripples and 25 fast ripples). Almost all HFOs co-occurred with sharp transients. We could not find a relationship between neonatal HFOs and outcome yet. ConclusionsNeonatal HFOs co-occur with ictal and interictal sharp transients. SignificanceThe neonatal brain can generate epileptic ripples and fast ripples, particularly during seizures, though their occurrence is not common and potential clinical value not evident yet.

Early diagnosis and treatment of infants with prenatal and perinatal risk factors for brain damage at the neurodevelopmental research unit in Mexico

Prenatal and perinatal risk factors for perinatal brain damage frequently produce brain injuries in preterm and term infants. The early diagnosis and treatment of these infants, in the period of higher brain plasticity, may prevent the neurological and cognitive sequels that accompany these lesions. The Neurodevelopmental Research Unit at the Institute of Neurobiology of the National Autonomous University of Mexico has taken this endeavor. A multidisciplinary approach is followed. Pediatric, neurologic and rehabilitation clinical studies, MRI, EEG, visual and auditory evoked responses, and Bayley II evaluations are carried out initially. Infants are followed up to 8 years, with periodic appointments for evaluation and treatment. Katona's neurohabilitation method is used for initial diagnosis and treatment. Selective visual and auditory attention are explored from 3 months of age. This method was created in the Unit and, if deficiencies are observed, the method also describes the treatment to avoid subsequent alterations of these processes. Deficiencies in the acquisition of language are evaluated from 4 months of age, implementing treatment through instructions to parents on how they should teach their children to speak. This method has also been developed in the Unit and is in its validation process. In the MRI, we pay special attention to subtle and diffuse patterns, due to the high frequency with which they appear in contemporary cohorts at a national and international level. More than 80% of these infants showed abnormal MRI findings that should be taken into consideration. The outcome of children at 8 years old showed that 78%, 76% and 78% of extremely preterm, very preterm and late preterm, respectively, had a normal neurodevelopment. In term infants, only 69% had a normal neurodevelopment; in this group, the majority of infants had very severe brain lesions. Conclusions: It is necessary to evaluate, at an early age, all newborns with prenatal and perinatal risk factors for brain damage. Special attention should be payed to all premature newborns and those newborns who have been discharged from the intensive care unit.

Sulforaphane (SFA) protects neuronal cells from oxygen & glucose deprivation (OGD).

BackgroundPerinatal brain injury results in neurodevelopmental disabilities (neuroDDs) that include cerebral palsy, autism, attention deficit disorder, epilepsy, learning disabilities and others. Commonly, injury occurs when placental circulation, that is responsible for transporting nutrients and oxygen to the fetus, is compromised. Placental insufficiency (PI) is a reduced supply of blood and oxygen to the fetus and results in a hypoxic-ischemic (HI) environment. A significant HI state in-utero leads to perinatal compromise, characterized by fetal growth restriction and brain injury. Given that over 80% of perinatal brain injuries that result in neuroDDs occur during gestation, prior to birth, preventive approaches are needed to reduce or eliminate the potential for injury and subsequent neuroDDs. Sulforaphane (SFA) derived from cruciferous vegetables such as broccoli sprouts (BrSps) is a phase-II enzyme inducer that acts via cytoplasmic Nrf2 to enhance the production of anti-oxidants in the brain through the glutathione pathway. We have previously shown a profound in vivo neuro-protective effect of BrSps/SFA as a dietary supplement in pregnant rat models of both PI and fetal inflammation. Strong evidence also points to a role for SFA as treatment for various cancers. Paradoxically, then SFA has the ability to enhance cell survival, and with conditions of cancer, enhance cell death. Given our findings of the benefit of SFA/Broccoli Sprouts as a dietary supplement during pregnancy, with improvement to the fetus, it is important to determine the beneficial and toxic dosing range of SFA. We therefore explored, in vitro, the dosing range of SFA for neuronal and glial protection and toxicity in normal and oxygen/glucose deprived (OGD) cell cultures.MethodsOGD simulates, in vitro, the condition experienced by the fetal brain due to PI. We developed a cell culture model of primary cortical neuronal, astrocyte and combined brain cell co-cultures from newborn rodent brains. The cultures were exposed to an OGD environment for various durations of time to determine the LD50 (duration of OGD required for 50% cell death). Using the LD50 as the time point, we evaluated the efficacy of varying doses of SFA for neuroprotective and neurotoxicity effects. Control cultures were exposed to normal media without OGD, and cytotoxicity of varying doses of SFA was also evaluated. Immunofluorescence (IF) and Western blot analysis of cell specific markers were used for culture characterization, and quantification of LD50. Efficacy and toxicity effect of SFA was assessed by IF/high content microscopy and by AlamarBlue viability assay, respectively.ResultsWe determined the LD50 to be 2 hours for neurons, 8 hours for astrocytes, and 10 hours for co-cultures. The protective effect of SFA was noticeable at 2.5 μM and 5 μM for neurons, although it was not significant. There was a significant protective effect of SFA at 2.5 μM (p<0.05) for astrocytes and co-cultures. Significant toxicity ranges were also confirmed in OGD cultures as ≥ 100 μM (p<0.05) for astrocytes, ≥ 50 μM (p<0.01) for co-cultures, but not toxic in neurons; and toxic in control cultures as ≥ 100 μM (p<0.01) for neurons, and ≥ 50 μM (p<0.01) for astrocytes and co-cultures. One Way ANOVA and Dunnett’s Multiple Comparison Test were used for statistical analysis.ConclusionsOur results indicate that cell death shows a trend to reduction in neuronal and astrocyte cultures, and is significantly reduced in co-cultures treated with low doses of SFA exposed to OGD. Doses of SFA that were 10 times higher were toxic, not only under conditions of OGD, but in normal control cultures as well. The findings suggest that: 1. SFA shows promise as a preventative agent for fetal ischemic brain injury, and 2. Because the fetus is a rapidly growing organism with profound cell multiplication, dosing parameters must be established to insure safety within efficacious ranges. This study will influence the development of innovative therapies for the prevention of childhood neuroDD.

