Brain age predicted using graph convolutional neural network explains neurodevelopmental trajectory in preterm neonates

OBJECTIVES: Dramatic brain morphological changes occur throughout the third trimester of gestation. In this study, we investigated whether the predicted brain age (PBA) derived from graph convolutional network (GCN) that accounts for cortical morphometrics in third trimester is associated with postnatal abnormalities and neurodevelopmental outcome. METHODS: In total, 577 T1 MRI scans of preterm neonates from two different datasets were analyzed; the NEOCIVET pipeline generated cortical surfaces and morphological features, which were then fed to the GCN to predict brain age. The brain age index (BAI; PBA minus chronological age) was used to determine the relationships among preterm birth (i.e., birthweight and birth age), perinatal brain injuries, postnatal events/clinical conditions, BAI at postnatal scan, and neurodevelopmental scores at 30 months. RESULTS: Brain morphology and GCN-based age prediction of preterm neonates without brain lesions (mean absolute error [MAE]: 0.96 weeks) outperformed conventional machine learning methods using no topological information. Structural equation models (SEM) showed that BAI mediated the influence of preterm birth and postnatal clinical factors, but not perinatal brain injuries, on neurodevelopmental outcome at 30 months of age. CONCLUSIONS: Brain morphology may be clinically meaningful in measuring brain age, as it relates to postnatal factors, and predicting neurodevelopmental outcome. CLINICAL RELEVANCE STATEMENT: Understanding the neurodevelopmental trajectory of preterm neonates through the prediction of brain age using a graph convolutional neural network may allow for earlier detection of potential developmental abnormalities and improved interventions, consequently enhancing the prognosis and quality of life in this vulnerable population. KEY POINTS: •Brain age in preterm neonates predicted using a graph convolutional network with brain morphological changes mediates the pre-scan risk factors and post-scan neurodevelopmental outcomes. •Predicted brain age oriented from conventional deep learning approaches, which indicates the neurodevelopmental status in neonates, shows a lack of sensitivity to perinatal risk factors and predicting neurodevelopmental outcomes. •The new brain age index based on brain morphology and graph convolutional network enhances the accuracy and clinical interpretation of predicted brain age for neonates

Diffusion-weighted and functional magnetic resonance imaging of the brain in preterm and term-born adolescents

