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      Automated cot‐side tracking of functional brain age in preterm infants

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          Abstract

          Objective

          A major challenge in the care of preterm infants is the early identification of compromised neurological development. While several measures are routinely used to track anatomical growth, there is a striking lack of reliable and objective tools for tracking maturation of early brain function; a cornerstone of lifelong neurological health. We present a cot‐side method for measuring the functional maturity of the newborn brain based on routinely available neurological monitoring with electroencephalography (EEG).

          Methods

          We used a dataset of 177 EEG recordings from 65 preterm infants to train a multivariable prediction of functional brain age (FBA) from EEG. The FBA was validated on an independent set of 99 EEG recordings from 42 preterm infants. The difference between FBA and postmenstrual age (PMA) was evaluated as a predictor for neurodevelopmental outcome.

          Results

          The FBA correlated strongly with the PMA of an infant, with a median prediction error of less than 1 week. Moreover, individual babies follow well‐defined individual trajectories. The accuracy of the FBA applied to the validation set was statistically equivalent to the training set accuracy. In a subgroup of infants with repeated EEG recordings, a persistently negative predicted age difference was associated with poor neurodevelopmental outcome.

          Interpretation

          The FBA enables the tracking of functional neurodevelopment in preterm infants. This establishes proof of principle for growth charts for brain function, a new tool to assist clinical management and identify infants who will benefit most from early intervention.

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          Most cited references42

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          Neonatal MRI to predict neurodevelopmental outcomes in preterm infants.

          Very preterm infants are at high risk for adverse neurodevelopmental outcomes. Magnetic resonance imaging (MRI) has been proposed as a means of predicting neurodevelopmental outcomes in this population. We studied 167 very preterm infants (gestational age at birth, 30 weeks or less) to assess the associations between qualitatively defined white-matter and gray-matter abnormalities on MRI at term equivalent (gestational age of 40 weeks) and the risks of severe cognitive delay, severe psychomotor delay, cerebral palsy, and neurosensory (hearing or visual) impairment at 2 years of age (corrected for prematurity). At two years of age, 17 percent of infants had severe cognitive delay, 10 percent had severe psychomotor delay, 10 percent had cerebral palsy, and 11 percent had neurosensory impairment. Moderate-to-severe cerebral white-matter abnormalities present in 21 percent of infants at term equivalent were predictive of the following adverse outcomes at two years of age: cognitive delay (odds ratio, 3.6; 95 percent confidence interval, 1.5 to 8.7), motor delay (odds ratio, 10.3; 95 percent confidence interval, 3.5 to 30.8), cerebral palsy (odds ratio, 9.6; 95 percent confidence interval, 3.2 to 28.3), and neurosensory impairment (odds ratio, 4.2; 95 percent confidence interval, 1.6 to 11.3). Gray-matter abnormalities (present in 49 percent of infants) were also associated, but less strongly, with cognitive delay, motor delay, and cerebral palsy. Moderate-to-severe white-matter abnormalities on MRI were significant predictors of severe motor delay and cerebral palsy after adjustment for other measures during the neonatal period, including findings on cranial ultrasonography. Abnormal findings on MRI at term equivalent in very preterm infants strongly predict adverse neurodevelopmental outcomes at two years of age. These findings suggest a role for MRI at term equivalent in risk stratification for these infants. Copyright 2006 Massachusetts Medical Society.
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            Extrapolating brain development from experimental species to humans.

            To better understand the neurotoxic effects of diverse hazards on the developing human nervous system, researchers and clinicians rely on data collected from a number of model species that develop and mature at varying rates. We review the methods commonly used to extrapolate the timing of brain development from experimental mammalian species to humans, including morphological comparisons, "rules of thumb" and "event-based" analyses. Most are unavoidably limited in range or detail, many are necessarily restricted to rat/human comparisons, and few can identify brain regions that develop at different rates. We suggest this issue is best addressed using "neuroinformatics", an analysis that combines neuroscience, evolutionary science, statistical modeling and computer science. A current use of this approach relates numeric values assigned to 10 mammalian species and hundreds of empirically derived developing neural events, including specific evolutionary advances in primates. The result is an accessible, online resource (http://www.translatingtime.net/) that can be used to equate dates in the neurodevelopmental literature across laboratory species to humans, predict neurodevelopmental events for which data are lacking in humans, and help to develop clinically relevant experimental models.
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              Spontaneous Neuronal Activity in Developing Neocortical Networks: From Single Cells to Large-Scale Interactions