Effects of therapeutic hypothermia on death among asphyxiated neonates with hypoxic-ischemic encephalopathy: A systematic review and meta-analysis of randomized control trials.

Hypoxic perinatal brain injury is caused by lack of oxygen to baby's brain and can lead to death or permanent brain damage. However, the effectiveness of therapeutic hypothermia in birth asphyxiated infants with encephalopathy is uncertain. This systematic review and meta-analysis was aimed to estimate the pooled relative risk of mortality among birth asphyxiated neonates with hypoxic-ischemic encephalopathy in a global context. We used the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines to search randomized control trials from electronic databases (PubMed, Cochrane library, Google Scholar, MEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and meta register of Current Controlled Trials (mCRT)). The authors extracted the author's name, year of publication, country, method of cooling, the severity of encephalopathy, the sample size in the hypothermic, and non-hypothermic groups, and the number of deaths in the intervention and control groups. A weighted inverse variance fixed-effects model was used to estimate the pooled relative risk of mortality. The subgroup analysis was done by economic classification of countries, methods of cooling, and cooling devices. Publication bias was assessed with a funnel plot and Eggers test. A sensitivity analysis was also done. A total of 28 randomized control trials with a total sample of 35, 92 (1832 hypothermic 1760 non-hypothermic) patients with hypoxic-ischemic encephalopathy were used for the analysis. The pooled relative risk of mortality after implementation of therapeutic hypothermia was found to be 0.74 (95%CI; 0.67, 0.80; I2 = 0.0%; p<0.996). The subgroup analysis revealed that the pooled relative risk of mortality in low, low middle, upper-middle and high income countries was 0.32 (95%CI; -0.95, 1.60; I2 = 0.0%; p<0.813), 0.5 (95%CI; 0.14, 0.86; I2 = 0.0%; p<0.998), 0.62 (95%CI; 0.41-0.83; I2 = 0.0%; p<0.634) and 0.76 (95%CI; 0.69-0.83; I2 = 0.0%; p<0.975) respectively. The relative risk of mortality was the same in selective head cooling and whole-body cooling method which was 0.74. Regarding the cooling device, the pooled relative risk of mortality is the same between the cooling cap and cooling blanket (0.74). However, it is slightly lower (0.73) in a cold gel pack. Therapeutic hypothermia reduces the risk of death in neonates with moderate to severe hypoxic-ischemic encephalopathy. Both selective head cooling and whole-body cooling method are effective in reducing the mortality of infants with this condition. Moreover, low income countries benefit the most from the therapy. Therefore, health professionals should consider offering therapeutic hypothermia as part of routine clinical care to newborns with hypoxic-ischemic encephalopathy especially in low-income countries.

Melatonin for the prevention of fetal injury associated with intrauterine inflammation.

