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      Invited Review: Factors associated with atypical brain development in preterm infants: insights from magnetic resonance imaging

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          Abstract

          Preterm birth (PTB) is a leading cause of neurodevelopmental and neurocognitive impairment in childhood and is closely associated with psychiatric disease. The biological and environmental factors that confer risk and resilience for healthy brain development and long‐term outcome after PTB are uncertain, which presents challenges for risk stratification and for the discovery and evaluation of neuroprotective strategies. Neonatal magnetic resonance imaging reveals a signature of PTB that includes dysconnectivity of neural networks and atypical development of cortical and deep grey matter structures. Here we provide a brief review of perinatal factors that are associated with the MRI signature of PTB. We consider maternal and foetal factors including chorioamnionitis, foetal growth restriction, socioeconomic deprivation and prenatal alcohol, drug and stress exposures; and neonatal factors including co‐morbidities of PTB, nutrition, pain and medication during neonatal intensive care and variation conferred by the genome/epigenome. Association studies offer the first insights into pathways to adversity and resilience after PTB. Future challenges are to analyse quantitative brain MRI data with collateral biological and environmental data in study designs that support causal inference, and ultimately to use the output of such analyses to stratify infants for clinical trials of therapies designed to improve outcome.

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          State of the Art Review: Poverty and the Developing Brain

          In the United States, >40% of children are either poor or near-poor. As a group, children in poverty are more likely to experience worse health and more developmental delay, lower achievement, and more behavioral and emotional problems than their more advantaged peers; however, there is broad variability in outcomes among children exposed to similar conditions. Building on a robust literature from animal models showing that environmental deprivation or enrichment shapes the brain, there has been increasing interest in understanding how the experience of poverty may shape the brain in humans. In this review, we summarize research on the relationship between socioeconomic status and brain development, focusing on studies published in the last 5 years. Drawing on a conceptual framework informed by animal models, we highlight neural plasticity, epigenetics, material deprivation (eg, cognitive stimulation, nutrient deficiencies), stress (eg, negative parenting behaviors), and environmental toxins as factors that may shape the developing brain. We then summarize the existing evidence for the relationship between child poverty and brain structure and function, focusing on brain areas that support memory, emotion regulation, and higher-order cognitive functioning (ie, hippocampus, amygdala, prefrontal cortex) and regions that support language and literacy (ie, cortical areas of the left hemisphere). We then consider some limitations of the current literature and discuss the implications of neuroscience concepts and methods for interventions in the pediatric medical home.
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            Fetal Origins of Mental Health: The Developmental Origins of Health and Disease Hypothesis.

            The quality of fetal growth and development predicts the risk for a range of noncommunicable, chronic illnesses. These observations form the basis of the "developmental origins of health and disease" hypothesis, which suggests that the intrauterine signals that compromise fetal growth also act to "program" tissue differentiation in a manner that predisposes to later illness. Fetal growth also predicts the risk for later psychopathology. These findings parallel studies showing that antenatal maternal emotional well-being likewise predicts the risk for later psychopathology. Taken together, these findings form the basis for integrative models of fetal neurodevelopment, which propose that antenatal maternal adversity operates through the biological pathways associated with fetal growth to program neurodevelopment. The authors review the literature and find little support for such integrated models. Maternal anxiety, depression, and stress all influence neurodevelopment but show modest, weak, or no associations with known stress mediators (e.g., glucocorticoids) or with fetal growth. Rather, compromised fetal development appears to establish a "meta-plastic" state that increases sensitivity to postnatal influences. There also remain serious concerns that observational studies associating either fetal growth or maternal mental health with neurodevelopmental outcomes fail to account for underlying genetic factors. Finally, while the observed relation between fetal growth and adult health has garnered considerable attention, the clinical relevance of these associations remains to be determined. There are both considerable promise and important challenges for future studies of the fetal origins of mental health.
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              The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome.

              Fetal growth restriction (FGR) is a significant complication of pregnancy describing a fetus that does not grow to full potential due to pathological compromise. FGR affects 3-9% of pregnancies in high-income countries, and is a leading cause of perinatal mortality and morbidity. Placental insufficiency is the principal cause of FGR, resulting in chronic fetal hypoxia. This hypoxia induces a fetal adaptive response of cardiac output redistribution to favour vital organs, including the brain, and is in consequence called brain sparing. Despite this, it is now apparent that brain sparing does not ensure normal brain development in growth-restricted fetuses. In this review we have brought together available evidence from human and experimental animal studies to describe the complex changes in brain structure and function that occur as a consequence of FGR. In both humans and animals, neurodevelopmental outcomes are influenced by the timing of the onset of FGR, the severity of FGR, and gestational age at delivery. FGR is broadly associated with reduced total brain volume and altered cortical volume and structure, decreased total number of cells and myelination deficits. Brain connectivity is also impaired, evidenced by neuronal migration deficits, reduced dendritic processes, and less efficient networks with decreased long-range connections. Subsequent to these structural alterations, short- and long-term functional consequences have been described in school children who had FGR, most commonly including problems in motor skills, cognition, memory and neuropsychological dysfunctions.
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                Author and article information

                Contributors
                james.boardman@ed.ac.uk
                Journal
                Neuropathol Appl Neurobiol
                Neuropathol. Appl. Neurobiol
                10.1111/(ISSN)1365-2990
                NAN
                Neuropathology and Applied Neurobiology
                John Wiley and Sons Inc. (Hoboken )
                0305-1846
                1365-2990
                12 December 2019
                August 2020
                : 46
                : 5 ( doiID: 10.1111/nan.v46.5 )
                : 413-421
                Affiliations
                [ 1 ] MRC Centre for Reproductive Health University of Edinburgh Edinburgh UK
                [ 2 ] Centre for the Developing Brain School of Imaging Sciences and Biomedical Engineering King's College London London UK
                Author notes
                [*] [* ] Correspondence: James P. Boardman, MRC Centre for Reproductive Health, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Tel: +44 131 242 2567; Fax: +44 (0)131 242 6441; E‐mail: james.boardman@ 123456ed.ac.uk

                Author information
                https://orcid.org/0000-0003-3904-8960
                https://orcid.org/0000-0002-8033-5673
                Article
                NAN12589
                10.1111/nan.12589
                7496638
                31747472
                f49190e0-71c6-45be-b7d7-a9b89be93faf
                © 2019 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 October 2019
                : 13 November 2019
                Page count
                Figures: 2, Tables: 0, Pages: 9, Words: 5140
                Categories
                Invited Review
                Invited Review
                Custom metadata
                2.0
                August 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020

                Neurosciences
                brain,development,magnetic resonance imaging,neonate,preterm birth
                Neurosciences
                brain, development, magnetic resonance imaging, neonate, preterm birth

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