              Neuronal activity has been shown to be essential for the proper formation of neuronal circuits, affecting developmental processes like neurogenesis, migration, programmed cell death, cellular differentiation, formation of local and long-range axonal connections, synaptic plasticity or myelination. Accordingly, neocortical areas reveal distinct spontaneous and sensory-driven neuronal activity patterns already at early phases of development. At embryonic stages, when immature neurons start to develop voltage-dependent channels, spontaneous activity is highly synchronized within small neuronal networks and governed by electrical synaptic transmission. Subsequently, spontaneous activity patterns become more complex, involve larger networks and propagate over several neocortical areas. The developmental shift from local to large-scale network activity is accompanied by a gradual shift from electrical to chemical synaptic transmission with an initial excitatory action of chloride-gated channels activated by GABA, glycine and taurine. Transient neuronal populations in the subplate (SP) support temporary circuits that play an important role in tuning early neocortical activity and the formation of mature neuronal networks. Thus, early spontaneous activity patterns control the formation of developing networks in sensory cortices, and disturbances of these activity patterns may lead to long-lasting neuronal deficits.
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                Author and article information

                Contributors
                nathan.stevenson@qimrberghofer.edu.au
                Journal
                Ann Clin Transl Neurol
                Ann Clin Transl Neurol
                10.1002/(ISSN)2328-9503
                ACN3
                Annals of Clinical and Translational Neurology
                John Wiley and Sons Inc. (Hoboken )
                2328-9503
                05 May 2020
                June 2020
                : 7
                : 6 ( doiID: 10.1002/acn3.v7.6 )
                : 891-902
                Affiliations
                [ 1 ] QIMR Berghofer Medical Research Institute Brisbane QLD 4006 Australia
                [ 2 ] Department of Pediatrics Division of Neonatology Pediatric Intensive Care and Neuropediatrics Medical University of Vienna Vienna Austria
                [ 3 ] Department of Neonatology University Medical Center Utrecht Utrecht The Netherlands
                [ 4 ] Priority Research Center for Mind and Brain University of Newcastle Newcastle NSW 2305 Australia
                [ 5 ] Centre for Clinical Research Faculty of Medicine University of Queensland Brisbane QLD 4029 Australia
                [ 6 ] Department of Children’s Clinical Neurophysiology BABA Center Pediatric Research Center Children’s Hospital HUS Medical Imaging Center Helsinki University Central Hospital University of Helsinki Finland
                Author notes
                [*] [* ] Correspondence

                Nathan J. Stevenson, Brain Modelling Group, QIMR Berghofer Medical Research Institute, Brisbane QLD 4006, Australia. Tel: +61 7 3845 3009; Fax: +61 7 3144 5641; E‐mail: nathan.stevenson@ 123456qimrberghofer.edu.au

                Author information
                https://orcid.org/0000-0002-5146-8450
                Article
                ACN351043
                10.1002/acn3.51043
                7318094
                32368863
                cbb7da56-10c2-4e15-a3a7-1db3099f792f
                © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

                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
                : 28 January 2020
                : 20 March 2020
                Page count
                Figures: 4, Tables: 2, Pages: 12, Words: 7203
                Funding
                Funded by: National Health and Medical Research Council , open-funder-registry 10.13039/501100000925;
                Award ID: APP1144936
                Award ID: APP1118153
                Funded by: Rebecca L. Cooper Foundation
                Award ID: PG2018109
                Funded by: Academy of Finland
                Award ID: 313242
                Award ID: 288220
                Funded by: Fonds zur Förderung der Wissenschaftlichen Forschung , open-funder-registry 10.13039/501100002428;
                Award ID: FWFKLI237
                Funded by: European Commission , open-funder-registry 10.13039/501100000780;
                Award ID: LSHM‐CT‐2006‐036534
                This work was funded by National Health and Medical Research Council , open-funder-registry 10.13039/501100000925; grants APP1144936 and APP1118153; Rebecca L. Cooper Foundation grant PG2018109; Academy of Finland grants 313242 and 288220; Fonds zur Förderung der Wissenschaftlichen Forschung , open-funder-registry 10.13039/501100002428; grant FWFKLI237; European Commission , open-funder-registry 10.13039/501100000780; grant LSHM‐CT‐2006‐036534.
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                June 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:26.06.2020

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