Aberrant Brain Development Research Articles

Prenatal assessment of brain malformations on neuroimaging: an expert panel review.

Brain malformations represent a heterogeneous group of abnormalities of neural morphogenesis, often associated with aberrations of neuronal connectivity and brain volume. Prenatal detection of brain malformations requires a clear understanding of embryology and developmental morphology through the various stages of gestation. This expert panel review is written with the central aim of providing an easy-to-understand roadmap to improve prenatal detection and characterization of structural malformations based on the current understanding of normal and aberrant brain development. The utility of each available neuroimaging modality including prenatal multiplanar neurosonography, anatomical magnetic resonance imaging (MRI), and advanced MRI techniques, as well as further insights from post-mortem imaging have been highlighted for every developmental stage.

Timed fetal inflammation and postnatal hypoxia cause cortical white matter injury, interneuron imbalances, and behavioral deficits in a double-hit rat model of encephalopathy of prematurity

Extreme preterm birth-associated adversities are a major risk factor for aberrant brain development, known as encephalopathy of prematurity (EoP), which can lead to long-term neurodevelopmental impairments. Although progress in clinical care for preterm infants has markedly improved perinatal outcomes, there are currently no curative treatment options available to combat EoP. EoP has a multifactorial etiology, including but not limited to pre- or postnatal immune activation and oxygen fluctuations. Elucidating the underlying mechanisms of EoP and determining the efficacy of potential therapies relies on valid, clinically translatable experimental models that reflect the neurodevelopmental and pathophysiological hallmarks of EoP. Here, we expand on our double-hit rat model that can be used to study EoP disease mechanisms and therapeutic options in a preclinical setting. Pregnant Wistar dams were intraperitoneally injected with 10 μg/kg LPS on embryonic day (E)20 and offspring was subjected to hypoxia (140 min, 8% O2) at postnatal day 4. Rats exposed to fetal inflammation and postnatal hypoxia (FIPH) showed neurodevelopmental impairments, such as reduced nest-seeking ability, ultrasonic vocalizations, social engagement, and working memory, and increased anxiety and sensitivity. Impairments in myelination, oligodendrocyte maturation and interneuron development were examined as hallmarks for EoP, in different layers and coordinates of the cortex using histological and molecular techniques. Myelin density and complexity was decreased in the cortex, which partially coincided with a decrease in mature oligodendrocytes. Furthermore, interneuron populations (GAD67+ and PVALB+) were affected. To determine if the timing of inducing fetal inflammation affected the severity of EoP hallmarks in the cortex, multiple timepoints of fetal inflammation were compared. Inflammation at E20 combined with postnatal hypoxia gave the most severe EoP phenotype in the cortex. In conclusion, we present a double-hit rat model which displays various behavioral, anatomical and molecular hallmarks of EoP, including diffuse white matter injury. This double-hit model can be used to investigate pathophysiological mechanisms and potential therapies for EoP.

Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner.

Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring. Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced TH17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy. Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1+ cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion. Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.

Unlocking the epigenome: Stress and exercise induced Bdnf regulation in the prefrontal cortex

Aversive caregiving in early life is a risk factor for aberrant brain and behavioral development. This outcome is related to epigenetic dysregulation of the brain-derived neurotrophic factor (Bdnf) gene. The Bdnf gene encodes for BDNF, a neurotrophin involved in early brain development, neural plasticity, learning, and memory. Recent work suggests that exercise may be neuroprotective in part by supporting BDNF protein and gene expression, making it an exciting target for therapeutic interventions. To our knowledge, exercise has never been studied as a therapeutic intervention in preclinical rodent models of caregiver maltreatment. To that end, the current study investigated the effect of an adult voluntary wheel running intervention on Bdnf methylation and expression in the prefrontal cortex of rats who experienced aversive caregiving in infancy. We employed a rodent model (Long Evans rats) wherein rat pups experienced intermittent caregiver-induced stress from postnatal days 1–7 and were given voluntary access to a running wheel (except in the control condition) from postnatal days 70–90 as a young adulthood treatment intervention. Our results indicate that maltreatment and exercise affect Bdnf gene methylation in an exon, CG site, and sex-specific manner. Here we add to a growing body of evidence of the ability for our experiences, including exercise, to permeate the brain. Keywords: Early life stress, Bdnf, exercise, prefrontal cortex.