Intrauterine inflammation is shown to be associated with preterm birth, fetal inflammatory response syndrome, and other pregnancy-related comorbidities such as central nervous system diseases including cerebral palsy and periventricular leukomalacia, pulmonary diseases such as bronchopulmonary dysplasia and respiratory distress syndrome, and necrotizing enterocolitis, to name a few. Many animal studies on intrauterine inflammation demonstrate that ascending infection of reproductive organs or the production of proinflammatory cytokines by some stimuli in utero results in such manifestations. Melatonin, known for its primary function in maintaining circadian rhythm, is now recognized as one of the most potent antioxidant and anti-inflammatory drugs. In some studies, melatonin injection in pregnant animals with intrauterine inflammation significantly reduced the number of preterm births, the severity of structural disintegration of the fetal lungs observed in bronchopulmonary dysplasia, and perinatal brain injuries with improvement in neuromotor function. These implicated benefits of melatonin in pregnant women with intrauterine inflammation seem promising in many research studies, strongly supporting the hypothesis that melatonin has antioxidative and anti-inflammatory properties that can potentially be taken by pregnant women who are at risk of having intrauterine inflammation. In this review, the potential of melatonin for improving outcomes of the pregnancies with intrauterine inflammation will be discussed.

Neonatal administration of erythropoietin attenuates cognitive deficits in adult rats following placental insufficiency.

Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.

Concurrent and predictive validity of the infant motor profile in infants at risk of neurodevelopmental disorders

BackgroundPreterm infants and infants with perinatal brain injury show a higher incidence of neurodevelopmental disorders (NDD). The Infant Motor Profile (IMP) is a clinical assessment which evaluates the complexity of early motor behaviour. More data are needed to confirm its predictive ability and concurrent validity with other common and valid assessments such as the Alberta Infant Motor Scale (AIMS) and Prechtl’s General Movement Assessment (GMA). The present study aims to evaluate the concurrent validity of the IMP with the AIMS, to assess its association with the GMA, to evaluate how the IMP reflects the severity of the brain injury and to compare the ability of the IMP and the AIMS to predict an abnormal outcome in 5-month-old infants at risk of NDD.Methods86 infants at risk of NDD were retrospectively recruited among the participants of two clinical trials. Preterm infants with or without perinatal brain injury and term infants with brain injury were assessed at 3 months corrected age (CA) using the GMA and at 5 months CA using the IMP and the AIMS. The neurodevelopmental outcome was established at 18 months.ResultsResults confirm a solid concurrent validity between the IMP Total Score and the AIMS (Spearman’s ρ 0.76; p < .001) and a significant association between IMP Total Score and the GMA. Unlike the AIMS, the IMP Total score accurately reflects the severity of neonatal brain injury (p < .001) and proves to be the strongest predictor of NDD (p < .001). The comparison of areas under receiver operating characteristic curves (AUC) confirms that the IMP Total score has the highest diagnostic accuracy at 5 months (AUC 0.92). For an optimal IMP Total Score cut-off value of 70, the assessment shows high sensitivity (93%) and specificity (81%) (PPV 84%; NPV 90%).ConclusionsEarly motor behaviour assessed with the IMP is strongly associated with middle-term neurodevelopmental outcome. The present study confirms the concurrent validity of the IMP with the AIMS, its association with the GMA and its ability to reflect brain lesion load, hence contributing to the construct validity of the assessment.Trial registrationNCT01990183 and NCT03234959 (clinicaltrials.gov).

Early maternal care restores LINE-1 methylation and enhances neurodevelopment in preterm infants

BackgroundPreterm birth affects almost 9–11% of newborns and is one of the leading causes of childhood neurodevelopmental disabilities; the underlying molecular networks are poorly defined. In neurons, retrotransposons LINE-1 (L1) are an active source of genomic mosaicism that is deregulated in several neurological disorders; early life experience has been shown to regulate L1 activity in mice.MethodsVery preterm infants were randomized to receive standard care or early intervention. L1 methylation was measured at birth and at hospital discharge. At 12 and 36 months, infants’ neurodevelopment was evaluated with the Griffiths Scales. L1 methylation and CNVs were measured in mouse brain areas at embryonic and postnatal stages.ResultsHere we report that L1 promoter is hypomethylated in preterm infants at birth and that an early intervention program, based on enhanced maternal care and positive multisensory stimulation, restores L1 methylation levels comparable to healthy newborns and ameliorates neurodevelopment in childhood. We further show that L1 activity is fine-tuned in the perinatal mouse brain, suggesting a sensitive and vulnerable window for the L1 epigenetic setting.ConclusionsOur results open the field on the inspection of L1 activity as a novel molecular and predictive approach to infants’ prematurity-related neurodevelopmental outcomes.Trial registrationClinicalTrial.gov (NCT02983513). Registered on 6 December 2016, retrospectively registered.