Magnetic resonance imaging (MRI) is widely used in clinical and research settings in the adolescent population. Technical development has allowed the use of fine-grained methods to assess both the structural and functional properties of the brain. However, the specific technical limitations and improvements are mostly studied in phantom or adult studies, which may have an impact on their reliability as research tools when studying the younger population. Very preterm (VPT) birth is associated with several neurodevelopmental impairments. The present MRI tools provide opportunities to study brain maturation in detail. This thesis is a part of the multidisciplinary longitudinal follow-up study on the development and functioning of very low birth weight infants from infancy to school age (PIPARI). The follow-up cohort consists of infants born VPT (birth weight ≤1500 g and/or gestational age <32 weeks) in Turku University Hospital in 2001–2006 and term-born controls born in 2001–2004 in the same hospital. This thesis includes only children born VPT in 2004–2006 and controls born between 2003–2004 due to an upgrade of the MRI scanner during the recruitment. In Study I, the diffusion-weighted imaging (DWI) metrics at term-equivalent age were compared to the motor outcome at 11 years of age in children born VPT. Study II assessed the effect of the susceptibility correction to the DWI metrics in a healthy adolescent population. In Study III, temporal fluctuation of the resting state brain functioning was compared between 13-year-old adolescents born VPT and at term. The main prematurity-related findings of this thesis were that the DWI metrics of the corpus callosum, left corona radiata and right optic radiation at term are associated with later motor outcome in children born VPT and that adolescents born VPT show a decrease in active time, fluidity and range in brain activation during rest. These findings may reflect the adjustments in brain microstructure and function caused by the VPT birth. Fine-grained MRI methods are reliable tools for studying the mechanisms behind the clinical phenotypes of adolescents when technical limitations and age-appropriate analysis adjustments are considered.Diffuusiopainotteisen ja toiminnallisen aivojen magneettikuvantamisen käyttö nuoruusiässä entisillä pikkukeskosilla ja täysiaikaisilla verrokeilla Magneettikuvaus (MRI) on laajassa kliinisessä ja tieteellisessä käytössä lapsia ja nuoria tutkittaessa. Tekninen kehitys mahdollistaa yhä hienojakoisempia aivojen tutkimuksia. MRI:n teknisiä korjauksia on tutkittu pääosin mallintamalla tai aikuisilla, mikä voi heikentää luotettavuutta alaikäisillä. Hyvin ennenaikaisesti syntyvillä lapsilla neurologisen kehityksen poikkeavuuksien riski on täysiaikaisena syntyviä suurempi. Poikkeavuudet voivat liittyä aivojen kehityksen muutoksiin, joita nykyisillä tekniikoilla voidaan tutkia aiempaa yksityiskohtaisemmin. Väitöskirja on osa PIPARI-tutkimusta (Pienipainoisten riskilasten käyttäytyminen ja toimintakyky imeväisiästä kouluikään). Seurantakohortti koostuu pikkukeskosina (syntymäpaino ≤1500 g ja/tai raskauden kesto <32 viikkoa) Tyksissä vuosina 2001–2006 syntyneistä lapsista sekä täysiaikaisena 2001–2004 syntyneistä verrokeista. MRI-laitteiston päivityksestä johtuen osatyöt käsittelevät pikkukeskosina vuosina 2004–2006 ja verrokkeina vuosina 2003–2004 syntyneitä. Ensimmäisessä osatyössä verrattiin aivojen diffuusiokuvantamistuloksia entisten pikkukeskosten motoriseen toimintakykyyn 11-vuotiaana. Toinen osatyö käsitteli suskeptibiliteettikorjauksen vaikutusta aivojen diffuusiokuvantamisen mittaustuloksiin. Kolmannessa osatyössä vertailtiin 13-vuotiaiden entisten pikkukeskosten ja verrokkien aivojen aktiivisuuden vaihtelua lepotilassa toiminnallisen MRI-kuvauksen aikana. Tämän väitöskirjan keskosuuteen liittyvät päätulokset olivat lasketun syntymäajan corpus callosumin, vasemman corona radiatan ja oikean optisen radaston diffuusiomittaustulosten yhteys motoriseen kehitykseen 11-vuotiaana sekä pikkukeskosina syntyneillä havaittu aivojen vähäisempi aktiivinen aika ja alentunut aktiivisuuden vaihtelun joustavuus 13-vuotiaana. Nämä löydökset saattavat olla seurausta varhaiseen syntymään liittyvistä aivojen mikrorakenteen ja toiminnan muutoksista. Hienojakoiset MRI-menetelmät vaikuttavat olevan luotettavia nuorisoikäisiä tutkittaessa, kunhan tekniset rajoitteet ja ikäsovitukset huomioidaan

Attention and regional gray matter development in very preterm children at age 12 years

Objectives: This study examines the selective, sustained, and executive attention abilities of very preterm (VPT) born children in relation to concurrent structural magnetic resonance imaging (MRI) measures of regional gray matter development at age 12 years. Methods: A regional cohort of 110 VPT (≤32 weeks gestation) and 113 full term (FT) born children were assessed at corrected age 12 years on the Test of Everyday Attention-Children. They also had a structural MRI scan that was subsequently analyzed using voxel-based morphometry to quantify regional between-group differences in cerebral gray matter development, which were then related to attention measures using multivariate methods. Results: VPT children obtained similar selective (p=.85), but poorer sustained (p=.02) and executive attention (p=.01) scores than FT children. VPT children were also characterized by reduced gray matter in the bilateral parietal, temporal, prefrontal and posterior cingulate cortices, bilateral thalami, and left hippocampus; and increased gray matter in the occipital and anterior cingulate cortices (family-wise error-corrected

Early changes in brain structure correlate with language outcomes in children with neonatal encephalopathy.