Brain developmental trajectories in offspring of parents with schizophrenia or bipolar disorder

AbstractEarly diagnosis and intervention are essential for managing and improving long-term outcomes of severe mental illness, highlighting the need for reliable early biomarkers. This longitudinal study explores whether the development of the brain during childhood and adolescence differs between offspring of parents with and without schizophrenia or bipolar disorder. Moreover, we will assess if the age-dependent change over time in brain volume, cortical thickness and surface, structural network indices, and cortical gyrification are related to the presence and severity of psychiatric symptoms and level of IQ. We obtained 286 T1-weighted MRI scans of 184 offspring (aged 8–18 years at baseline) of at least one parent diagnosed with bipolar disorder (n=78) or schizophrenia (n=52) and offspring of parents without severe mental illness (n=54); 102 offspring underwent a follow-up scan (on average 3.9 years between scans).Group comparisons and the associations with clinical and cognitive measures were analysed with linear mixed-effects models. To correct for multiple comparisons, we applied a Benjamini-Hochberg false discovery rate (FDR) correction (q=0.05). A significant effect of age was found on most of the included brain features, with suggestive evidence for subtle deviations in trajectories in the cortical thickness, structural network indices but not in gyrification index, sulcal depth, length and width or surface area in offspring of parents with schizophrenia. Interestingly, these deviations in brain development in schizophrenia offspring remained significant after taking the presence of a diagnosis or level of IQ into account. These findings suggest the aberrant brain development in familial high-risk youngsters is associated with being at familial risk and not with (also) being at clinical high-risk.Disclosure of InterestNone Declared

A Survey on the Expression of the Ubiquitin Proteasome System Components HECT- and RBR-E3 Ubiquitin Ligases and E2 Ubiquitin-Conjugating and E1 Ubiquitin-Activating Enzymes during Human Brain Development.

Human brain development involves a tightly regulated sequence of events that starts shortly after conception and continues up to adolescence. Before birth, neurogenesis occurs, implying an extensive differentiation process, sustained by changes in the gene expression profile alongside proteome remodeling, regulated by the ubiquitin proteasome system (UPS) and autophagy. The latter processes rely on the selective tagging with ubiquitin of the proteins that must be disposed of. E3 ubiquitin ligases accomplish the selective recognition of the target proteins. At the late stage of neurogenesis, the brain starts to take shape, and neurons migrate to their designated locations. After birth, neuronal myelination occurs, and, in parallel, neurons form connections among each other throughout the synaptogenesis process. Due to the malfunctioning of UPS components, aberrant brain development at the very early stages leads to neurodevelopmental disorders. Through deep data mining and analysis and by taking advantage of machine learning-based models, we mapped the transcriptomic profile of the genes encoding HECT- and ring-between-ring (RBR)-E3 ubiquitin ligases as well as E2 ubiquitin-conjugating and E1 ubiquitin-activating enzymes during human brain development, from early post-conception to adulthood. The inquiry outcomes unveiled some implications for neurodevelopment-related disorders.

The Role of Bcl11 Transcription Factors in Neurodevelopmental Disorders.

Neurodevelopmental disorders (NDDs) comprise a diverse group of diseases, including developmental delay, autism spectrum disorder (ASD), intellectual disability (ID), and attention-deficit/hyperactivity disorder (ADHD). NDDs are caused by aberrant brain development due to genetic and environmental factors. To establish specific and curative therapeutic approaches, it is indispensable to gain precise mechanistic insight into the cellular and molecular pathogenesis of NDDs. Mutations of BCL11A and BCL11B, two closely related, ultra-conserved zinc-finger transcription factors, were recently reported to be associated with NDDs, including developmental delay, ASD, and ID, as well as morphogenic defects such as cerebellar hypoplasia. In mice, Bcl11 transcription factors are well known to orchestrate various cellular processes during brain development, for example, neural progenitor cell proliferation, neuronal migration, and the differentiation as well as integration of neurons into functional circuits. Developmental defects observed in both, mice and humans display striking similarities, suggesting Bcl11 knockout mice provide excellent models for analyzing human disease. This review offers a comprehensive overview of the cellular and molecular functions of Bcl11a and b and links experimental research to the corresponding NDDs observed in humans. Moreover, it outlines trajectories for future translational research that may help to better understand the molecular basis of Bcl11-dependent NDDs as well as to conceive disease-specific therapeutic approaches.