Longitudinal Stability of Spatial Inattention in Children With Perinatal Stroke

BackgroundSigns of contralateral hemispatial inattention may be witnessed in children following perinatal brain infarcts (lesions), and evidence shows a pattern distinct from that in adults. This study is a longitudinal analysis of children with perinatal infarcts, with the goals of determining the pattern of inattention found in children with left or right hemisphere lesions and whether this pattern shows signs of change over time. MethodsTwenty-one children with left hemishpere lesions, nine children with right hemisphere lesions, and 80 neurologically healthy control children were given the Infant and Toddler Neglect Task at two different time points. At time 1, median age was 1.54 years (interquartile range [IQR] = 0.92 to 2.29). At time 2, median age was 3.25 years (IQR = 2.23 to 5.00). A standardized scoring system was developed to compare the children’s preference for the left versus right side of space. ResultsChildren with left hemisphere lesions showed a significantly increased preference for the left side of space and a slightly decreased preference for the right side of space at time 1 and a significantly decreased preference for the right side of space at time 2 compared with controls. Children with right hemisphere lesions showed a significantly decreased preference for the left side of space and a significantly increased preference for the right side of space compared with controls at time 1 and a significantly decreased preference for the left side of space and a significantly increased preference for the right side of space compared with controls at time 2. There were no significant within-subjects effects across time. ConclusionsThese data suggest that mechanisms of hemispatial inattention affect children early in the developmental process and that hemispatial inattention in children with both left and right hemisphere perinatal lesions likely persists at least through the early elementary school years.

Congenital Externally Communicating Porencephaly Presenting as Hemiplegic Cerebral Palsy: Imaging Study of a Rare Condition.

Congenital porencephaly is a very rare condition characterized by cystic degeneration encephalomalacia and cysts or cavities within the brain. Porencephalic cysts have a variable size and site and therefore it result in a variable clinical presentations including asymptomatic, various forms of cerebral palsy, seizures and cognitive impairment. The disorder is heterogeneous in nature and the brain lesions can be caused by developmental abnormalities, infection, perinatal brain ischemia, trauma and hemorrhage. Genetic factors have been suggested and familial cases have been reported. Congenital porencephaly is generally classified into, internally communicating with the ventricle and externally communicating with the subarachnoid space. The aim of this paper is to report the rare finding of externally communicating porencephaly in a child with hemiplegic cerebral palsy.

Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries.

Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these.

Neuroprotection offered by mesenchymal stem cells in perinatal brain injury: Role of mitochondria, inflammation, and reactive oxygen species.

Preclinical studies have shown that mesenchymal stem cells have a positive effect in perinatal brain injury models. The mechanisms that cause these neurotherapeutic effects are not entirely intelligible. Mitochondrial damage, inflammation, and reactive oxygen species are considered to be critically involved in the development of injury. Mesenchymal stem cells have immunomodulatory action and exert mitoprotective effects which attenuate production of reactive oxygen species and promote restoration of tissue function and metabolism after perinatal insults. This review summarizes the present state, the underlying causes, challenges and possibilities for effective clinical translation of mesenchymal stem cell therapy.

White matter injury in the neonatal hypoxic-ischemic brain and potential therapies targeting microglia.

Neonatal hypoxic-ischemic (H-I) injury, which mainly causes neuronal damage and white matter injury (WMI), is among the predominant causes of infant morbidity (cerebral palsy, cognitive and persistent motor disabilities) and mortality. Disruptions to the oxygen and blood supply in the perinatal brain affect the cerebral microenvironment and may affect microglial activation, excitotoxicity, and oxidative stress. Microglia are significantly associated with axonal damage and myelinating oligodendrocytes, which are major pathological components of WMI. However, the effects of H-I injury on microglial functions and underlying transformation mechanisms remain poorly understood. The historical perception that these cells are major risk factors for ischemic stroke has been questioned due to our improved understanding of the diversity of microglial phenotypes and their alterable functions, which exacerbate or attenuate injuries in different regions in response to environmental instability. Unfortunately, although therapeutic hypothermia is an efficient treatment, death and disability remain the prognosis for a large proportion of neonates with H-I injury. Hence, novel neuroprotective therapies to treat WMI following H-I injury are urgently needed. Here, we review microglial mechanisms that might occur in the developing brain due to neonatal H-I injury and discuss whether microglia function as a double-edged sword in WMI. Then, we emphasize microglial heterogeneity, notably at the single-cell level, and sex-specific effects on the etiology of neurological diseases. Finally, we discuss current knowledge of strategies aiming to improve microglia modulation and remyelination following neonatal H-I injury. Overall, microglia-targeted therapy might provide novel and valuable insights into the treatment of neonatal H-I insult.