Global patterns of brain injury correlate with motor, cognitive, and language outcomes in survivors of neonatal encephalopathy (NE). However, it is still unclear whether local changes in brain structure predict specific deficits. We therefore examined whether differences in brain structure at 6 months of age are associated with neurodevelopmental outcomes in this population. We enrolled 32 children with NE, performed structural brain MR imaging at 6 months, and assessed neurodevelopmental outcomes at 30 months. All subjects underwent T1-weighted imaging at 3 T using a 3D IR-SPGR sequence. Images were normalized in intensity and nonlinearly registered to a template constructed specifically for this population, creating a deformation field map. We then used deformation based morphometry (DBM) to correlate variation in the local volume of gray and white matter with composite scores on the Bayley Scales of Infant and Toddler Development (Bayley-III) at 30 months. Our general linear model included gestational age, sex, birth weight, and treatment with hypothermia as covariates. Regional brain volume was significantly associated with language scores, particularly in perisylvian cortical regions including the left supramarginal gyrus, posterior superior and middle temporal gyri, and right insula, as well as inferior frontoparietal subcortical white matter. We did not find significant correlations between regional brain volume and motor or cognitive scale scores. We conclude that, in children with a history of NE, local changes in the volume of perisylvian gray and white matter at 6 months are correlated with language outcome at 30 months. Quantitative measures of brain volume on early MRI may help identify infants at risk for poor language outcomes

Maternal Hypertension Influences Mortality and Severe Morbidity in Infants Born Extremely Preterm

Worldwide, more than 1 million infants die as a result of premature birth. In the United States, where 1 in 10 births occurs preterm, premature birth is the leading cause of infant mortality. Premature infants have high rates of mortality and morbidity, with the highest rates seen in those infants born extremely preterm -- prior to 30 weeks gestation. Severe morbidity in these infants often contributes to life-long health problems. Maternal hypertension (HTN) is one contributor to preterm birth and also contributes to fetal growth restriction, resulting in birth weights which are small for gestational age (SGA, and generally within the lowest 10th percentile). Within this high risk population, SGA infants have increased risk of mortality compared to appropriate for gestational age infants. Therefore the impact of maternal HTN on neonatal outcome might be presumed to be negative. Previous studies however, have been contradictory, with both higher and lower rates of infant mortality reported in infants born to mothers with HTN, as well as differing reports analyzing the relationship between serious morbidity and maternal HTN. Utilizing the Vermont Oxford Network Very Low Birth Weight database, a collaborative database of Level III Neonatal Intensive Care Units across the world, 88,275 North American infants born between 22+0 and 29+6 weeks gestational age between 2008 and 2011 were identified. This dissertation explores the relationship between maternal HTN and gestational age at time of birth within this population, and the reported rates of morbidity and mortality in infants born prior to 30 weeks gestation. The independent contributions of maternal HTN with neonatal morbidity and mortality in our population were estimated using logistic regression and adjusting for factors previously known to be associated with risk, including birth weight, antenatal steroid exposure, infant sex, maternal race/ethnicity, prenatal care, inborn/outborn status, and birth year. We hypothesized that mortality rates would be lower for infants born to mothers with HTN compared to those born due to other factors, when corrected for the noted confounding variables and surviving infants would have better prognoses, as evidenced by lower rates of severe morbidity, including bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and infection. Within the higher-risk SGA population, we hypothesized that mortality rates would be higher than observed in appropriately grown infants, but decreased in those born to mothers with HTN, despite the association between maternal HTN and SGA. This dissertation begins with an explanation of current knowledge about preterm birth, maternal HTN, and their associations. Chapter 2 focuses on the relationship between maternal HTN and infant mortality in extremely preterm infants. Chapter 3 examines the risk associated with severe morbidities in surviving infants. In addition, we also use a combined morbidity risk assessment score which has previously been used to determine future risk of long term disability. In Chapter 4, SGA infants are separately evaluated for their risk of mortality and the association with maternal HTN. These analyses support the high mortality and morbidity rates seen in extremely preterm infants. Maternal HTN, after adjustment, results in reduced risk of both mortality and severe morbidities in infants compared to infants born to mothers with other underlying contributors to preterm birth. This suggests that clinical practices and parental counseling should reflect differing risk profiles in sub-populations of extremely preterm infants