A heterozygous mutation in UBE2H in a patient with developmental delay leads to an aberrant brain development in zebrafish

BackgroundUbiquitin-related rare diseases are generally characterized by developmental delays and mental retardation, but the exact incidence or prevalence is not yet fully understood. The clinical application of next-generation sequencing for pediatric seizures and developmental delay of unknown causes has become common in studies aimed at identification of a causal gene in patients with ubiquitin-related rare diseases that cannot be diagnosed using conventional fluorescence in situ hybridization or chromosome microarray tests. Our study aimed to investigate the effects of ubiquitin–proteasome system on ultra-rare neurodevelopmental diseases, through functional identification of candidate genes and variants.MethodsIn our present work, we carried out genome analysis of a patient with clinical phenotypes of developmental delay and intractable convulsion, to identify causal mutations. Further characterization of the candidate gene was performed using zebrafish, through gene knockdown approaches. Transcriptomic analysis using whole embryos of zebrafish knockdown morphants and additional functional studies identified downstream pathways of the candidate gene affecting neurogenesis.ResultsThrough trio-based whole-genome sequencing analysis, we identified a de novo missense variant of the ubiquitin system-related gene UBE2H (c.449C>T; p.Thr150Met) in the proband. Using zebrafish, we found that Ube2h is required for normal brain development. Differential gene expression analysis revealed activation of the ATM-p53 signaling pathway in the absence of Ube2h. Moreover, depletion of ube2h led to induction of apoptosis, specifically in the differentiated neural cells. Finally, we found that a missense mutation in zebrafish, ube2h (c.449C>T; p.Thr150Met), which mimics a variant identified in a patient with neurodevelopmental defects, causes aberrant Ube2h function in zebrafish embryos.ConclusionA de novo heterozygous variant in the UBE2H c.449C>T (p.Thr150Met) has been identified in a pediatric patient with global developmental delay and UBE2H is essential for normal neurogenesis in the brain.

A simplified protocol for the generation of cortical brain organoids.

Human brain organoid technology has the potential to generate unprecedented insight into normal and aberrant brain development. It opens up a developmental time window in which the effects of gene or environmental perturbations can be experimentally tested. However, detection sensitivity and correct interpretation of phenotypes are hampered by notable batch-to-batch variability and low reproducibility of cell and regional identities. Here, we describe a detailed, simplified protocol for the robust and reproducible generation of brain organoids with cortical identity from feeder-independent induced pluripotent stem cells (iPSCs). This self-patterning approach minimizes media supplements and handling steps, resulting in cortical brain organoids that can be maintained over prolonged periods and that contain radial glial and intermediate progenitors, deep and upper layer neurons, and astrocytes.

Structural Racism, Social Determinants of Health, and Provider Bias: Impact on Brain Development in Critical Congenital Heart Disease.

Critical congenital heart disease (cCHD) has neurodevelopmental sequelae that can carry into adulthood, which may be due to aberrant brain development or brain injury in the prenatal and perinatal/neonatal periods and beyond. Health disparities based upon the intersection of sex, geography, race, and ethnicity have been identified for poorer pre- and postnatal outcomes in the general population, as well as those with cCHD. These disparities are likely driven by systemic racism, disparities in social determinants of health (SDOH), and provider bias, which further compound negative brain development outcomes. The current review discusses how aberrant brain development in cCHD early in life is impacted by reduced access to quality care (i.e., prenatal care and testing, postnatal care) due to divestment in non-White neighborhoods (e.g., redlining) and food insecurity, differences in insurance status, location of residence, and perceived interpersonal racism and bias which disproportionately affects pregnant people of color who have fewer economic resources. Suggestions are discussed for moving forward with implementing strategies in medical education, clinical care, research, and gaining insight into the communities served to combat disparities and bias while promoting cultural humility.

DETECTION OF AUTISM SPECTRUM DISORDER BY FEATURE EXTRACTION OF EEG SIGNALS AND MACHINE LEARNING CLASSIFIERS

Autism Spectrum Disorder (ASD), a neurodevelopmental disorder, impacts the subject’s social communication and interaction and the subjects exhibit restricted and repetitive behaviors. Subjects with ASD may need assistance throughout their life, depending on the severity. Early diagnosis of ASD is therefore critical for early intervention. ASD is diagnosed clinically based on behavioral assessments of the subjects, which results in delayed diagnosis, since the typical ASD traits due to aberrant brain development take time to develop. Neurological disorders associated with aberrant brain electrical activity have been detected by analyzing Electroencephalogram (EEG) signal patterns. In this study, we used features extracted from EEG brain waves to categorize ASD and normal subjects using Machine Learning (ML) classifiers. Autoregressive (AR) coefficients, Shannon entropy, Multifractal wavelet leader estimates, Multiscale wavelet variance and Discrete Fourier Transform (DFT) coefficients were extracted from EEG brain waves of ASD and normal subjects. Support Vector Machine (SVM), Decision Tree (DT), Logistic Regression (LR), k-Nearest Neighbor (k-NN) and Feed-forward Neural Network (FNN) were utilized as classification algorithms to categorize the ASD subjects and the control subjects. An accuracy of 90% was achieved by k-NN algorithm using AR features, Shannon entropy, Multifractal wavelet leader estimates and Multiscale wavelet variance estimates in ASD categorization. An accuracy of 93% was achieved by k-NN using the DFT features. The findings of this study indicate that features extracted from EEG are sufficient enough for categorization of ASD subjects and the control subjects.

Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring.

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are conducted in rodents, the nonhuman primate provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a nonhuman primate MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.

Multiomic Profiling of Iron Deficient Infant Monkeys Detects Biochemical Signatures of Inflammatory and Neural Dysfunction in Blood and CSF Prior to Anemia

Background: Pre-anemic iron deficiency (ID) and ID anemia in infancy is associated with long-term effects on brain development. Iron is an essential micronutrient needed for multiple neurodevelopmental processes, including energy production, myelination and neurotransmission. Serum and cerebrospinal fluid (CSF) metabolomic and proteomic analyses can potentially characterize the metabolic and protein signatures of aberrant iron-dependent brain development pathways. A better understanding of the timing and course of the biochemical signatures of ID-induced dysfunction in the heme and intrathecal compartments may help with early diagnosis and treatment of iron deficiency prior to onset of anemia. Objective: To determine proteomic and metabolomic signatures of ID-induced dysfunction in serum and CSF of infant monkeys prior to the onset of iron deficiency anemia (IDA). Methods: Hematological parameters were determined in rhesus monkey infants (Macaca mulatta) at 4 and 6 months of age as they progressed from preanemic ID to IDA (ID group; n=6) or remained iron-sufficient(IS group; n=12). Blood and CSF were collected at 4 and 6 months and metabolically profiled using HPLC/MS with isobaric standards for identification and quantification. Proteomic quantification utilized a custom TMT-labeled workflow with an Orbitrap Fusion Tribrid mass spectrometer. Serum and CSF metabolomic and proteomic profiles of the ID and IS groups were compared, along with a a third group of infants that became IDA earlier at 4 months of age (IDA group; n=3). Results: Evidence of pre-anemic ID was apparent in some infant at 4 months of age with clinical IDA evident at 6 months A (Hgb <10 g/dL and MCV <60 fL). A total of 1,128 CSF proteins and 251 serum proteins were identified and quantified. Over 4,000 metabolite features were observed in serum and CSF across three modalities including reverse phase positive, reverse phase negative and HILIC mode. Pathway analyses provided evidence of increased inflammatory activity, impacts on neural pathways, and bioindicators of acute phase responses in ID and IDA groups. Signs of these metabolic changes were already present in the preanemic ID? period (4 months). Conclusions: Biomarkers indicating indicative of increased inflammatory activity with downstream effects on pathways involved in normal neural function were detectable in both the CSF and serum of ID monkeys prior to the onset of clinical anemia. Brain-specific proteomic and metabolomic profiling of novel analytes in circulation can facilitate earlier diagnosis and treatment of infantile ID to reduce neurodevelopmental risk. Funded by NIH/NICHD Grant HD089989, this abstract is sponsored by ASH member Zohar Sachs MD, PhD Disclosures No relevant conflicts of interest to declare.