The Vulnerable Brain and Very Preterm Infants - Findings from the PIPARI-Study

Preterm birth is a risk for normal brain development. Brain maturation that normally happens in the uterus is in very preterm infants a developmental challenge during their stay in a neonatal intensive care unit (NICU). Typical brain injuries of preterm infants include ischemic injuries, brain haemorrhages, ventricular dilatation (VD), and reduced brain volumes. Brain injury is a serious complication of prematurity leading to possible long term consequences for the neurodevelopment of the very low birth weight (VLBW) infant, such as cerebral palsy (CP), hearing impairments, vision problems, and delay in cognitive development.There is a need for further studies to ascertain the potential risk factors and their causal relationships to brain vulnerability, growth and development in the increasing number of surviving VLBW infants. This thesis consists of four studies evaluating the definitions, causes and consequences of brain lesions in VLBW(<1500g) or very low gestationalage (VLGA) (gestational age <32 gestational weeks) infants. We showed that the redistribution of fetal blood flow is a risk factor for smaller brain volumes at term. In addition,we showed that brain lesions related to prematurity are not associated with increased spontaneous crying behaviour or circadian rhythm development in infancy. However, the preterm infants began to fuss more often and were held more than term infants at five months of age. Furthermore, we showed that VD is associated with brain lesions and smaller brain volumes. Therefore, brain magneticresonance imaging can be recommended for infants with VD. VD together with other brain pathology is a risk factor for the onset of developmental impairments in VLBW/VLGA infants at two years of age.Ennenaikainen syntymä on riski aivojen normaalille kehitykselle. Pikkukeskosilla aivojen tärkeitä kehitysvaiheita tapahtuu tehohoidon aikana kohdun ulkopuolella. Pikkukeskosen tyypillisiin aivokomplikaatioihin kuuluvat aivoverenvuodot, hapenpuutteen aiheuttamat vauriot, aivojen sivukammioiden laajentuminen ja aivoaineksen tilavuuksien pieneneminen. Aivovaurio on vakava keskosuuden komplikaatio, koska se voi johtaa pitkäaikaisiin kehityksen ongelmiin, kuten esimerkiksi CP-vammaisuuteen, kuulon tai näön ongelmiin tai älyllisen kehityksen viiveeseen. Koska yhä useampi pikkukeskonen jää henkiin ennenaikaisuudesta huolimatta, on tärkeä tutkia mahdollisia ris¬kitekijöitä pikkukeskosen aivojen vaurioitumiselle. Tämän väitöskirjan neljä osatyötä käsittelivät aivojen kuvantamistutkimuksissa todetun aivovaurion luokittelua, mahdollisia syitä aivovauriolle ja aivojen vaurioitumi¬sen seurauksia pikkukeskosen (<1500g / <32 raskausviikkoa syntyessä) kehitykselle. Tutkimuksemme osoitti, että sikiön verenkierron uudelleenjakautuminen hapenpuutteen seurauksena aiheuttaa riskin aivojen kasvulle. Osoitimme myös, ettei aivovaurio lisää spontaanin kokonaisitkun määrää tai vaikuta vuorokausirytmin kehittymiseen pikkukeskosilla imeväisiässä. Keskoset aloittivat täysiaikaisia lapsia useammin kitinäjakson viiden kuukauden korjatussa iässä ja heitä pidettiin sen seurauksena enemmän sylissä kuin täysiaikaisia verrokkeja. Lisäksi osoitimme, että keskosilla, joilla aivojen sivukammiot ovat laajentuneet, on usein muitakin poikkeavia aivolöydöksiä ja pienemmät aivojen kokonais- ja osatilavuudet lasketussa ajassa. Mikäli aivojen sivukammiot ovat poikkeavasti laajentuneet ultraäänitutkimuksessa lasketussa ajassa, voidaan tulostemme perusteella suositella aivojen magneettitutkimusta mahdollisten lisälöydösten varmentamiseksi. Aivojen sivukammioiden laajentuminen yhdessä muun aivovaurion kanssa liittyi suurentuneeseen riskiin kehityksen ongelmille kahden vuoden korjatussa iässä pikkukeskosilla.Siirretty Doriast