M179. ALTERNATED BRAIN AND BEHAVIORAL DEVELOPMENT IN A NONHUMAN PRIMATE MODEL OF MATERNAL IMMUNE ACTIVATION

BackgroundChildren born to women who experience infection during pregnancy have an increased risk of brain disorders with neurodevelopmental origins, including both schizophrenia (SZ) and autism spectrum disorder (ASD). Rodent models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant brain and behavior development in offspring. The nonhuman primate MIA model provides an opportunity to maximize the translational utility of this model in a species more closely related to humans. Our previous pilot study found that rhesus monkeys (Macaca mulatta) born to MIA-treated dams developed behavioral abnormalities and increased striatal dopamine during adolescence. Here we present emerging behavioral outcomes from a larger cohort of MIA-treated nonhuman primates.MethodsA modified form of the viral mimic, Polyinosinic-polycytidylic acid (PolyIC), was delivered to a new cohort of pregnant rhesus monkeys (N=14) in the late first trimester (gestational days 43, 44, 46) to stimulate a maternal immune response. Control dams received saline injections at the same gestational time points (N=10) or were untreated (N=4). The offspring are undergoing ongoing comprehensive behavioral evaluations paired with longitudinal neuroimaging to quantify the emergence of brain and behavior pathology associated with prenatal maternal immune challenge.ResultsMIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature and inflammatory cytokines. Although MIA offspring developed species-typical milestones and showed no overt signs of atypical interactions with mothers or peers early in development, they had significantly smaller gray matter volume in the prefrontal and frontal cortices than control offspring at 6, 12 and 24 months of age (p < 0.05). At 24 months of age, the animals were tested in a reversal learning paradigm that requires a subject to flexibly adjust its behavior when the reward-related contingencies that it has previously learned are reversed. All animals advanced and performed similarly on the training and initial discrimination phases of the test. However, on the first day of the initial reward reversal, the MIA-treated animals more frequently failed to make a choice as compared to controls (Wilcoxon two-sample test p-value = .005). These emerging data suggest that MIA-treated animals exhibit subtle impairments in cognitive processing. Additional assessments social and cognitive development, including non-invasive eye tracking data, will be presented to further explore the impact of MIA on primate behavioral development.DiscussionThese findings provide new insights into the emergence of brain pathology in MIA-exposed primates and have implications for the developmental pathophysiology of human psychiatric disorders associated with maternal gestational infection.

An analysis of MRI derived cortical complexity in premature-born adults: Regional patterns, risk factors, and potential significance

Premature birth bears an increased risk for aberrant brain development concerning its structure and function. Cortical complexity (CC) expresses the fractal dimension of the brain surface and changes during neurodevelopment. We hypothesized that CC is altered after premature birth and associated with long-term cognitive development.One-hundred-and-one very premature-born adults (gestational age <32 weeks and/or birth weight <1500 ​g) and 111 term-born adults were assessed by structural MRI and cognitive testing at 26 years of age. CC was measured based on MRI by vertex-wise estimation of fractal dimension. Cognitive performance was measured based on Griffiths-Mental-Development-Scale (at 20 months) and Wechsler-Adult-Intelligence-Scales (at 26 years).In premature-born adults, CC was decreased bilaterally in large lateral temporal and medial parietal clusters. Decreased CC was associated with lower gestational age and birth weight. Furthermore, decreased CC in the medial parietal cortices was linked with reduced full-scale IQ of premature-born adults and mediated the association between cognitive development at 20 months and IQ in adulthood.Results demonstrate that CC is reduced in very premature-born adults in temporoparietal cortices, mediating the impact of prematurity on impaired cognitive development. These data indicate functionally relevant long-term alterations in the brain’s basic geometry of cortical organization in prematurity.

Advances in the understanding of cellular pathogenesis associated with Autism Spectrum Disorder

Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental disorders with an estimated worldwide prevalence of 1-2%. Although it is highly heritable, the contribution of environmental factors and risk associated genes on the aberrant brain development is not well understood.In this review, we summarise some of the key risk factors and explore ASD associated cellular pathology from the perspective of the four predominant cells in the brain; neurons, oligodendrocytes, microglia and astrocytes. Further, we discuss the contributions of the associated cellular pathology to the three common hypotheses of ASD.We highlight the major neuro-pathologies underlying ASD, however more research is needed to ensure appropriate and efficient therapies can be directed towards ASD.

Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome.

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P= 0.033), the subcortical parenchyma (P= 0.010), and the cerebellar hemispheres (P< 0.0001) in DS compared to controls. This study provides proof of principle that regional volumetric analysis of fetal brain MRI facilitates successful evaluation of brain development in living fetuses with DS.

The “systems approach” to treating the brain: opportunities in developmental psychopharmacology

The significance of early life for the long-term programming of mental health is increasingly being recognized. However, most psychotropic medications are currently intended for adult patients, and early psychopharmacological approaches aimed at reverting aberrant neurodevelopmental trajectories are missing. Psychopharmacologic intervention at an early age faces the challenge of operating in a highly plastic system and requires a comprehensive knowledge of neurodevelopmental mechanisms. Recently the systems biology approach has contributed to the understanding of neuroplasticity mechanisms from a new perspective that interprets them as the result of complex and dynamic networks of signals from different systems. This approach is creating opportunities for developmental psychopharmacology, suggesting novel targets that can modulate the course of development by interfering with neuroplasticity at an early age. We will discuss two interconnected systems—the immune and gut microbiota—that regulate neurodevelopment and that have been implicated in preclinical research as new targets in the prevention of aberrant brain development.

Neuropathology in intrauterine growth restricted newborn piglets is associated with glial activation and proinflammatory status in the brain

BackgroundThe fetal brain is particularly vulnerable to intrauterine growth restriction (IUGR) conditions evidenced by neuronal and white matter abnormalities and altered neurodevelopment in the IUGR infant. To further our understanding of neurodevelopment in the newborn IUGR brain, clinically relevant models of IUGR are required. This information is critical for the design and implementation of successful therapeutic interventions to reduce aberrant brain development in the IUGR newborn. We utilise the piglet as a model of IUGR as growth restriction occurs spontaneously in the pig as a result of placental insufficiency, making it a highly relevant model of human IUGR. The purpose of this study was to characterise neuropathology and neuroinflammation in the neonatal IUGR piglet brain.MethodsNewborn IUGR (< 5th centile) and normally grown (NG) piglets were euthanased on postnatal day 1 (P1; < 18 h) or P4. Immunohistochemistry was utilised to examine neuronal, white matter and inflammatory responses, and PCR for cytokine analysis in parietal cortex of IUGR and NG piglets.ResultsThe IUGR piglet brain displayed less NeuN-positive cells and reduced myelination at both P1 and P4 in the parietal cortex, indicating neuronal and white matter disruption. A concurrent decrease in Ki67-positive proliferative cells and increase in cell death (caspase-3) in the IUGR piglet brain was also apparent on P4. We observed significant increases in the number of both Iba-1-positive microglia and GFAP-positive astrocytes in the white matter in IUGR piglet brain on both P1 and P4 compared with NG piglets. These increases were associated with a change in activation state, as noted by altered glial morphology. This inflammatory state was further evident with increased expression levels of proinflammatory cytokines (interleukin-1β, tumour necrosis factor-α) and decreased levels of anti-inflammatory cytokines (interleukin-4 and -10) observed in the IUGR piglet brains.ConclusionsThese findings suggest that the piglet model of IUGR displays the characteristic neuropathological outcomes of neuronal and white matter impairment similar to those reported in the IUGR human brain. The activated glial morphology and elevated proinflammatory cytokines is indicative of an inflammatory response that may be associated with neuronal damage and white matter disruption. These findings support the use of the piglet as a pre-clinical model for studying mechanisms of altered neurodevelopment in the IUGR newborn.

Reduced hippocampal subfield volumes and memory function in school-aged children born preterm with very low birthweight (VLBW).

BackgroundThe hippocampus, an essential structure for learning and memory, has a reduced volume in preterm born (gestational age < 37 weeks) individuals with very low birth weight (VLBW: birth weight < 1500 g), which may affect memory function. However, the hippocampus is a complex structure with distinct subfields related to specific memory functions. These subfields are differentially affected by a variety of neuropathological conditions, but it remains unclear how these subfields may be affected by medical complications following preterm birth which may cause aberrant brain development, and the consequences of this on learning and memory function in children with VLBW.MethodsChildren born preterm with VLBW (n = 34) and term-born controls from the Norwegian Mother and Child Cohort Study (MoBa) (n = 104) underwent structural MRI and a neuropsychological assessment of memory function at primary school age. FreeSurfer 6.0 was used to analyze the volumes of hippocampal subfields which were compared between groups, as was memory performance. Correlations between abnormal hippocampal subfields and memory performance were explored in the VLBW group.ResultsAll absolute hippocampal subfield volumes were lower in the children with VLBW compared to MoBa term-born controls, and the volumes of the left and right dentate gyrus and the right subiculum remained significantly lower after correcting for total intracranial volume. The VLBW group had inferior working memory performance and the score on the subtest Spatial Span backwards was positively correlated to the volume of the right dentate gyrus.ConclusionsHippocampal subfield volumes seem to be differently affected by early brain development related to preterm birth. The dentate gyrus appears particularly susceptible to adverse effects of preterm birth. Reduced working memory function among children with VLBW was associated with smaller volume of right dentate gyrus. This finding demonstrates alterations in hippocampal structure-function relationships associated with early brain development related to preterm birth.